Abstract:
The invention herein provides an improved manufacturing process for sterile containers pre-filled with topical antimicrobial solutions that reduces or avoids undesirable by-products as a result of the ethylene oxide gas sterilization technique. The process of the invention produces containers pre-filled with antimicrobial solution that are sterilized in accordance with the ethylene oxide technique, while at the same time have a toxic residue content within acceptable limits. The invention is particularly useful in the manufacture of plastic containers pre-filled with iodine-based antimicrobial solutions.

Description:
FIELD OF THE INVENTION  
       [0001]     The invention relates to the field of surgery. In particular, the invention pertains to the manufacture of topical antimicrobial solutions used to prepare surgical sites.  
       BACKGROUND OF THE INVENTION  
       [0002]     Fluorination of plastics has long been used in the preparation of permeation-resistant plastic, non-glass bottles and containers. When fluorine gas is brought into contact with a polymer, its molecular structure is altered on the exposed surfaces. The fluorination process is a gas modified plastic technology that reduces permeability and improves chemical resistance through surface treatment of the polymer. Fluorine gas is a strong oxidant that reacts with the plastic surface to replace the weak hydrogen molecule in the polymer. The process prevents contaminants from entering the containers, as well as inhibiting contents from exiting the container, by forming a chemical barrier produced by the chemical interaction between fluorine and polymers, such as polyethylene.  
         [0003]     The advantages of fluorination of plastic containers have long been exploited in the manufacturing industry as substitutes for breakable glass containers. Examples of chemicals and products that have been contained in fluorinated bottles include acetone, auto additives, lighter fluid, degreasers, electronics chemicals, health and beauty care products, insecticides, kerosene, lubricants, paint thinners, plant growth chemicals, waxes, cleaners and polishes, weed killers and herbicides, wood preservatives, and the like. Joffre U.S. Pat. No. 2,811,468, for example, describes the fluorination of polyethylene containers to render the containers impermeable to atmospheric contamination of their liquid contents.  
         [0004]     In the medical field, ethylene oxide sterilization, also referred to as EtO sterilization, is often used in the manufacture and sterilization of sterile medical devices and instruments. Ethylene oxide vaporizes at relatively low temperatures comparable to room temperature. As a result of the substantial chemical activity of the molecules, ethylene oxide gas readily combines with microbial cells to inactivate or kill them. Further, the small size of the ethylene oxide molecule allows penetration into minute openings and porous substances thereby allowing the passage of the sterilant into areas that otherwise, using other sterilization methods, would not have received exposure and antimicrobial effect.  
         [0005]     Topical antimicrobial solutions, including those containing iodine-based antimicrobial ingredient, are well known in the art. Critical to the manufacture of containers filled with topical antimicrobial solutions is the preservation and maintenance of sterility during the manufacture and subsequently during storage of the pre-filled containers. Typically, the sterilization of plastic containers pre-filled with antimicrobial solutions involves the first step of filling the containers, the second step of assembly and packaging, and a final step of subjecting the filled containers to ethylene oxide sterilization. Tawa et al., Published U.S. patent application No. 2001/0010145 describes a method of molding and filling aseptic containers by sterilizing the containers using ethylene oxide sterilization, filling with aseptic liquid, and then sealing.  
         [0006]     One problem associated with filled container ethylene oxide sterilization processes is the adverse interaction between ethylene oxide and iodine-based antimicrobial solutions. Ethylene oxide gas can readily penetrate thin layers of most plastics. Once inside, the gas is difficult to dissipate quickly. The interaction of ethylene oxide gas and iodine-containing solutions is that it can result in the formation of additional toxic residues. These contaminants include ethylene oxide (EtO), ethylene chlorohydrin (ECH), and ethylene glycol (EG). Iodine-containing antimicrobial liquids are especially sensitive to compromise of their chemical integrity by the ethylene oxide sterilization process. Furthermore, iodo-ethanol contaminants produced by the interaction can cause topical allergic reactions in some patients. In order to provide product safety, residual levels of these contaminants must be at acceptable levels under given circumstances and context (e.g., anticipated product use, location and manner of use, and duration of use).  
         [0007]     Excessive or unacceptable levels of ethylene oxide residues in topical applications can cause contact dermatitis, rashes and lesions. Prolonged exposure to ethylene oxide residues have demonstrated carcinogenicity and can be mutagenicity as well.  
         [0008]     Accordingly, there is a problem in the manufacture and packaging of contained sterile antimicrobial solutions, especially antimicrobial solutions containing ingredients sensitive to reaction with ethylene oxide. There is a need in the field of manufacture of topical antimicrobials for a process which accomplishes sterilization of the liquid contents and container while avoiding the production of undesirable contaminants generated as a result of the sterilization techniques employed. Particularly desirable would be the accomplishment of these objectives while including the use of non-glass containers and their advantages.  
       SUMMARY OF THE INVENTION  
       [0009]     The invention provides an improved manufacturing process for sterile containers pre-filled with topical antimicrobial solutions that reduces or avoids undesirable by-products as a result of the ethylene oxide gas sterilization technique. The invention is particularly useful in the containment of iodine-based antimicrobial solutions sensitive to chemical interaction with ethylene oxide gas. The process of the invention produces containers pre-filled with antimicrobial solution that are sterilized in accordance with the ethylene oxide technique, while at the same time have a toxic residue content within acceptable limits.  
         [0010]     The invention provides a process for assembling and packaging a container filled with antimicrobial solution comprising the steps of: 
        a) providing a formed empty plastic container;     b) subjecting said container to fluorination;     c) filling said fluorinated container with liquid antimicrobial solution;     d) sealing the filled container; and     e) subjecting said filled container to ethylene oxide sterilization.        
 
         [0016]     The invention also provides a sealed and sterilized plastic container filled with antimicrobial solution being substantially free of contaminants from the interaction of ethylene oxide gas and iodine-containing antimicrobial solution, said filled container prepared by the above process.  
         [0017]     The invention further provides a method of reducing contaminants produced by the interaction of ethylene oxide gas sterilization and iodine-containing antimicrobial solutions comprising: 
        selecting a fluorinated plastic container;     filling said container with iodine-containing antimicrobial solution;     sealing said filled container; and     subjecting said filled container to ethylene oxide sterilization.       
 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0022]     In general, the invention includes a process for assembling and packaging a plastic container containing antimicrobial solution. The process according to the invention comprises the steps: 
        a) providing a formed empty container;     b) subjecting said container to fluorination;     c) filling said fluorinated container with liquid antimicrobial solution;     d) sealing the filled container; and     e) subjecting said filled container to ethylene oxide sterilization.        
 
         [0028]     A variety of plastic container shapes and sizes can be used in accordance with the invention. Container materials employable with the invention are those plastic materials that can be fluorinated to form a barrier to permeation as associated with the fluorination process of plastic containers. Suitable container materials include, but are not limited to, polyolefins; polyethylenes, such as high density polyethylene (HDPE), low density polyethylene (LDPE), and polyethylene terephthalate (PET); polypropylene (PP); and ultra-high molecular weight polyethylene (UHMW-PE); vinyl and polyvinyl chloride (PVC); polystyrene (PS); other thermoplastic polymers; elastomeric polymers; and other like materials provided they are capable of fluorination without significantly compromising their structural integrity. The container can be made from any plastic conductive to conventional extrusion blow-molding or injection blow-molding processes and equipment readily available to those in the field.  
         [0029]     Containers composed of polyethylene terephthalate (PET) can include ethylene glycol, terephthalic acid, dimethyle terephthalate, and additives such as catalysts and stabilizers. Polyethylene terephthalate containers can be manufactured using injection blow-molding, unoriented or biaxially oriented injection stretch blow molding equipment and techniques. Polyethylene terephthalate containers typically have good clarity, good impact and scratch resistance, a high gloss finish and good barrier properties.  
         [0030]     High density polyethylene (HDPE) containers are typically impact resistant, translucent, flexible, have a wide range of chemical compatibility with acids and caustic chemicals, and good moisture barrier properties. Low density polyethylene (LDPE) is translucent, but less rigid than HDPE and generally less chemical resistant.  
         [0031]     Vinyl and polyvinyl chloride (PVC) containers are clear, semi-rigid, have good chemical resistance and provide fairly good gas/oxygen barrier properties. Polystyrene (PS) has good clarity and rigidity, but exhibits relatively less impact resistance and barrier properties. Polypropylene (PP) exhibits translucency, good moisture barrier properties, good chemical resistance, good thermal stability at relatively higher temperatures and can withstand steam sterilization, but exhibits relatively less impact resistance at lower temperatures.  
         [0032]     The container can have a variety of forms, shapes and sizes. The container can be in the form of a bottle, bag, tube, or any suitable configuration intended as an applicator component. In one embodiment, the container can be in the form of a bottle with a neck portion. Shapes that can be used include cylindrical or oblong configurations, cuboid and rectangular shapes. In a preferred embodiment, a bottle configuration is used that includes a neck conforming to SPI standards form opening size and thread geometry.  
         [0033]     The liquid antimicrobial solution can comprise a water or alcohol-based broad spectrum antimicrobial agent topically applied to a patient&#39;s skin in preparation for surgery or treatment of injured tissues. Antimicrobial solutions containing iodine-containing anti-microbial agents are particularly suited for the process of the invention, since iodine-containing compositions have broad spectrum germicidal properties but are particularly susceptible to contamination caused by ethylene oxide gas. In use, these antimicrobial solutions can be applied using any medically-appropriate manner, such as wet-soaking or spraying onto the site. Antimicrobial solutions are also used to reduce the likelihood of post-operative infections as well.  
         [0034]     Accordingly, the process of the invention is particularly useful for the sterilization of containers pre-filled with povidone iodine, or PVP-I. Povidone iodine is known to have broad-spectrum antimicrobial properties against bacteria, fungi, yeast, viruses, protozoa and is useful in pre-surgical preparation and emergency disinfection needs. The liquid antimicrobial composition can be in a form for paint, wet soak or spray application or delivery to the disinfection site.  
         [0035]     In general, the fluorination process involves placing plastic containers into a sealed reactor. The containers are then exposed to a measured amount of elemental fluorine gas under controlled conditions. Various levels and treatment options can be provided. The fluorination step can be performed using conventional equipment and techniques readily available to those skilled in the art.  
         [0036]     There are two general procedures for fluorination of containers: in-line fluorination and post-molding fluorination. In-line fluorination is described in U.S. Pat. No. 3,862,242 and also known as the AIROPAK® System and incorporated herein by reference. This system utilizes standard blow-molding technology to produce an effective permeation barrier at the inner walls of the container as part of the blow-mold cycle. Post-molding fluorination techniques, such as the commercially available Fluoro-Seal™ process, introduces fluorine gas to containers in a process reactor.  
         [0037]     The fluorinated container is subsequently filled with liquid antimicrobial solution and hermetically sealed in accordance with readily available techniques, equipment and materials. In one embodiment, HDPE or MDPE necked bottles can be capped using a rupturable HDPE seal. The filled and sealed containers with liquid antimicrobial solution within are then subjected to the sterilization process.  
         [0038]     The sterilization process used in accordance with the invention is the ethylene oxide gas sterilization technique. The ethylene oxide sterilization process involves four basic phases: 1) air removal; 2) steam injection and conditioning dwell; 3) EtO injection and gas dwell; and 4) gas purge and air inbleed. The parameters for the sterilization step include temperature, pressure, humidity, ethylene oxide concentration, and gas dwell time. The sterilization process must be effected to a degree that ensures a 10 −6  sterility assurance level (SAL) without causing deleterious effects to the product or packaging. The process parameters can be adjusted in order to optimize fluorination effect and results. Effective EtO sterilization processes account for the medical product being sterilized, e.g., antimicrobial liquid solution, and the permeability of its packaging, e.g., bottle or container, and also produce complete and consistent results.  
         [0039]     At the conclusion of the sterilization process, the filled and sterilized containers with antimicrobial solution are removed from the sterilization equipment and packaged for shipping.  
       EXAMPLES  
     Example 1  
     Determination of Ethylene Oxide Sterilization Residuals using Fluorinated Polyethylene Bottles for Iodine-Containing Antimicrobial Solution  
       [0040]     High density polyethylene (HDPE) and medium density polyethylene (MDPE) bottles (obtained from Carrow International, Inc., Crystal Lake, Ill.), and the high density polyethylene (HDPE) applicator component to be coupled thereto in use to dispense the contents, were evaluated for the presence of ethylene oxide residues following ethylene oxide gas sterilization treatments. Two fluorinated container-applicator assemblies were evaluated for the presence of sterilant residues ethylene oxide (EO), ethylene chlorohydrin (ECH) and ethylene glycol (EG) following ethylene oxide sterilization. The container-applicator assemblies used were those used with commercially available 15 cc Prevail™ Gel and Prevail™ Fx bottle and applicator assemblies (available from Cardinal Health, Inc., Medical Products and Services, McGaw Park, Ill.).  
         [0041]     The container-applicator assemblies tested comprise a bottle component and applicator component. The container component comprised a capped bottle. Bottles composed of two materials were tested—high density polyethylene (HDPE) and medium density polyethylene (MDPE). Each bottle had a 15 cc volume capacity and had a necked configuration. The bottles were capped using frangible HDPE. For purposes of the experiment, the bottles were filled with an amount of water corresponding to the typical volume used with the iodine-containing antimicrobial solution. The applicator component included an applicator head composed of HDPE, and polyurethane foam (disc) attached to the head for distribution of the contents. The applicator was structured to couple to the container.  
         [0042]     Three sterilization sample runs were performed for each sample, and the measured amounts averaged to calculate the mean value. Control samples for each of the container/water and applicator were not subjected to sterilization, and corresponding measurements were taken.  
         [0043]     The deionized water-filled containers (bottles) were packaged in Tyvek™ pouches and subjected to ethylene oxide sterilization (100% EO) using 1× and 2× sterilization cycles using a production sterilization vessel. Following sterilization, the samples were exposed to 48 hours of ambient aeration following 18 hours of heated aeration at 110° F. The samples were placed in vacuum sealed foil pouches and shipped to a separate testing facility (IBA Analytical Laboratory, Itasca, Ill.), and the EO residuals were measured using their internal standard operating procedures and Good Laboratory Practices. Post-sterilization amounts of ethylene oxide sterilization residues were measured in the water using gas chromatography and data acquisition systems complying with ANSI/AAMI/ISO 10993-7:1995 system suitability and calibration requirements.  
         [0044]     The applicator component from each sample was removed and residuals obtained by extraction by immersion in water for one hour at room temperature in accordance with Biological Evaluation of Medical Devices—Part 7: Ethylene Oxide Sterilization Residuals; and ANSI/AAMI/ISO 10993-7 (Baltimore—Association for the Advancement of Medical Instrumentation, 1995) and APL 09-07D, APL-09-07D/Form 1, Component Evaluation Form. The EO residuals were calculated into parts per million (ppm) for the containers plus water, and mg/device for the applicator component. For the container and water components, the results were compared alongside the FDA 1978 Proposed Guidelines for Surgical Scrub Sponges containing a drug. ISO 10993-7 residue limits were used as the acceptance criteria for the applicator component.  
         [0045]     The corresponding sterilization residues ethylene chlorohydrin (ECH) and ethylene glycol (EG) amounts detected in the water can be used to predict the corresponding amount of ethylene oxide-iodine interactive contaminants )(2-iodoethanol) that would have been generated.  
         [0046]     The following table contains the results for the HDPE bottle and applicator assembly.  
                                                                                                                                                                                                                                       TABLE 1                           Ethylene Oxide and Residue Levels for HDPE Bottle and Applicator                            Disposition       # 100% EO       Mean value (ppm   Acceptance   (accept or       sterilization cycles   Residue   or mg/device)   Criteria   reject)                    Container + water   EO   121 ± 9.6   ppm   25   ppm   Reject       (1X)           ECH   &lt;1 ± 0   ppm   250   ppm   Accept           EG   114 ± 17.6   ppm   500   ppm   Accept       Applicator   EO   &lt;0.1 ± 0   ppm   20   mg/device   Accept       (1X)           ECH   &lt;0.1 ± 0   ppm   12   mg/device   Accept                EG   0.5 ± 0.3   ppm   None*   N/A            Container + water   EO   164 ± 9.4   ppm   25   ppm   Reject       (2X)           ECH   2 ± 0   ppm   250   ppm   Accept           EG   329 ± 30.2   ppm   500   ppm   Accept       Applicator   EO   &lt;0.1 ± 0   mg/device   20   mg/device   Accept       (2X)           ECH   &lt;0.1 ± 0   mg/device   12   mg/device   Accept                EG   0.6 ± 0.1   mg/device   None*   N/A            Container + water   EO   N/D   25   ppm   N/A       (control)           ECH   N/D   250   ppm   N/A                EG   &lt;10   ppm   500   ppm   N/A       Applicator   EO   &lt;0.1   mg/device   20   mg/device   N/A       (control)           ECH   &lt;0.1   mg/device   12   mg/device   N/A                EG   &lt;0.1   mg/device   None*   N/A                 1X = one sterilization cycle performed on sample.            2X = two sterilization cycles performed on sample.            *No limits were set for ethylene glycol because risk assessment indicates that when EO residues levels are within the limit, corresponding ethylene glycol levels will not be biologically significant.             
 
         [0047]     The following table contains the results for the MDPE bottle and applicator assembly.  
                                                                                                                                                     TABLE 2                           Ethylene Oxide and Residue Levels for MDPE Bottle and Applicator                            Disposition       # 100% EO       Mean value (ppm   Acceptance   (accept or       sterilization cycles   Residue   or mg/device)   Criteria   reject)                    Container + water   EO   235 ± 15.4   ppm   25   ppm   Reject       (1X)           ECH   1 ± 0   ppm   250   ppm   Accept           EG   255 ± 24.1   ppm   500   ppm   Accept       Container + water   EO   341 ± 68.5   ppm   25   ppm   Reject       (2X)           ECH   3 ± 1   ppm   250   ppm   Accept           EG   672 ± 113   ppm   500   ppm   Accept            Container + water   EO   N/D   25   ppm   N/A       (control)           ECH   N/D   250   ppm   N/A                EG   &lt;10   ppm   500   ppm   N/A       Applicator   EO   &lt;0.1   mg/device   20   mg/device   N/A       (control)           ECH   &lt;0.1   mg/device   12   mg/device   N/A                EG   &lt;0.1   mg/device   None*   N/A                 1X = one sterilization cycle performed on sample.            2X = two sterilization cycles performed on sample.            *No limits were set for ethylene glycol because risk assessment indicates that when EO residues levels are within the limit, corresponding ethylene glycol levels will not be biologically significant.            Note:            The applicator component for MDPE bottles is composed of the same material as that used with the HDPE bottles and, therefore, testing was not repeated for the MDPE bottles.             
 
       RESULTS  
       [0048]     The amount of ECH and EG measured in the water were within the limits of 250 ppm and 500 ppm, respectively. The amount of EO in the water, however, exceeds the limit of 25 ppm EO per FDA 1978 Proposed Guidelines for Surgical Scrub Sponges (containing a drug). Nevertheless, the levels of EO residuals present in the water would not be expected to correspond to a generated iodoethanol level that would produce adverse effects on a user. The EO residuals in the HDPE applicator components tested are below the ISO 1097:7 limits of 20 mgEO/device or 12 mgEO/device.  
         [0049]     The results demonstrate that the use of fluorinated bottles in the container component of an iodine-containing antimicrobial solution would reduce or inhibit the generation of ethylene oxide residuals. Therefore, a lower amount of iodine-interactive contaminants would be generated in ethylene oxide-sterilized delivery devices containing topical antimicrobial solutions in fluorinated polyethylene containers.  
       INDUSTRIAL APPLICABILITY  
       [0050]     The process of the invention can be used to manufacture contained antimicrobial solutions using ethylene oxide sterilization techniques in circumstances wherein the contents of the container, e.g., iodine containing antimicrobial surgical preparations solutions, are particularly susceptible to containment barrier-related loss of chemical integrity and undesirable by-products caused by the sterilization process used. The invention is particularly useful in the preparation and packaging of povidone iodine solutions, or PVP-I.  
         [0051]     The invention has been described herein above with reference to various and specific embodiments and techniques. It will be understood by one of ordinary skill in the art, however, that variations and modifications of such embodiments and techniques are possible without substantially departing from either the spirit or scope of the invention defined by the claims set forth below.