US 20140051771 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0051771 A1 Hufen et al. (43) Pub. Date: Feb. 20, 2014

(54) BOMEDICAL DEVICES COMPRISING Publication Classification MOLDED POLYETHYLENE COMPONENTS (51) Int. Cl. (71) Applicant: Ticona LLC, Florence, KY (US) CSF IO/02 (2006.01) B29D 23/00 (2006.01) (72) Inventors: Julia Hufen, Rheinberg (DE); Anthony A61N I/05 (2006.01) Verrocchi, Covington, KY (US); Rainer (52) U.S. Cl. Walkenhorst, Melle (DE) CPC ...... C08F 10/02 (2013.01); A61N I/0551 (2013.01); B29D 23/00 (2013.01) USPC ..... 514/772.4; 526/352; 526/348.6; 526/348; (73) Assignee: Ticona LLC, Florence, KY (US) 525/333.7:521/143; 524/585; 525/55; 525/185; 525/190; 525/240; 525/70; 525/232; 525/222; 525/227: 525/238; 607/116; 607/119:607/137; (21) Appl. No.: 13/964,884 428/523; 428/516; 428/461; 428/451; 428/36.9; 53/441; 264/250 (22) Filed: Aug. 12, 2013 (57) ABSTRACT A molded polyethylene component that comprises polyeth ylene having a melt flow index of about 3.5 g/10 min or Related U.S. Application Data greater as measured by ASTM D1238 at 190° C./21.5 kg (60) Provisional application No. 61/787,237, filed on Mar. weight and having an ash content of about 500 ppm or less 15, 2013, provisional application No. 61/684.947, may be useful biomedical devices, including kits and meth filed on Aug. 20, 2012. ods relating thereto. US 2014/005 1771 A1 Feb. 20, 2014

BIOMEDICAL DEVICES COMPRISING of a biomedical device; and Substantially encasing the com MOLDED POLYETHYLENE COMPONENTS ponent in polyethylene having a melt flow index of about 3.5 g/10 min or greater as measured by ASTM D1238 at 190° BACKGROUND C./21.5 kg weight and having an ash content of about 500 ppm or less. 0001. The present invention relates to molded polyethyl 0009. In yet another embodiment, the present invention ene components for use in conjunction with biomedical provides for a method that comprises polymerizing at least devices, including methods relating thereto. one olefin in the presence of a catalyst So as to form polyeth 0002 Polyethylene is often used in conjunction with bio ylene having a melt flow index of about 3.5 g/10 min or medical devices because of interalia, its chemical resistance, greater as measured by ASTM D1238 at 190° C./21.5 kg biocompatibility, low specific gravity relative to metals, and weight, the at least one olefin being selected from the group wear resistance. Typically, polyethylene, having a purity Suf consisting of ethylene, propylene, and/or butylene, and any ficient for use in biological environments (e.g., minimal con combination thereof, and treating the polyethylene to yield a centration of residual catalyst), has a low melt flow index, and treated polyethylene having an ash content of about 500 ppm in Some instances essentially no melt flow index. Due to the or less. hardness of low melt flow index polyethylene, production of 0010. In another embodiment, the present invention pro biomedical devices and components therefrom is typically vides for a method that comprises providing a sheet compris achieved through machining methods. While machining fab ing a polyethylene composition that comprises polyethylene rication methods may allow for high precision components having a melt flow index of about 3.5 g/10 minor greater as capable of meeting tight tolerances, these methods generally measured by ASTM D1238 at 190° C./21.5 kg weight and have a low throughput and can produce significant waste of having an ash content of about 500 ppm or less; and thermo the polyethylene material, both of which increase the cost of forming the sheet into a molded polyethylene component of a manufacturing. Further, machine fabrication can require biomedical device. large capital investments in equipment. Accordingly, meth 0011. In yet another embodiment, the present invention ods and compositions that enable higher throughput manu provides for a method that comprises providing a sheet com facturing, like molding, may be desirable in the production of prising a polyethylene composition that comprises polyeth polyethylene-based biomedical device components. ylene having a melt flow index of about 3.5 g/10 min or greater as measured by ASTM D1238 at 190° C./21.5 kg SUMMARY OF THE INVENTION weight and having an ash content of about 500 ppm or less; 0003. The present invention relates to molded polyethyl and shrink wrapping the sheet onto a portion of a biomedical ene components for use in conjunction with biomedical device or component thereof. devices, including methods relating thereto. 0012. The features and advantages of the present invention 0004. In one embodiment, the present invention provides will be readily apparent to those skilled in the art upon a for a biomedical device that comprises a molded polyethylene reading of the description of the preferred embodiments that component that comprises a polyethylene composition that follows. comprises polyethylene having a melt flow index of about 3.5 g/10 min or greater as measured by ASTM D1238 at 190° DETAILED DESCRIPTION C./21.5 kg weight and having an ash content of about 500 0013 The present invention relates to molded polyethyl ppm or less. ene components for use in conjunction with biomedical 0005. In another embodiment, the present invention pro devices, including methods relating thereto. In some vides for a biomedical device that comprises a conduit that instances, the molded polyethylene components may be bio comprises at least one wall defining an internal Volume, the at medical devices themselves. least one wall comprising polyethylene having a melt flow 0014. The molded polyethylene components of the index of about 3.5 g/10 minor greater as measured by ASTM present invention for use in conjunction with biomedical D1238 at 190° C./21.5 kg weight and having anash content of devices may, in Some embodiments, comprise polyethylene about 500 ppm or less. compositions with high purity that is melt flowable, thereby 0006. In yet another embodiment, the present invention enabling the molded polyethylene components to be pro provides for a method that comprises providing a polyethyl duced via molding and/or extruding methods. The ability to ene composition melt that comprises polyethylene having a form a polyethylene component via these methods may melt flow index of about 3.5 g/10 minor greater as measured advantageously enable faster production of high precision by ASTM D1238 at 190° C./21.5 kg weight and having anash components as compared to machining methods. Molding content of about 500 ppm or less; and extruding the polyeth method may also enable the production of complex and ylene composition melt to form a molded polyethylene com Smaller components that are time and cost prohibitive if pro ponent of a biomedical device. duced by machining methods. Further, the waste associated 0007. In another embodiment, the present invention pro with manufacturing may be reduced as compared to machin vides for a method that comprises providing a polyethylene ing methods. Accordingly, for at least these reasons, the abil composition melt that comprises polyethylene having a melt ity to mold and/or extrude polyethylene components of the flow index of about 3.5 g/10 min or greater as measured by present invention for use in conjunction with biomedical ASTM D1238 at 190° C./21.5 kg weight and having an ash devices as described herein may, in turn, reduce manufactur content of about 500 ppm or less; and injection molding the ing costs, and consequently consumer costs, which especially polyethylene composition melt to form a molded polyethyl in the biomedical sector may be especially advantageous. ene component of a biomedical device. (0015. It should be noted that when “about” is provided at 0008. In yet another embodiment, the present invention the beginning of a numerical list, “about modifies each num provides for a method that comprises providing a component ber of the numerical list. It should be noted that in some US 2014/005 1771 A1 Feb. 20, 2014 numerical listings of ranges, some lower limits listed may be suitable for measuring the molecular weight of the HPMF greater than some upper limits listed. One skilled in the art polyethylene described herein include ASTM D4020. will recognize that the selected subset will require the selec 0022. In some embodiments, the HPMF polyethylene tion of an upper limit in excess of the selected lower limit. described herein of the molded polyethylene component of 0016. In some embodiments, a biomedical device may the present invention may have a molecular weight distribu comprise a molded polyethylene component of the present tion that is multimodal (i.e., having more than one local invention. A molded polyethylene component of the present maxima, e.g., bimodal, trimodal, and the like) with each mode invention may, in some embodiments, comprise a polyethyl (i.e., local maxima) being between a lower limit of about ene composition that comprises a high-purity, melt-flowable 30,000 g/mol, 50,000 g/mol, 100,000 g/mol, 250,000 g/mol, polyethylene. It should be noted that the term “molded poly or 500,000 g/mol and an upper limit of about 2,500,000 ethylene component' is used herein for clarity and should not g/mol, 2,000,000 g/mol, 1,000,000 g/mol, or 500,000 g/mol, be seen as limiting as to how the polyethylene component is and wherein each mode of the molecular weight distribution produced. As used herein, the terms “high-purity, melt-flow may range from any lower limit to any upper limit and encom able polyethylene' and “HPMF polyethylene' refers to a pass any range therebetween. composition that comprises polyethylene having a melt flow (0023. In some embodiments, the HPMF polyethylene index of about 3.5 g/10 minor greater as measured by ASTM described herein of the molded polyethylene component of D1238 at 190° C./21.5 kg weight and having anash content of the present invention may be crosslinked, which may be about 500 ppm or less. It should be noted that as used herein achieved by with chemical crosslinkers, e.g., peroxides or "polyethylene' encompasses copolymers of ethylene with silanes, and/or with radiation (e.g., electron beam crosslink other olefinic monomers, e.g., propylene, butylene, and the ing). Crosslinking may, in Some embodiments, be useful for, like, including mixtures and blend polymers thereof. interalia, tailoring the mechanical properties of the polyeth 0017. In some embodiments, the HPMF polyethylene ylene compositions described herein (e.g., increasing at least described herein of the molded polyethylene component of Some mechanical properties so as to allow for molded poly the present invention may have a melt flow index of about 3.5 ethylene components of the present invention to, in some g/10 min or greater, about 5 g/10 min or greater, or about 7 embodiments, be useful in low load applications). g/10 min or greater as measured by ASTM D1238 at 190° 0024. In some embodiments, polyethylene compositions C./21.5 kg weight. In some embodiments, the HPMF poly suitable for use in conjunction with molded polyethylene ethylene described herein of the molded polyethylene com components of the present invention may comprise HPMF ponent of the present invention may have a melt flow index polyethylene described herein and optionally further com ranging from a lower limit of about 3.5 g/10 min, 5 g/10 min, prise ingredients selected from second polymers, compatibi or 10 g/10 minto an upper limit of about 30 g/10 min, 25 g/10 lizers, plasticizers, APIs, imaging agents, additives, and any min, 20 g/10 min, or 15 g/10 min as measured by ASTM combination thereof. D1238 at 190° C./21.5 kg weight. 0025. In some embodiments, the polyethylene composi 0018. In some embodiments, the HPMF polyethylene tions for use in conjunction with molded polyethylene com described herein of the molded polyethylene component of ponents of the present invention may comprise HPMF poly the present invention may have an ash content of about 500 ethylene described herein and optionally comprise at least ppm or less, about 250 ppm or less, about 100 ppm or less, 50 one second polymer. In some instances, second polymers ppm or less, or 10 ppm or less. In some embodiments, the may be miscible, partially miscible, or non-miscible with the HPMF polyethylene described herein of the molded polyeth HPMF polyethylene. ylene component of the present invention may have an ash 0026 Second polymers suitable for use in conjunction content ranging from a lower limit of about 0.1 ppm, 1 ppm, with polyethylene compositions described herein may, in 10 ppm, 25ppm, 50 ppm, 75 ppm, 100 ppm, or 150 ppm to an Some embodiments, include, but are not limited to, other upper limit of about 500 ppm, 400 ppm, 300 ppm, 250 ppm, polyethylenes (e.g., linear low density polyethylenes (LL 200 ppm, 150 ppm, 100 ppm, 50 ppm, or 10 ppm, and wherein DPE) and low density polyethylenes (LDPE)), polypropy the ash content may range from any lower limit to any upper lenes, polybutylene, graft-modified olefin polymers, chlori limit and encompass any Subset therebetween. nated polyethylenes, thermoplastic Vulcanizates, polyether 0019. In some embodiments, the HPMF polyethylene ether ketone (PEEK), polyisoprenes, polyesters, polyamides, described herein of the molded polyethylene component of ethylene copolymers, ethylene vinyl acetate copolymers, eth the present invention may be compliant with USP Class IV ylene vinyl-methacrylate copolymers, silicones, polyethyl and/or ISO 10993 standards at the filing date of this applica ene glycols, polyethylene oxide (PEO), ethylene oxide-pro tion. pylene oxide copolymers (include block copolymers like 0020. In some embodiments, the HPMF polyethylene PLURONICSR) (polyethylene oxide-polypropylene oxide described herein of the molded polyethylene component of polyethylene oxide triblock polymers, available from the present invention may be further characterized as having BASF)), polyethylene-polypropylene glycol (e.g., poloX a specific gravity of about 0.93 g/cm to about 0.97 g/cm. amer), carbomer, polycarbophil, polyethylene imine, poly 0021. In some embodiments, the HPMF polyethylene urethanes, polyacrylonitrile, styrene block copolymers, rub described herein of the molded polyethylene component of bers, ethylene-carboxylic acid copolymers, ethylene acrylate the present invention may have an average molecular weight copolymers, polybutylene, polybutadiene, nylons, polycar ranging from a lower limit of about 30,000 g/mol, 50,000 bonates, ethylene ethylacrylate polymers (EEA), ethylene g/mol, 100,000 g/mol, 250,000 g/mol, or 500,000 g/mol to an styrene interpolymers (ESI), aliphatic polyesters, poly(lactic upper limit of about 2,500,000 g/mol, 2,000,000 g/mol, acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly 1,000,000 g/mol, or 500,000 g/mol, and wherein the average (butylene Succinate), poly(caprolactone), polyanhydrides, molecular weight may range from any lower limit to any poly(vinyl alcohol), cellulosics, chitans, chitosans, cellulose upper limit and encompass any range therebetween. Methods esters, cellulose acetate, nitrocellulose, methyl cellulose, US 2014/005 1771 A1 Feb. 20, 2014 polyvinyl pyrrolidone (PVP), hydroxyalkyl celluloses (e.g., prene, polyvinyl pyrrolidone, and the like, any derivative hydroxypropyl cellulose (HPC), hydroxyethyl cellulose thereof, any copolymer thereof, and any combination thereof. (HEC), hydroxymethyl cellulose, and hydroxypropyl meth 0030. In some embodiments, plasticizers and/or compati ylcellulose (HPMC)), carboxymethyl cellulose, sodium car bilizers may be included in polyethylene compositions boxymethyl cellulose, methylcellulose, hydroxyethyl meth described herein in an amount ranging from a lower limit of ylcellulose, hydroxypropyl methylcellulose, polyacrylates, about 0.005%, 0.01%, 0.1%, 0.5%, 1%, 2%, or 5% to an polyacrylamides, polymethacrylamides, polyphosphazines, upper limit of about 50%, 25%, 10%, or 5% by weight of the polyoxazolidines, polyhydroxyalkylcarboxylic acids, alginic polyethylene composition, wherein the amount may range acids (e.g., carrageenate alginates, ammonium alginate, and from any lower limit to any upper limit and encompass any Sodium alginate), starch and starch derivatives, polysaccha subset therebetween. The amount of plasticizers and/or com rides, carboxypolymethylene, and the like, any derivative patibilizers may depend on a number of factors that include, thereof, any copolymer thereof, and any combination thereof. inter alia, the biomedical device in which the molded poly 0027. In some embodiments, second polymers for use in ethylene component will be utilized, the desired properties conjunction with the polyethylene compositions described (e.g., strength) of the molded polyethylene component, and herein may be absorbable. As used herein, the term “absorb any additional ingredients utilized in conjunction with the able compositions” and the like refers to compositions that polyethylene composition. are capable of being absorbed by the local environment, 0031. In some embodiments, the polyethylene composi where absorption may be of a complete composition or a tions for use in conjunction with molded polyethylene com component thereof (e.g., a polymer or a component thereof ponents of the present invention may comprise HPMF poly that may be produced if the polymer is degraded, e.g., by ethylene described herein and optionally comprise at least hydrolysis). As used herein, the term “bioabsorbable' and the one active pharmaceutical ingredient (API). It should be like refers to absorbable compositions where the local envi noted that the term “API encompasses prodrugs. ronment is biological in nature, e.g., in vivo. The use of 0032. In some embodiments, the APIs described herein absorbable second polymers may, in some embodiments, may be dispersed in at least a portion of the polyethylene allow for the formation of the pores and/or void spaces in situ. compositions described herein and/or disposed on at least a Further, the use of absorbable additional polymers may, in portion of a Surface of the polyethylene compositions Some embodiments, enhance the release of active pharmaceu described herein. By way of nonlimiting example, a biomedi tical ingredients, described further herein. Suitable bioab cal device (e.g., an artificial joint) may comprise a molded Sorbable second polymers for use in conjunction with the polyethylene component (e.g., a base-plate stem cap) that present invention may include, but are not limited to, aliphatic consists essentially of a polyethylene composition that com polyesters, poly(lactic acid), poly(glycolic acid), poly(lactic prises a HPMF polyethylene and an active pharmaceutical, co-glycolic acid), poly(butylene Succinate), poly(caprolac like an anti-inflammatory. Additional nonlimiting examples tone), polyanhydrides, poly(Vinyl alcohol), starches, cellulo of APIs suitable for use in conjunction with the polyethylene sics, chitans, chitosans, cellulose esters, cellulose acetate, composition of molded polyethylene components of the nitrocellulose, and the like, any derivative thereof, and any present invention are described further herein. combination thereof. 0033. In some embodiments, APIs may be included in 0028. In some embodiments, second polymers may be polyethylene compositions herein in an amount ranging from included in the polyethylene compositions described herein a lower limit of about 0.005%, 0.01%, 0.1%, 0.5%, 1%, or 2% in an amount ranging from a lower limit of about 0.005%, to an upper limit of about 10%. 5%, or 2% by weight of the 0.01%, 0.1%, 0.5%, 1%, 2%, or 5% to an upper limit of about polyethylene composition described herein, wherein the 50%, 25%, 10%, or 5% by weight of the polyethylene com amount may range from any lower limit to any upper limit and position, wherein the amount may range from any lower limit encompass any subset therebetween. The amount of APIs to any upper limit and encompass any Subset therebetween. may depend on a number of factors that include, interalia, the The amount of second polymer may depend on a number of biomedical device in which the molded polyethylene compo factors that include, interalia, the biomedical device in which nent will be utilized and any additional ingredients utilized in the molded polyethylene component will be utilized, the conjunction with the polyethylene composition. desired properties (e.g., strength) of the molded polyethylene 0034. In some embodiments, the polyethylene composi component, the composition of the second polymer, and any tions for use in conjunction with molded polyethylene com additional ingredients utilized in conjunction with the poly ponents of the present invention may comprise HPMF poly ethylene composition. ethylene described herein and optionally comprise at least 0029. In some embodiments, the polyethylene composi one imaging agent. As used herein, the term "imaging agent tions for use in conjunction with molded polyethylene com refers to a molecule, compound, or particle that interacts with ponents of the present invention may comprise HPMF poly electromagnetic radiation to enable one to ascertainanimage. ethylene described herein and optionally comprise at least 0035. In some embodiments, the imaging agents one plasticizer and/or compatibilizer. Plasticizers and/or described herein may be dispersed in at least a portion of the compatibilizers may, in Some embodiments, be useful for, polyethylene compositions described herein and/or disposed interalia, tailoring the mechanical properties of the polyeth on at least a portion of a Surface of the polyethylene compo ylene compositions described herein and/or aiding in the sitions described herein. homogeneous incorporation of additional ingredients into the 0036. Examples of imaging agents suitable for use in con polyethylene compositions. Examples of plasticizers and/or junction with the polyethylene compositions described herein compatibilizers suitable for use in conjunction with polyeth may, in some embodiments, include, but are not limited to, ylene compositions described herein may include, but are not magnetic resonance imaging agents (e.g., barium sulfate, iron limited to, polydimethylsiloxane, polyvinylbutyral, fluo oxide particles, gadolinium compounds, erbium compounds, ropolymers, polyvinylidene fluoride, polybutadiene, polyiso gadolinium endofullerenes, and gadolinium endonanotubes), US 2014/005 1771 A1 Feb. 20, 2014

X-ray imaging agents (e.g., barium sulfate, iodine com graphite, aluminum powder, talc, chalk, silicates, carbonates, pounds, and iodine endonanotubes), ultrasound imaging calcium carbonate, alumina trihydrate, marble dust, cement agents (e.g., perfluorocarbons and air bubbles), near infrared dust, clay, feldspar, fumed silica, alumina, magnesium oxide, imaging agents (e.g., carbon nanotubes, gold nanoparticles, magnesium hydroxide, antimony oxide, Zinc oxide, barium silver nanoparticles, and gold nanoshells), bismuth com Sulfate, aluminum silicate, calcium silicate, titanium dioxide, pounds, tungsten compounds, and the like, and any combina titanates, glass microspheres, carbon fibers, metallic fibers, tion thereof. carbon nanotubes, wood flour, carbon black, and the like, and 0037. In some embodiments, imaging agents may be use any combination thereof. ful in monitoring the condition of the molded polyethylene 0043. Examples of pigments and/or dyes suitable for use component of the present invention (or polyethylene compo in conjunction with polyethylene compositions described sition thereof) over the long-term. By way of nonlimiting herein may, in Some embodiments, include, but are not lim example, an imaging agent disposed on the Surface of the ited to, inorganic-based colorants, organic-based colorants, polyethylene compositions and/or dispersed in the polyeth and the like, and any combination thereof. ylene composition near the surface of the molded polyethyl 0044 Examples of antifouling agents suitable for use in ene component may be useful for noninvasively monitoring conjunction with polyethylene compositions described degradation (e.g., physical wear) of the molded polyethylene herein may, in Some embodiments, include, but are not lim component. ited to, Sulfoamides, penicillin, cephalosorins, carbapenems, 0.038. In some embodiments, imaging agents may be quinolones, oxazolidones, quanternary ammonium com included in polyethylene compositions described herein in an pounds, nobel metals (e.g., silver, gold, copper, and the like), amount ranging from a lower limit of about 0.005%, 0.01%. amine containing polymers, and the like, and any combina 0.1%, 0.5%, 1%, 2%, or 5% to an upper limit of about 25%, tion thereof. 10%. 5%, or 1% by weight of the polyethylene compositions 0045. In some embodiments, any of the additives described herein, wherein the amount may range from any described herein may be included in polyethylene composi lower limit to any upper limit and encompass any Subset tions described herein in an amount ranging from a lower therebetween. The amount of imaging agents may depend on limit of about 0.005%, 0.01%, 0.1%, 0.5%, 1%, 2%, or 5% to a number of factors that include, inter alia, the biomedical an upper limit of about 50%, 25%, 10%, 5%, or 1% by weight device in which the molded polyethylene component will be of the polyethylene composition, wherein the amount may utilized and any additional ingredients utilized in conjunction range from any lower limit to any upper limit and encompass with the polyethylene composition. any subset therebetween. The amount of additives may 0039. In some embodiments, the polyethylene composi depend on a number of factors that include, inter alia, the tions for use in conjunction with molded polyethylene com biomedical device in which the molded polyethylene compo ponents of the present invention may comprise HPMF poly nent will be utilized, the desired properties (e.g., strength) of ethylene described herein and optionally comprise at least the polyethylene composition, and any additional ingredients one additive. In some embodiments, the additives may be utilized in conjunction with the polyethylene composition. dispersed in at least a portion of the polyethylene composi 0046. In some embodiments, polyethylene compositions tions described herein and/or disposed on at least a portion of described herein may have a tensile modulus ranging from a a surface of the polyethylene compositions described herein. lower limit of about 1 MPa, 10 MPa, 25 MPa, 50 MPa, 100 0040. Examples of additives suitable for use in conjunc MPa, or 250 MPa to an upper limit of about 2500 MPa, 1500 tion with the polyethylene compositions described herein MPa, 1000 MPa, 750 MPa, 500 MPa, or 250 MPa, and may, in some embodiments, include, but are not limited to, wherein the tensile modulus may range from any lower limit antioxidants, reinforcing fillers, pigments and/or dyes, to any upper limit and encompass any Subset therebetween. radioopaque fillers, lubricants, processing aids, light stabiliz 0047. In some embodiments, polyethylene compositions ers, neutralizers, antiblocks, antifouling agents, and the like, described herein may have a Young's modulus (elastic modu and any combination thereof. lus) ranging from a lower limit of about 200 MPa, 500 MPa, 0041 Antioxidants may, in Some embodiments, mitigate 1000 MPa, or 1500 MPa to an upper limit of about 6000 MPa, oxidation and/or chemical degradation of polyethylene com 5000 MPa,2500 MPa, or 1000 MPa, and wherein theYoung's positions described herein during storage, transportation, modulus may range from any lower limit to any upper limit and/or implementation (in vivo and/or ex vivo). Examples of and encompass any Subset therebetween. antioxidants Suitable for use in conjunction with the polyeth 0048. In some embodiments, polyethylene compositions ylene compositions described herein may, in Some embodi suitable for use in conjunction with molded polyethylene ments, include, but are not limited to, ascorbic acid, glu components of the present invention may comprise HPMF tathione, lipoic acid, uric acid, resveratrol, flavonoids, polyethylene (according to any combination of a melt flow carotenes (e.g., beta-carotene), carotenoids, tocopherols index described herein, an ash content described herein, and (e.g., alpha-tocopherol), tocotrienols, ubiquinol, melatonin, a specific gravity described herein) (which may, in some secondary aromatic amines, benzofuranones, hindered phe embodiments, be compliant with USP Class IV and/or ISO nols, polyphenols, hindered amines, organophosphorus com 10993 standards at the filing date of this application) and pounds, thioesters, benzoates, lactones, hydroxylamines, and optionally further comprise ingredients selected from second any combination thereof. polymers, compatibilizers, plasticizers, APIs, imaging 0042. Reinforcing fillers may, in some embodiments, inter agents, additives, and any combination thereof (including any alia, enhance the mechanical strength of polyethylene com combination thereof at concentrations described herein), and positions described herein. Examples of reinforcing fillers optionally have a tensile modulus and/or Young's modulus Suitable for use in conjunction with the polyethylene compo described herein. sitions described herein may, in Some embodiments, include, 0049. In some embodiments, molded polyethylene com but are not limited to, glass spheres, glass fibers, bioglass, ponents of the present invention may comprise polyethylene US 2014/005 1771 A1 Feb. 20, 2014 compositions described herein and optionally further com ocular orbital wall implant or transdermal patch) may be in a prise a reinforcing structure. In some embodiments, the poly shape similar to that of a sheet. By way of another nonlimiting ethylene compositions may be disposed on at least a portion example, in some embodiments, a molded polyethylene com of a surface of a reinforcing structure. Reinforcing structures ponent (e.g., cranio-maxillofacial implant) may be in a shape may, in Some embodiments, interalia, enhance the mechani similar to that of a bone or the like. cal strength of the molded polyethylene component of the 0057. In some embodiments, a molded polyethylene com present invention, enable post-production shaping of the ponent of the present invention may be nonload-bearing. molded polyethylene component of the present invention, 0058. In some embodiments, molded polyethylene com enable securing of the molded polyethylene component ponents of the present invention may be utilized in assem within a biomedical device and/or to another object (e.g., a bling biomedical devices. In some embodiments, a biomedi bone), and any combination thereof. cal device comprising at least one molded polyethylene 0050 Reinforcing structures suitable for use in conjunc component of the present invention may be a load-bearing or tion with molded polyethylene components of the present nonload-bearing biomedical device. As used herein, the term invention may, in some embodiments, comprise ultra high "load-bearing refers to a component, device, or material that molecular weight polyethylene, metals (e.g., titanium), metal is capable of maintaining a structural load. For example, in alloys (e.g., cobalt chromium alloys and trabecular metal), biomedical devices, a hip implant, a tibia implant, a wrist or ceramics, glass, bioglass, and the like, and any combination hand implant, and the like are considered load-bearing bio thereof. Reinforcing structures suitable forusein conjunction medical devices. with the molded polyethylene components of the present 0059 Examples of biomedical devices that may comprise invention may, in some embodiments, be in the form of a rod, molded polyethylene components of the present invention a tube, wire, mesh, a sheet, beads, and the like, and any hybrid may, in some embodiments, include, but are not limited to, thereof. chips, RFID tags, tubing, pumps, feeding tubes, catheters, 0051. In some embodiments, the molded polyethylene vascular catheters, prosthesis, inflatable balloons, Stents, components of the present invention may comprise a Surface heart valves, neurostimulators, cochlear implants, cranio coating. It should be noted that the term “coating does not maxillofacial implants, synthetic cartilage, stomach rings, imply 100% surface coverage. In some embodiments, the Surgical instruments, blood vessel clamps, aneurysm clamps, Surface coating may be a polymeric layer disposed on at least spinal plugs for use in conjunction with a joint fusion system, a portion of the surface of the molded polyethylene compo base plates for use in artificial joints, muscle implants, nentS. nasopharyngeal implants, laryngeal implants, drug delivery 0052 Polymers suitable for use in conjunction with sur devices, transdermal patches, Subdermal implants, oromu face layers described herein may include, but are not limited cosal inserts, intrauterine devices, intravaginal rings, dental to, a second HPME polyethylene, a second polymer fibers, and the like. described herein, and any combination thereof. In some 0060. In some embodiments, molded polyethylene com embodiments, a Surface layer may comprise a bioabsorbable ponents of the present invention may be a conduit that com polymer, e.g., those described herein. prises at least one wall defining an internal Volume, the at least 0053. In some embodiments, a surface layer (e.g., a poly one wall comprising polyethylene compositions described meric layer) may be involved with at least one of controlling herein. the release profile of an API, providing burst release in the 0061. In some embodiments, a conduit molded polyethyl release profile of an API, delaying release of an API, and any ene component may be designed to allow fluid to flow through combination thereof. the internal volume. For example, biomedical devices like 0054. In some instances, the surface (orportion thereof) of pumps, tubings, feeding tubes, catheters, vascular catheters, the molded polyethylene component may be treated to stents, heart valves, Surgical instruments (e.g., Surgical Suc enhance adhesion between the molded polyethylene compo tion instruments), nasopharyngeal implants, and laryngeal nent and the Surface layer. Suitable treatments may include, implants may each comprise at least one conduit molded but are not limited to, plasma treatment, corona treatment, polyethylene component designed to allow fluid to flow and the like. through the internal Volume. 0055. In some instances, the polyethylene composition 0062. In some embodiments, a conduit molded polyethyl may be adjusted to enhance adhesion between the molded ene component may have at least one wire disposed within the polyethylene component and the Surface layer, e.g., by inclu internal Volume. By way of nonlimiting example, in some sion of a second polymer. embodiments, a biomedical device (e.g., a pacemaker) may 0056. In some embodiments, the molded polyethylene comprise at least one wire having a conduit molded polyeth components of the present invention have a desired shape. As ylene component disposed thereabout. should be recognized by one of ordinary skill in the art, the 0063. In some embodiments, molded polyethylene com desired shape may depend on, inter alia, the biomedical ponents described herein may be the primary composition of device in which the molded polyethylene components of the a biomedical device (e.g., cranio-maxillofacial implants). In present invention are utilized. By way of nonlimiting Some instances, the polyethylene compositions of the molded example, in Some embodiments, a molded polyethylene com polyethylene components may comprise HPMF polyethyl ponent, e.g., a sheath to a wire or a portion of a drug delivery ene and a bioabsorbable polymer, such that when imple device, may be in the shape of a conduit. By way of another mented, the bioabsorbable polymer is absorbed leaving voids nonlimiting example, in Some embodiments, a molded poly in the polyethylene composition. ethylene component (e.g., an aneurysm clamp) may be in a 0064. In some embodiments, molded polyethylene com more complex shape that is designed for both movement and ponents of the present invention may substantially encase locking. By way of yet another nonlimiting example, in some other components of a biomedical device. In some embodi embodiments, a molded polyethylene component (e.g., an ments, the encasement may be such that when implanted in a US 2014/005 1771 A1 Feb. 20, 2014 patient the Surrounding tissue may be primarily exposed to described herein and any Suitable optional ingredients (e.g., the molded polyethylene component. In some embodiments, second polymers, plasticizers, compatibilizers, APIs, imag encasement may be achieved by over molding, thermoform ing agents, additives, and the like). ing, or shrink wrapping a polyethylene composition 0070 Temperatures suitable for extruding (or the like as described herein at least partially about the other components described above) a polyethylene composition melt described to be encased. In some embodiments, encasement may be herein may, in Some embodiments, range from a lower limit achieved by forming a molded polyethylene component of about 60°C., 75° C., or 100° C. to an upper limit of about appropriately sized for placement of a biomedical device 300° C., 250° C., 200° C., or 100° C., and wherein the tem and/or component thereoftherein. perature may range from any lower limit to any upper limit 0065. By way of nonlimiting example, in some embodi and encompass any subset therebetween. It should be noted ments, a biomedical device, e.g., a cochlear implant or an that forming methods that utilize pressure, like compression RFID tag, may be substantially encased in a molded polyeth molding, may, in some embodiments, enable forming molded ylene component, such that the molded polyethylene compo polyethylene components of the present invention at lower nent resembles a coating disposed substantially about the temperatures and/or shorter times. biomedical device. By way of another nonlimiting example, a biomedical device, e.g., a pacemaker or a neurostimulator, 0071. In some embodiments, forming molded polyethyl may comprise a molded polyethylene component that com ene components of the present invention may involve extrud prises a wire having a coating disposed substantially there ing (or the like as described above) a polyethylene composi about, the coating comprising a polyethylene composition tion melt onto at least a portion of a surface of a reinforcing described herein. By way of another nonlimiting example, the structure described herein. power Supply for a neurostimulator may comprise a molded 0072. In some embodiments, forming molded polyethyl polyethylene component Substantially encasing the power ene components of the present invention may involve extrud Supply, e.g., achieved by over molding, thermoforming, or ing (or the like as described above) a polyethylene composi shrink wrapping. tion melt onto and/or at least partially about (e.g., to encase) 0066. In some embodiments, molded polyethylene com other components of a biomedical device (e.g., encasing con ponents described herein may be a drug delivery device or ductive wires, applying a Surface layer to at least one side of portion thereof. In some embodiments, a transdermal patch a metal plate, or Substantially over molding a pacemaker). may comprise a backing, a medicated layer, and a release 0073. In some embodiments, forming molded polyethyl layer (which may optionally comprise APIs), wherein the ene components of the present invention may involve extrud molded polyethylene component may be the medicated layer ing (or the like as described above) a polyethylene composi and/or the release layer. By way of nonlimiting example, the tion melt according to any embodiments described herein into medicated layer may be a molded polyethylene component a desired shape and then treating the desired shape with (e.g., comprising HPMF polyethylene and an API) and the Suitable optional ingredients (e.g., APIs, imaging agents, release layer may comprise a second polymer (e.g., an ethyl additives like antioxidants, dyes, and pigments, and the like). ene copolymer like ethylene vinyl acetate). In some instances, Treating the desired shape after forming by polymer melt the molded polyethylene component may comprise HPMF methods may, in Some embodiments, be advantageously uti polyethylene and a second polymer. In some instances, the lized when the Suitable optional ingredients are temperature medicated layer and the release layer may independently be sensitive (e.g., thermally degrade). Further, treating after molded polyethylene components with different composi forming by polymer composition melt methods may advan tions (e.g., different HPMF polyethylene, optionally blended tageously allow for placement of the Suitable optional ingre with a second polymer, optionally comprising an API or dients on at least a portion of the surface of the molded another additive, and so on). polyethylene component and/or dispersed in and near the 0067 Similar to the transdermal patch examples, other Surface of the molded polyethylene component. drug delivery devices may comprise molded polyethylene 0074. In some embodiments, forming molded polyethyl components. For example, a vaginal ring with a core similar ene components of the present invention may involve ther to the medicated layer above and the sheath similar to the moforming (or the like as described above) a sheet compris release layer above. In another example, a Subdermal implant ing a polyethylene composition on or about at least a portion like a rod or sheet with a multi-layer structure may have at of a biomedical device or component thereof. In some least one layer similar to the medicated layer and at least one embodiments, thermoforming may involve compressing and layer similar to the release layer described above. heating a sheet (e.g., a molded polyethylene composition in 0068 Forming molded polyethylene components of the sheet form) between at least two surfaces so as to form a present invention into a desired shape may involve extruding, biomedical device or component thereof. In some embodi injection molding, blow molding, over molding, thermoform ments, at least one of the Surfaces may be at least a portion of ing, shrink Wrapping, compression molding, casting, calen a surface of a biomedical device or component thereof. Some daring, near net shape molding, adhesive bonding, mechani embodiments may involve stretching and/or orienting a sheet cal fastening, and the like, any hybrid thereof, and any in the longitudinal and/or transverse directions on or about a combination thereof. biomedical device or component thereof, the sheet compris 0069. In some embodiments, forming molded polyethyl ing a polyethylene composition; and heating the sheet. ene components of the present invention may involve extrud 0075. In some embodiments, the shape of biomedical ing (or the like as described above) a polyethylene composi devices may be manipulated after forming, e.g., minor tion in melt form (i.e., a polyethylene composition melt) into changes to curvature to cranio-maxillofacial implants to a desired shape. In some embodiments, a polyethylene com match a desired bone structure. Shaping biomedical devices position melt Suitable for use in forming a molded polyeth may be performed by applying heat and pressure to the bio ylene component may comprise HPMF polyethylene medical device or component thereof. US 2014/005 1771 A1 Feb. 20, 2014

0076. In some instances forming molded polyethylene tubing or a catheter, may be included in a kit along with a set components may involve foaming the polyethylene compo of instructions for how to properly utilize the conduit molded sition. Foaming polyethylene compositions may be by any polyethylene component, e.g., installing the tubing into bio Suitable method, e.g., with pore forming agents or fluid intro medical device like a pump or inserting the catheter into a duction during extrusion. patient. 0077 Suitable pore forming compounds may include, but I0082 In some embodiments, molded polyethylene com are not limited to, the bioabsorbable polymers described ponents of the present invention may comprise polyethylene herein. Some embodiments may involve forming a molded compositions that comprise HPMF polyethylene (according polyethylene component from a polyethylene composition to any combination of a melt flow index described herein, an comprising a HPMF polyethylene and a bioabsorbable poly ash content described herein, and a specific gravity described mer; extracting a portion of the bioabsorbable polymer from herein) (which may, in some embodiments, be compliant with the molded polyethylene component (e.g., via exposure to an USPClass IV and/or ISO 10993 standards at the filing date of aqueous fluid optionally with a desired pH, temperature, and this application) and optionally further comprise ingredients salinity for extraction), thereby yielding a foamed polyethyl selected from second polymers, compatibilizers, plasticizers, ene component. APIs, imaging agents, additives, and any combination thereof 0078 Some embodiments may involve extruding a poly (including any combination thereof at concentrations ethylene component from a polyethylene composition melt; described herein), and optionally have a tensile modulus and/ and introducing a pore forming fluid into the polyethylene or Young's modulus described herein, and the molded poly composition melt while extruding. Pore forming fluids Suit ethylene components may optionally further comprise a rein able for foaming polyethylene compositions described herein forcing structure, have a desired shape, and be nonload may include, but are not limited to, air, an inert gas (e.g., bearing. Such molded polyethylene components may be a helium, nitrogen, argon, carbon dioxide, n-butane, or isobu biomedical device or be a component of a biomedical device. tane), Volatile liquids (e.g., water, methanol, or acetone), Such a biomedical device may, in some embodiments, be hydrocarbons (e.g., butane, isobutane, or pentane), haloge included in a kit and/or used for treating a patient, which may nated hydrocarbons, perfluorocarbons, and the like, or any include implantation. Such molded polyethylene components mixture thereof. In some embodiments, the pore forming may beformed according to any method or hybrid of methods fluids may be in a gas, liquid, Subcritical, or Supercritical form described herein. dissolved in the polyethylene composition melt. In some embodiments, pore forming fluids may serve to form the I. High-Purity, Melt-Flowable Polyethylene pores and as an agent, e.g., a perfluorocarbon gas that pro vides contrast in ultrasound imaging. In some embodiments, I0083. As described above, the terms “high-purity, melt pore forming fluids may be a volatile liquid that serves to form flowable polyethylene' and “HPMF polyethylene,” as used the pores and plasticize the polyethylene composition melt. In herein, refer to polyethylene having a melt flow index of Some embodiments, the amount of pore forming fluids added about 3.5 g/10 minor greater as measured by ASTM D1238 to a polyethylene composition melt may be at or below the at 190° C./21.5 kg weight and having an ash content of about saturation point of the pore forming fluids in the polyethylene 500 ppm or less. composition melt. I0084. Some embodiments of the present invention may 007.9 The parameters of introducing pore forming fluids involve producing the HPMF polyethylene described herein. into the polyethylene composition melt may be controlled to In some embodiments, producing the HPMF polyethylene provide control over the diameter distribution of the pores of described herein may involve polymerizing at least one olefin the resultant molded polyethylene component. Suitable (e.g., comprising ethylene and optionally at least one of pro parameters to adjust may include, but are not limited to, pylene and/or butylene) so as to yield polyethylene having a temperature of the polyethylene composition melt, tempera melt flow index of about 3.5 g/10 minor greater as measured ture of the pore forming fluids, pressure of pore forming by ASTM D1238 at 190° C./21.5 kg weight, and then treating fluids, composition of the pore forming fluids, composition of the polyethylene so as to yield HPMF polyethylene. the polyethylene composition melt, pressure of the polyeth I0085. In some embodiments, the polymerization of at least ylene composition melt, conditions of extrusion, and any one olefin may be carried out in Suspension at low pressure combination thereof. and temperature in one or multiple steps in a continuous, 0080. In some embodiments, biomedical devices compris batch, or hybrid process. In some embodiments, polymeriZ ing molded polyethylene components of the present invention ing the at least one olefin may optionally be performed in the may be implanted in and/or used in conjunction with the presence of at least one of molar mass regulators, catalysts treatment of a patient. As used herein, the terms “subject' and (e.g., titanium catalysts, aluminum/titanium catalysts, metal “patient” are used interchangeably and refer to both human locenes, post metallocenes, and alumoxane), Supported cata and nonhuman animals and insects. The term “nonhuman lysts, organoaluminum compounds, hydrogen, anti-fouling animals' as used herein includes all vertebrates, e.g., mam agents, anti-static agents, and the like, and any combination mals and non-mammals, such as nonhuman primates, mice, thereof. rats, sheep, dogs, cats, horses, cows, chickens, amphibians, 0086. In some embodiments, the melt flow index of the fish, reptiles, and the like. The term “insects” as used herein polyethylene produced may be manipulated by, interalia, the includes all arthropods, e.g., bees, flies, Drosophila flies, concentration and composition of the materials/compounds beetles, spiders, and the like. present during reaction (e.g., the at least one olefin, molar 0081. In some embodiments, molded polyethylene com mass regulators, catalysts, organoaluminum compounds, ponents of the present invention may be included in a kit that hydrogen, and the like), the polymerization temperature, the also includes a set of instructions. By way of nonlimiting catalyst, the composition of the solvents used, and any com example, a conduit molded polyethylene component, e.g., a bination thereof. US 2014/005 1771 A1 Feb. 20, 2014

0087. In some embodiments, the at least one olefin may be 1-dodecpyrrolidinone, 20-epi-1.25 dihydroxyvitamin D3, presentata partial pressure of about 10 MPa or less. In some 22-oxacalcitriol, 2CW. 2'-nor-cGMP 3-isobutyl GABA, embodiments, the at least one olefin may be present in a 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, abamectin, polymerization reaction at a partial pressure ranging from a abanoquil, abcizimab (commercially available as REOPROR) lower limit of about 0.01 MPa, 0.05 MPa, 0.1 MPa, or 0.5 from Eli Lilly and Company), abecarnil, abiraterone, MPa to an upper limit of about 10 MPa, 7 MPa, 5 MPa, or 3 ablukast, ablukast sodium, acadesine, acamprosate, acarbose, MPa, and wherein the partial pressure of the at least one olefin acebutolol, acecamide hydrochloride, aceclidine, aceclofe may range from any lower limit to any upper limit and encom nae, acedapsone, aceglutamide aluminum, acemannan, pass any Subset therebetween. 0088. In some embodiments, the polymerization may be acenocoumarol, acetaminophen, acetazolamide, acetohexa performed in the presence of hydrogen Such that the partial mide, acetohydroxamic acid, acetomepregenol, acetophena pressure ratio of the at least one olefin to hydrogen ranges Zine maleate, acetosulfone sodium, acetylcholine chloride, from a lower limit of about 0.01:1, 0.05:1, 0.1:1, 5:1, 10:1, or acetylcysteine, acetyl-L-carnitine, acetylmethadol, acifran, 25:1 to an upper limit of about 100:1, 75:1, or 50:1, and acipimox, acitemate, acitretin, acivicin, aclarubicin, aclato wherein the ratio may range from any lower limit to any upper nium, acodazole hydrochloride, aconiazide, acrisorcin, acriv limit and encompass any Subset therebetween. astine, acronine, actisomide, actodigin, acyclovir, acylful 0089. In some embodiments, the polymerization may be Vene, adafenoxate, adalimumab (commercially available as performed at a temperature ranging from a lower limit of HUMIRAR) from Abbott Laboratories), adapalene, ada about 30° C., 50° C., or 70° C. to an upper limit of about 130° tanserin, adatanserin hydrochloride, adecypenol, adefovir, C., 100°C., or 90°C., and wherein the temperature may range adelmidrol, ademetionine, adenosine, adinazolam, adiphein from any lower limit to any upper limit and encompass any ine hydrochloride, adiposin, adoZelesin, adrafinil, adrena subset therebetween. lone, airbutamine, alacepril, alamecin, alanine, alaproclate, 0090 Solvents suitable for use in conjunction with poly alaptide, albendazole, albolabrin, albuterol (commercially merization reactions described herein may include, but are available as VENTOLINR from GlaxoSmithKline), albutoin, not limited to, butane, pentane, hexane, cyclohexene, octane, alclofenae, alclometasone dipropionate, aluminum chlorhy nonane, decane, isomers thereof, and the like, and any com droxyallantoinate (commercially available as ALCOLOXAR) bination thereof. from TRI-K Industries, Inc.), aldecalmycin, aldesleukin, 0091. In some embodiments, after polymerization, treat aldioxa, alendronate sodium (commercially available as ing the polyethylene so as to yield the HPMF polyethylene FOSAMAX(R) from Merck), alendronic acid, alentemol, may be achieved by treatment with at least one of steam, an alentemol hydrobromide, aletamine hydrochloride, aleuro inert Solvent the catalyst is at least partially soluble in (e.g., an nium chloride, alexidine, alfacalcidol, alfentanil hydrochlo acid, acetone, water, and a halogenated Solvent), and the like, ride, alfuZosin, algestone acetonide, alglucerase, alliflurane, and any combination thereof, concurrently or in series. In alinastine, alipamide, allantoin, allobarbital, allopurinol, a Some embodiments, the inert Solvent may be chosen based on, tachy-kinins (TK) antagonist, alonimid, alosetron, alosetron interalia, the molded polyethylene component to be produced hydrochloride, alovudine, alpertine, alpha amylase, alpha with the HPMF polyethylene. For example, a halogenated idosone, alpidem, alprazolam (commercially available as Solvent may be avoided or used early in a series of treatments XANAX(R) from Pfizer, Inc.), alprenolol hydrochloride, in the production of HPMF polyethylene so as to reduce the alprenoXime hydrochloride, alprostadil, alrestatin Sodium, potential for halogenated Solvent contamination in the altanserin tartrate, alteplase, althiazide, altretamine, altromy molded polyethylene components for in vivo applications. cin B. alverinc citrate, alvircept Sudotox, amadinone acetate, 0092. In some embodiments, treating may further com amantadine hydrochloride, ambamustine, ambomycin, prise elevated temperatures and/or reduced pressures to ambruticin, ambuphylline, ambuside, amcinafal, amcinon remove any reaction solvents and/or inert solvents described ide, amdinocillin, amdinocillin pivoxil, amedalin hydrochlo herein. ride, amelometasone, ameltolide, ameSergide, ametantrone 0093. In some embodiments, the treating may be for a acetate, amezinium metilsulfate, amfebutamone, amfenac prolonged period of time so as to yield a HPMF polyethylene Sodium, amflutizole, amicycline, amidephrine mesylate, ami dox, amifloxacin, amifostine, amikacin, amiloride hydro with an ash content of about 500 ppm or less, about 250 ppm chloride, aminacrine hydrochloride, aminobenzoate potas or less, about 100 ppm or less, or most preferably about 50 sium, aminobenzoate Sodium, aminocaproic acid, ppm or less. aminoglutethimide, aminohippurate Sodium, aminolevulinic acid, aminophylline, aminorex, aminosalicylate sodium, ami II. Active Pharmaceutical Ingredients nosalicylic acid, amiodarone, amiprilose hydrochloride, 0094) Active pharmaceutical ingredients (APIs) for use amidulinsin hydrochloride, amisulpride, amitraz, amitrip in conjunction with the molded polyethylene components of tyline hydrochloride, amlexanox, amlodipine, amobarbital the present invention may include, but are not limited to, Sodium, amodiaquine, amodiaquine hydrochloride, amorolf therapeutic agents, antibiotics, antifungals, active biologi ine, amoxapine, amoxicillin, amphecloral, amphetamine Sul cals, antitoxins, antigens, nutritional Supplements, nutraceu fate, amphomycin, amphotericin B, amplicillin, ampiroxicam, ticals, and the like, any proversion thereof, and any combina ampyZine Sulfate, amduinate, amrinone, aminone, amrubicin, tion thereof. amsacrine, amythiamicin, anagestone acetate, anagrelide, 0095 Examples of suitable therapeutic agents for use in anakinra, ananain, anaritide, anaritide acetate, anastroZole conjunction with the molded polyethylene components of (commercially available as ARIMIDEXR from AstraZen present invention may include, but are not limited to, 16-alpha eca), anazolene Sodium, ancrod, andrographolide, andros fluoroestradiol, 16-alpha-gitoxin, 16-epiestriol, 17-alpha tenedione, angiogenesis inhibitors, angiotensin amide, ani dihydroequilenin, 17-alpha estradiol, 17-beta estradiol, doXime, anilleridine, anilopam hydrochloride, aniracetam, 17-hydroxy progesterone, 1-alpha-hydroxyvitamin D2, anirolac, anisotropine methylbromide, anistreplase, ani US 2014/005 1771 A1 Feb. 20, 2014

traZafen, anordrin, antagonist D, antagonist G, antarelix, chloride, bethanidine sulfate, betulinic acid, bevacizumab antazoline phosphate, anthelmycin, anthralin, anthramycin, (commercially available as AVASTINR) available from antiandrogen, antihemophilic factor (commercially available Genenetech), bevantolol, bevantolol hydrochloride, bezafi as XYNTHAR) from Pfizer, Inc.), acedapsone, felbamate, brate, bFGF inhibitor, bialamicol hydrochloride, biapenem, antiestrogen, antineoplaston, antipyrine, antisense oligo bicalutamide, bicifadine hydrochloride, biclodil hydrochlo nucleotides, apadoline, apafant, apalcillin Sodium, apaxifyl ride, bidisomide, bifemelane, bifonazole, bimakalim, line, apaZone, aphidicolin glycinate, apixifylline, apomor bimithil, bindarit, biniramycin, binospirone, bioxalomycin phine hydrochloride, apraclonidine, apraclonidine alpha2, bipenamol hydrochloride, biperiden, biphenamine hydrochloride, apramycin, aprindine, aprindine hydrochlo hydrochloride, biriperone, bisantrene, bisaramil, bisaziridi ride, aprosulate sodium, aprotinin, aptazapine maleate, apti nylspermine, bis-benzimidazole A, bis-benzimidazole B. ganel, apurinic acid, apurinic acid, aranidipine, aranotin, bisnafide, bisobrin lactate, bisoprolol, bispyrithione mag arbaprostil, arbekicin, 1-methyl-2-((phenylthio) methyl)-3- sulfex, bistramide D, bistramide K, bistratene A, bithionolate carbethoxy-4-(dimethylamino) methyl)-5-hydroxy-6-bro sodium, bitolterol besylate, bivalirudin, bizelesin, bleomycin mindole (commercially available as ARBIDOL(R) from Mas sulfate, bolandiol dipropionate, bolasterone, boldenone terlek), arbutamine hydrochloride, arclofenin, ardeparin undecylenate, boldine, bolenol, bolmantalate, bopindolol, sodium, (2R,4R)-1-(2S)-5-(diaminomethylideneamino)-2- bosentan, boxidine, brefeldin, breflate, brequinar sodium, (3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl) sulfony bretazenil, bretylium bosylate, brifentanil hydrochloride, bri lamino pentanoyl-4-methyl-piperidine-2-carboxylic acid monidine, brinolase, brocresine, brocrinat, brofoxine, broma (commercially available as ARGATROBANR) from Glaxo doline maleate, bromazepam, bromchlorenone, bromelains, SmithKline), arginine, argipressin tannate, arildone, aripipra bromfenac, brominidione, bromocriptine, bromodiphenhy Zol, arotinolol, arpinocid, arteflene, artilide fumarate, asima dramine hydrochloride, bromoxamide, bromperidol, bromp doline, aspalatone, asparaginase, aspartic acid, aspartocin, eridol decanoate, brompheniramine baleate, broperamole, asperfuran, aspirin, aspoxicillin, asprelin, astemizole, astro bropirimine, brotizolam, bucamide maleate, bucindolol. micin Sulfate, asulacrine, atameStane, atenolol, atevirdine, buclizine hydrochloride, bucromarone, budesonide (com atipamezole, atiprosin maleate, atolide, atorvastatin (com mercially available as RHINOCORTR and ENTOCORTR mercially available as LIPITORR) from Pfizer, Inc.), atosiban, from AstraZeneca), budipine, budotitane, buformin, bumeta atovaquone, atpenin B, atracurium besylate, atrimustine, atri mide, bunaprolast, bunaZosin, bunolol hydrochloride, bupi nositol, atromentin, atropine, auranofin, aureobasidin A, comide, bupivacaine hydrochloride, buprenorphine hydro aurothioglucose, avilamycin, avoparcin, avridine, nizatidine chloride, bupropion hydrochloride, buramate, buserelin (commercially available as AXID(R) from GlaxoSmithKline), acetate, buspirone hydrochloride, busulfan, butabarbital, axinastatin 1, axinastatin 2, axinastatin 3, azabon, azacitidi butacetin, butaclamol hydrochloride, butalbital, butamben, nie, azaclorzine hydrochloride, azaconazole, azadirachtine, butamirate citrate, butaperazine, butaprost, butedronate tetra azalanstat dihydrochloride, azaloxan fumarate, azanator Sodium, butenafine, buterizine, buthionine Sulfoximine, maleate, azanidazole, azaperone, azaribine, azaserine, aza butikacin, butilfenin, butirosin sulfate, butixirate, butixocort setron, azatadine maleate, azathioprine, azathioprine Sodium, propionate, butoconazole nitrate, butonate, butopamine, aZatoxin, azatyrosine, azelaic acid, azelastine, azelnidipine, butoprozine hydrochloride, butorphanol, butoxamine hydro azepindole, azetepa, azimilide, azithromycin, azlocillin, chloride, butriptyline hydrochloride, cactinomycin, cadex aZolimine, azosemide, azotomycin, aztreonam, aZumolene omer iodine, caffeine, calanolide A, calcifediol, calcipot Sodium, bacampicillin hydrochloride, baccatin III, bacitra riene, calcipotriol, calcitonin, calcitriol, calcium cin, baclofen, bacoside A, bacoside B, bactobolamine, bal undecylenate, callphostin C, calusterone, cambendazole, anol, balaZipone, balhimycin, balofloxacin, balsalazide, bam camonagrel, camptothecin derivatives, canarypox IL-2, can bermycins, bambuterol, bamethan sulfate, bamifylline desartan, candicidin, candoXatril, candoxatrilat, caniglibose, hydrochloride, bamidazole, baohuoside 1, barmastine, barni canrenoate potassium, canrenone, capecitabine, capobenate dipine, basifungin, batanopride hydrochloride, batebulast, Sodium, capobenic acid, capreomycin Sulfate, capromab, batelapine maleate, batimastat, beauvericin, becanthone capsaicin, captopril, capuride, caracemide, carbachol, carba hydrochloride, becaplermin, becliconazole, beclomethasone dox, carbamazepine, carbamide peroxide, carbantel lauryl dipropionate, befloxatone, beinserazide, belfosdil, bella Sulfate, carbaspirin calcium, carbazeran, carbazomycin C, donna, beloxamide, bemesetron, bemitradine, bemoradan, carbenicillin potassium, carbenoXolone sodium, carbetimer, benapryzine hydrochloride, benazepril hydrochloride, carbetocin, carbidopa, carbidopa-levodopa, carbinoxamine benazeprilat, bendacalol mesylate, bendazac, bendroflume maleate, carbiphene hydrochloride, carbocloral, carbocys thiazide, benflumetol, benidipine, benorterone, benoxapro teine, carbol-fuchsin, carboplatin, carboprost, carbovir, car fen, benoxaprofen, benoximate hydrochloride, benperidol, boxamide-amino-triazole, carboxyamidotriazole, carboxym bentazepam, bentiromide, benurestat, benzbromarone, ben ethylated beta-1,3-glucan, carbuterol hydrochloride, CaRest Zethonium chloride, benzetimide hydrochloride, benzilo M3, carfentanil citrate, carisoprodol, carmantadine, carmus nium bromide, benzindopyrine hydrochloride, benzisox tine, CARN 700, camidazole, caroxazone, carperitide, car azole, benzocaine, benzochlorins, benzoctamine phenazine maleate, carprofen, carsatirin Succinate, carta hydrochloride, benzodepa, benzoidazoxan, benzonatate, Zolate, carteolol, carteolol hydrochloride, cartilage derived benzoyl peroxide, benzoylpas calcium, benzoylstaurospo inhibitor, carubicin hydrochloride, carumonam Sodium, rine, benzquinamide, benzthiazide, benztropine, benztropine carvedilol, carvotroline, carvotroline hydrochloride, carze mesylate, benzydamine hydrochloride, benzylpenicilloyl lesin, casein kinase inhibitors (ICOS), castanospermine, cau polylysine, bepridil, bepridil hydrochloride, beractant, bera rumonam, cebaracetam, cecropin B, cedefingol, cefaclor, prost, berefrine, berlafenone, bertosamil, berythromycin, cefadroxil, cefamandole, cefaparole, cefatrizine, cefazaflur besipirdine, beta-alethine, betaclamycin B, betamethasone, Sodium, cefazolin, cefbuperaZone, cefcapene pivoxil, cefdal betamipron, betaxolol, betaxolol hydrochloride, bethanechol oxime pentexil tosilate, cefdinir, cefditoren pivoxil, US 2014/005 1771 A1 Feb. 20, 2014 cefepime, cefetamet, cefetecol, cefixime, cefluprenam, complestatin, conagenin, conorphone hydrochloride, conti cefinenoXime hydrochloride, cefinetazole, cefiminlox, cefo gnasterol, contortrostatin, cormethasone acetate, corticorelin dizime, cefonicid sodium, cefoperaZone sodium, ceforamide, ovine triflutate, corticotropin, cortisone acetate, cortivaZol. cefoselis, cefotaxime Sodium, cefotetan, cefotiam, cefoxitin, cortodoxone, cosalane, costatolide, cosyntropin, cotinine, cefoZopran, cefpimizole, cefpiramide, cefpirome, cefpo warfarin (commercially available as COUMADINR) from doXime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazi Bristol-Myers Squibb), coumermycin, coumarins, crambes dime, cefteram, ceftibuten, ceftizoxime Sodium, ceftriaxone, cidin 816, crilvastatin, crisinatol, cromitrile Sodium, cromolyn cefuroxime, celastrol, celikalim, celiprolol, cepacidine A, Sodium, crotamiton, cryptophycin 8, cucumariosid, cephacetrile Sodium, cephalexin, cephaloglycin, cephalori cuprimyxin, curacin A, curdlan Sulfate, Zinc hyaluran (com dine, cephalothin Sodium, cephapirin Sodium, cephradine, mercially available as CURIOSINR) from Gedeon Richter), cericlamine, cerivastatin, ceronapril, certoparin Sodium, cyclacillin, cyclazocine, cyclazosin, cyclic HPMPC, cyclin ceruletide, cetaben Sodium, cetalkonium chloride, cetamolol dole, cycliramine maleate, cyclizine, cyclobendazole, hydrochloride, cetiedil, cetirizine, cetophenicol, cetraxate cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, hydrochloride, cetrorelix, cetuximab (commercially avail cycloguanil pamoate, cycloheximide, cyclopentanthraquino able as ERBITUXOR) from Eli Lilly and Company), cetylpy nes, cyclopenthiazide, cyclopentolate hydrochloride, cyclo ridinium chloride, chenodiol, chlophedianol hydrochloride, phenazine hydrochloride, cyclophosphamide, cycloplatam, chloral betaine, chlorambucil, chloramphenicol, chlordan cyclopropane, cycloserine, cyclosin, cyclosporine, cyclothia toin, chlordiazepoxide, chlorhexidine gluconate, chlorins, lidine, cyclothiazide, cyclothiazomycin, cyheptamide, cype chlormadinone acetate, chloroorienticin A, chloroprocaine mycin, cypenamine hydrochloride, cyprazepam, cyprohepta hydrochloride, chloropropamide, chloroquine, chloroqui dine hydrochloride, cyprolidol hydrochloride, cyproterone, noxaline Sulfonamide, chlorothiazide, chlorotrianisene, cyproximide, cysteamine, cysteine hydrochloride, cystine, chloroxine, chloroxylenol, chlorphenesin carbamate, chlor cytarabine, cytarabine hydrochloride, cytarabine ocfosfate, pheniramine maleate, chlorpromazine, chlorpropamide, cytochalasin B, cytolytic factor, cytostatin, dabigatran, dac chlorprothixene, chlortetracycline bisulfate, chlorthalidone, arbazine, dacliximab, dactimicin, dactinomycin, daidzein, chlorZoxazone, cholestyramine resin, chromonar hydrochlo daledalintosylate, dalfopristin, dalteparin sodium, daltroban, ride, cibenzoline, cicaprost, ciclafrine hydrochloride, dalvastatin, danaparoid, danazol, dantrolene, daphlnodorin ciclazindol, ciclesonide, cicletanine, ciclopiroX, cicloprofen, A dapiprazole, dapitant, dapoxetine hydrochloride, dapsone, cicloprolol, cidofovir, cidoxepin hydrochloride, cifenline, daptomycin, dargilitaZone sodium, darifenacin, darlucin A, ciglitazone, ciladopa hydrochloride, cilansetron, cilastatin darodipine, darsidomine, darusentan, daunorubicin hydro Sodium, cilaZapril, cilnidipine, cilobamine mesylate, cilobra chloride, dazadrol maleate, dazepinil hydrochloride, dine, cillofungin, cilostazol, cimaterol, cimetidine, daZmegrel, dazopride fumarate, daZOXiben hydrochloride, cimetropium bromide, cinalukast, cinanserin hydrochloride, debrisoquin Sulfate, decitabine, deferiprone, deflazacort, cinepazet maleate, cinflumide, cingestol, cinitapride, cin dehydrocholic acid, dehydrodidemnin B, dehydroepiandros namedrine, cinnarizine, cinolazepam, cinoxacin, cinperene, terone, delapril, delapril hydrochloride, delavirdine mesylate, cinromide, cintaZone, cintriamide, cioteronel, cipamfylline, deleduanine, delfaprazine, delmadinone acetate, delmopi ciprefadol Succinate, ciprocinonide, ciprofibrate, ciprofloxa nol, delphinidin, demecarium bromide, demeclocycline, cin, ciprostene, ciramadol, cirolemycin, cisapride, cisatracu demecycline, demoxepam, denofungin, deoxypyridinoline, rium besilate, cisconazole, cisplatin, cisporphyrin, cistineX 2-propylpentanoic acid (commercially available as DEPA ine, citalopram, citenamide, citicoline, citreamicin alpha, KOTER) from Abbott), deprodone, deprostil, depsidomycin, cladribine, clamoxyquin hydrochloride, clarithromycin, deramciclane, dermatan Sulfate, desciclovir, descinolone clausenamide, clavulanate potassium, claZolam, claZolimine, acetonide, desflurane, desipramine hydrochloride, desirudin, clebopride, clemastine, Clentiazem maleate, clidinium bro deslanoside, deslorelin, desmopressin, desogestrel, desonide, mide, clinafloxacin, clindamycin, clioquinol, clioxamide, desoximetaSone, desoxoamiodarone, desoxycorticosterone cliprofen, clobazam, clobetasol propionate, clobetaSone acetate, detajmium bitartrate, deterenol hydrochloride, butyrate, clocortolone acetate, clodanolene, clodazon hydro detirelix acetate, devaZepide, dexamethasone, dexamisole, chloride, clodronic acid, clof azimine, clofibrate, clofilium dexbrompheniramine maleate, dexchlorpheniramine male phosphate, clogestone acetate, clomacran phosphate, clom ate, dexclamol hydrochloride, dexetimide, dexfenfluramine egestone acetate, clometherone, clomethiazole, clomifene hydrochloride, dexifosfamide, deximafen, dexivacaine, analogues, clominorex, clomiphene, clomipramine hydro dexketoprofen, dexloxiglumide, dexmedetomidine, dexor chloride, clonazepam, clonidine, clonitrate, clonixeril, maplatin, dexoxadrol hydrochloride, dexpanthenol, dex clonixin, clopamide, clopenthixol, cloperidone hydrochlo pemedolac, dexpropranolol hydrochloride, dexraZoxane, ride, clopidogrel (commercially available as PLAVIX(R) from deXSotalol, dextrin 2-Sulphate, dextroamphetamine, dex Bristol-Myers Squibb and Sanofi Pharmaceuticals), clopi tromethorphan, dextrorphan hydrochloride, dextrothyroxine mozide, clopipazan mesylate, clopirac, cloprednol, clopros Sodium, dexVerapamil, dezaguanine, dezinamide, dezocine, tenol sodium, cloraZepate dipotassium, clorethate, clorex diacetolol hydrochloride, diamocaine cyclamate, diapamide, olone, cloroperone hydrochloride, clorprenaline diatrizoate meglumine, diatrizoic acid, diaveridine, diaz hydrochloride, clorsulon, clortermine hydrochloride, closan epam, diaziquone, diaZOxide, dibenzepin hydrochloride, tel, closiramine aceturate, clothiapine, clothixamide maleate dibenzothiophene, dibucaine, dichliorvos, dichloral cloticaSone propionate, clotrimazole, cloxacillin benzathine, phenaZone, dichlorphenamide, dicirenone, diclofenac cloxyquin, clozapine, cocaine, coccidioidin, codeine, Sodium, dicloxacillin, dicranin, dicumarol, dicyclomine codoxime, colchicine, colestimide, colestipol hydrochloride, hydrochloride, didanosine, didemnin B, didox, dienestrol, colestolone, colforsin, colfosceril palmitate, colistimethate dienogest, diethylcarbamazine citrate, diethylhomosper Sodium, colistin Sulfate, collismycin A, collismycin B, col mine, diethylnorspermine, diethylpropion hydrochloride, terol mesylate, combretastatin A4, combretastatin analogue, diethylstilbestrol, difenoximide hydrochloride, difenoxin, US 2014/005 1771 A1 Feb. 20, 2014

diflorasone diacetate, difloxacin hydrochloride, difluanine etibendazole, etidocaine, etidronate disodium, etidronic acid, hydrochloride, diflucortolone, diflumidone sodium, etifenin, etintidine hydrochloride, etizolam, etodolac, etofe diflunisal, difluprednate, diftalone, digitalis, digitoxin, namate, etoformin hydrochloride, etomidate, etonogestrel, digoxin, dihexyverine hydrochloride, dihydrexidine, dihy etoperidone hydrochloride, etoposide, etoprine, etoxadrol dro-5-azacytidine, dihydrocodeine bitartrate, dihydroergota hydrochloride, etoZolin, etrabamine, etretinate, etryptamine mine mesylate, hihydroestosterone, dihydrostreptomycin acetate, eucatropine hydrochloride, eugenol, euprocin hydro Sulfate, dihydrotachysterol, dihydrotaxol, phenytoin (com chloride, eveninomicin, exametazine, examorelin, exaprolol mercially available as DILANTINR) from Parke, Davis & hydrochloride, exemestane, exetimibe (commercially avail Company), dilevalolhydrochloride, diltiazem hydrochloride, able as ZETIAR) from Merck), fadrozole, faerieflungin, fam dimefadane, dimefline hydrochloride, dimenhydrinate, ciclovir, famotidine (commercially available as PEPCIDR) dimercaprol, dimethadione, dimethindene maleate, dimethis from Merck), fampiridine, fantofarone, fantridone hydrochlo terone, dimethyl prostaglandin A1, dimethyl sulfoxide, dim ride, faropenem, fasidotril, fasudil, faZarabine, fedotozine, ethylhomospermine, dimiracetam, dimoxamine hydrochlo felbamate, felbinac, felodipine, fely pressin, femalamide, fen ride, dinoprost, dinoprostone, dioxadrol hydrochloride, amole, fenbendazole, fenbufen, fencibutirol, fenclofenac, dioxamycin, diphenhydramine citrate, diphenidol, diphe fenclonine, fenclorac, fendosal, fenestrel, fenethylline hydro noxylate hydrochloride, diphenyl spiromustine, diplivefin chloride, fenfluramine hydrochloride, fengabine, fenimide, hydrochloride, diplivefrin, dipliency prone, diprafenone, fenisorex, fenmetozole hydrochloride, fenmetramide, dipropylnorspermine, dipyridamole, dipyrithione, dipyrone, fenobam, fenoctimine sulfate, fenofibrate, fenoldopam, feno dirithromycin, discodermolide, disobutamide, disofenin, dis profen, fenoterol, fenpipalone, fenprinast hydrochloride, fen opyramide, disoxaril, disulfuram, ditekiren, divalproex prostalene, fenguizone, fenretinide, fenspiride, fentanyl cit Sodium, dizocilpine maleate, dobutamine, docarpamine, rate, fentiazac, fenticlor, fenticonazole, fenyripol docebenone, docetaxel, doconazole, docosanol, dolfetilide, hydrochloride, fepradinol, ferpifosate sodium, ferristene, fer dolasetron, drotrecogin alfa (commercially available as rixan, ferrous Sulfate, ferumoxides, ferumoxsil, fetoxylate XIGRIS(R) from Eli Lilly and Company), dulloxetine hydro hydrochloride, fexofenadine, fezolamine fumarate, fiacitab chloride (commercially available as CYMBALTAR) from Eli ine, fialuridine, fibrinogen I 125, filgrastim, filipin, finasteride Lilly and Company), ebastine, ebiratide, ebrotidine, ebselen, (commercially available as PROPECIAR) from Merck), fla ecabapide, ecabet, ecadotril, ecdlisteron, echicetin, echistatin, vodilol maleate, flavopiridol, flavoxate hydrochloride, flaza echothiophate iodide, eclanamine maleate, eclaZolast, eco lone, flecamide, flerobuterol, fleroxacin, flesinoxan, flestolol mustine, econazole, ecteinascidin 722, edaravone, edatrex sulfate, fletazepam, flezelastine, flobufen, floctafenine, flo ate, edelfosine, edifolone acetate, edobacomab, edoxudine, moxef, flordipine, florfenicol, florifenine, flosatidil, flose edrecolomab, edrophonium chloride, edroxyprogesteone quinan, floxacillin, floXuridine, fluasterone, fluazacort, fluba acetate, efegatran, eflornithine, efonidipine, egualcen, elant nilate hydrochloride, flubendazole, flucindole, flucloronide, rine, eleatonin, elemene, eletriptan, elgodipine, eliprodil, fluconazole, flucytosine, fludalanine, fludarabine phosphate, elsamitrucin, eltenae, elucaine, emalkalim, emedastine, fludazonium chloride, fludeoxyglucose F 18, fludorex, emetine hydrochloride, emiglitate, emilium tosylate, emite fludrocortisone acetate, flufenamic acid, flufenisal, flumaze fur, emoctakin, enadoline hydrochloride, enalapril, enalapri nil, flumecinol, flumequine, flumeridone, flumethasone, flu lat, enalkiren, enaZadrem, encyprate, endralazine mesylate, metramide, flumeZapine, fluminorex, flumizole, flumox endrysone, enflurane, englitaZone, enilconazole, enisoprost, onide, flunarizine, flunidazole, flunisolide, flunitrazepam, enlimomab, enloplatin, enofelast, enolicam sodium, enoxa flunixin, fluocalcitriol, fluocinolone acetonide, fluocinonide, cin, enoxacin, enoxaparin Sodium, enoxaparin Sodium, fluocortin butyl, fluocortolone, fluorescein, fluorodaunoruni enoXimone, enpiroline phosphate, enprofylline, empromate, cin hydrochloride, fluorodopa F 18, fluoroformylone, fluoro entacapone, enterostatin, enviradene, enviroXime, ephedrine, quinolones, fluorometholone, fluorouracil, fluotracen hydro epicillin, epimestrol, epinephrine, epinephrylborate, epipro chloride, fluoxetine, fluoxymesterone, fluparoxan, pidine, epirizole, epirubicin, epitetracycline hydrochloride, fluperamide, fluperolone acetate, fluphenazine decanoate, epithiazide, epoetinalfa, epoetin beta, epoprostenol, epopros flupirtine, fluprednisolone, fluproduaZone, fluprostenol tenol sodium, epoxymeXrenone, epristeride, eprosartan, Sodium, fluquaZone, fluradoline hydrochloride, flurandreno eptastigmine, eptifibatide, equilenin, equilin, erbuloZole, lide, flurazepam hydrochloride, flurbiprofen, fluretofen, flu erdosteine, ergoloid mesylates, ergonovine maleate, ergota rithromycin, fluorocitabine, fluorof amide, fluorogestone mine tartrate, ersentilide, ersofermin, erythritol, erythrityl acetate, flurothyl, fluoroxene, fluspiperone, fluspirilene, flu tetranitrate, erythromycin, esmolol hydrochloride, esomepra ticasone propionate (commercially available as ADVAIRR Zole (commercially available as NEXIUM(R) from AstraZen from GlaxoSmithKline), fluticasone furoate, flutrimazole, eca), esorubicin hydrochloride, esproquin hydrochloride, flutroline, fluvastatin, fluvastatin sodium, fluvoxamine, fluzi estazolam, estradiol, estramustine, estramustine analogue, namide, folic acid, follicle regulatory protein, folliculostatin, estraZinol hydrobromide, estriol, estrofurate, estrogen ago fomepizole, fonazine mesylate, fondaparinux, forasartan, nists, estrogen antagonists, estrogens, conjugated estrogens, forfenimex, forfenirmex, formestane, formocortal, formot esterified, estrone, estropipate, esuprone, etafedrine hydro erol, fosarilate, foSazepam, foScarnet Sodium, fosfomycin, chloride, etanidazole, etanterol, etarotene, etazolate hydro foSfonet sodium, fosinopril, fosinoprilat, fosphenyloin, fos chloride, eterobarb, ethacizin, ethacrynate Sodium, quidone, fostedil, fostriecin, fotemustine, fuchsin, basic, ethacrynic acid, ethambutol hydrochloride, ethamivan, etha fumoxicillin, fungimycin, furaprofen, furazolidone, furazo nolamine oleate, ethehlorvynol, ether, ethinyl estradiol, lium chloride, furegrelate sodium, furobufen, furodazole, ethiodized oil, ethionamide, ethonam nitrate, ethopropazine furosemide, fusidate sodium, fusidic acid, gabapentin, gado hydrochloride, ethosuximide, ethotoin, ethoxazene hydro benate dimeglumine, gadobenic acid, gadobutrol, gadodia chloride, ethybenztropine, ethyl chloride, ethyl dibunate, eth mide, gadolinium texaphyrin, gadopentetate dimeglumine, ylestrenol, ethyndiol, ethynerone, ethynodiol diacetate, gadoteric acid, gadoteridol, gadoversetamide, galantamine, US 2014/005 1771 A1 Feb. 20, 2014 galdansetron, galdansetron hydrochloride, gallamine tri pamide meglumine, iodixanol, iodoamiloride, iodoantipyrine ethiodide, gallium nitrate, gallopamil, galocitabine, gamfex I 131, iodocholesterol I 131, iododoxorubicin, iodohippurate ine, gamolenic acid, ganciclovir, ganirelix, ganirelix acetate, Sodium I 131, iodopyriacet I 125, iodoquinol, iodoxamate gelatinase inhibitors, gemcadiol, gemcitabine (commercially meglumine, iodoxamie acid, ioglicic acid, iofetamine hydro available as GEMZAR(R) from Eli Lilly and Company), chloride I 123, iofratol, ioglucol, ioglucomide, ioglycamic gemeprost, gemfibrozil, gentamicin Sulfate, gentian violet, acid, iogulamide, iohexyl, iomeprol, iomethin I 125, iopami gepirone, gestaclone, gestodene, gestonorone caproate, dol, iopanoic acid, iopentol, iophendylate, ioprocemic acid, gestrinone, geVotroline hydrochloride, girisopam, glaspi iopromide, iopronic acid, iopydol, iopydone, iopyrol, iose mod, glaucocalyxin A, glemanserin, gliamilide, glibornuride, famic acid, io.seric acid, ioSulamide meglumine, ioSumetic glicetanile Sodium, gliflumide, glimepiride, glipizide, gloxi acid, iotasul, iotetric acid, iothalamate sodium, iothalamic monam, glucagon, glutapyrone, glutathione inhibitors, glute acid, iotriside, iotrolan, iotroXic acid, iotyrosine I 131, iover thimide, glyburide, glycopine, glycopril, glycopyrrolate, gly Sol, ioXagiate Sodium, ioxaglate meglumine, ioxaglic acid, hexamide, glymidine sodium, glyoctamide, glyparamide, ioXilan, ioxotrizoic acid, ipazilide, ipenoxazone, ipidacrine, colloidal gold Au 198, gonadoctrinins, gonadorelin, gonadot ipodate calcium, ipomeanol, 4-, ipratropium bromide, iprifla ropins, goserelin, gramicidin, granisetron, grepafloxacin, vone, iprindole, iprofenin, ipronidazole, iproplatin, iproxam griseofulvin, guaiapate, guaithylline, guanabenz, guanabenz ine hydrochloride, ipsapirone, irbesartan, irinotecan, irloxa acetate, guanadrel Sulfate, guancydine, guanethidine mono cin, iroplact, irsogladine, irtemazole, isalsteine, isamoxole, Sulfate, guanfacine hydrochloride, guanisoquin Sulfate, gua isbogrel, isepamicin, isobengaZole, isobutamben, isocarbox noclor Sulfate, guanoctine hydrochloride, guanoxabenz, gua azid, isoconazole, isoetharine, isofloxythepin, isoflupredone noxan Sulfate, guanoxyfen Sulfate, gusperimus acetate, isoflurane, isofluorophate, isohomohalicondrin B, trihydrochloride, halazepam, halcinonide, halichondrin B, isoleucine, isomazole hydrochloride, isomylamine hydro halobetasol propionate, halofantrine, halofantrine hydro chloride, isoniazid, isopropamide iodide, isopropyl alcohol, chloride, halofenate, halofuginone hydrobromide, halomon, isopropyl unoprostone, isoproterenol hydrochloride, isosor galopemide, galoperidol, halopredone, haloprogesterone, bide, isosorbide mononitrate, isotiquimide, isotretinoin, isox haloprogin, halothane, halquinols, hamycin, han menopausal epac, isoxicam, isoxSuprine hydrochloride, isradipine, itame gonadotropins, hatomamicin, hatomarubigin A, hatomarubi line, itasetron, itaZigrel, itopride, itraconazole, ivermectin, gin B, hatomarubigin C, hatomarubigin D, heparin Sodium, jasplakinolide.josamycin, kahalalide F. kalafungin, kanamy hepsulfam, heregulin, hetacillin, heteronium bromide, cin Sulfate, ketamine hydrochloride, ketanserin, ketazocine, hexachlorophene:hydrogen peroxide, hexafluorenium bro ketazolam, kethoxal, ketipramine fumarate, ketoconazole, mide, hexamethylene bisacetamide, hexedine, hexobendine, ketoprofen, ketorfanol, ketorolac, ketotifen fumarate, kitasa hexoprenaline Sulfate, hexylresorcinol, hirudin, histamine mycin, labetalol hydrochloride, lacidipine, lacidipine, lacti phosphate, histidine, histoplasmin, histrelin, homatropine tol, lactivicin, laennec, lafutidine, lamellarin-n triacetate, hydrobromide, hoquizil hydrochloride, human chorionic lamifiban, lamivudine, lamotrigine, lanoconazole, LAN gonadotropin, hycanthone, hydralazine hydrochloride, OXINR) (digoxin, available from GlaxoSmithKline), lan hydralazine polistirex, hydrochlorothiazide, hydrocodone perisone, lanreotide, lanSoprazole (commercially available as bitartrate, hydrocortisone, hydroflumethiazide, hydromor PREVAID(R) from Takeda Pharmaceuticals, Inc.), latano phone hydrochloride, hydroxyamphetamine hydrobromide, prost, lateritin, laurocapram, lauryl isoquinolinium bromide, hydroxychloroquine Sulfate, hydroxyphenamate, hydrox lavoltidine Succinate, lazabemide, lecimibide, leinamycin, yprogesterone caproate, hydroxyurca, hydroxy Zine hydro lemildipine, leminoprazole, lenercept, leniquinsin, chloride, hymecromone, hyoscyamine, hypericin, ibafloxa lenograstim, lenperone, lentinan Sulfate, lepirudin, leptin, cin, ibandronic acid, ibogaine, ibopamine, ibudilast, leptolstatin, lercanidipine, lergotrile, lerisetron, letimide ibufenac, ibuprofen, ibutilide fumarate, icatibant acetate, ich hydrochloride, letraZuril, letrozole, leucine, leucomyzin, leu thammol, icotidine, idarubicin, idoxifene, idoxuridine, idra prolide acetate, leuprolide, leuprorelin, levamfetamine Succi mantone, idraparinux, iemefloxacin, iesopitron, ifetroban, nate, levamisole, levdobutamine lactobionate, levcro ifosfamide, ilepeimide, illimaquinone, ilmofosine, illomastat, makalim, levetiracetam, levobetaxolol, levobunolol, ilonidap, illoperidone, iloprost, imafen hydrochloride, ima levobupivacaine, levocabastine, levocarnitine, levodopa, Zodan hydrochloride, imidapril, imidazenil, imidazoacri levodropropizine, levofloxacin (commercially available as dones, imidecyl iodine, imidocarb hydrochloride, imidoline LEVAQUINR) from Jessen Pharmaceuticals, Inc.), levofural hydrochloride, imidurea, imiloxanhydrochloride, imipenem, tadone, levoleucovorin calcium, levomethadyl acetate, imipramine hydrochloride, imiquimod, immunostimulant levomethadyl acetate hydrochloride, levomoprolol, levonant peptides, impromidine hydrochloride, indacrinone, indapam radol hydrochloride, levonordefrin, levonorgestrel, levopro ide, indecamide hydrochloride, indeloxazine hydrochloride, poxyphene napsylate, levopropylcillin potassium, indigotindisulfonate Sodium, indinavir, indocyanine green, levormeloxifene, levorphanol tartrate, levosimendan, levo indolapril hydrochloride, indolidan, indometacin, Sulpiride, levothyroxine sodium, levoxadrol hydrochloride, indomethacin Sodium, indoprofen, indoramin, indorenate lexipafant, lexithromycin, liarozole, libenZapril, lidamidine hydrochloride, indoxole, indriline hydrochloride, infliximab hydrochloride, lidocaine, lidofenin, lidoflazine, lifarizine, (commercially available as REMICADE(R) from Janssen Bio lifibrate, lifibrol, linarotene, lincomycin, linear polyamine tech, Inc.), inocoterone, inogatran, inolimomab, inositol analogue, linogliride, linopirdine, linotroban, linsidomine, niacinate, insulin, insulin glargine (commercially available as lintitript, lintopride, liothyronine I 125, liothyronine sodium, LANTUS(R) from Sanofi-Aventis), interferons, interferon liotrix, lirexapride, lisinopril, lissoclinamide 7, lixazinone beta-1a (commercially available as AVONEX(R) from BIO sulfate, lobaplatin, lobenzarit sodium, lobucavir, lodelaben, GEN), interleukins, intrazole, intriptyline hydrochloride, lodoxamide, lofemizole hydrochloride, lofentanil oxalate, iobenguane, iobenzamic acid, iobitridol, iocarmate meglu lofepramine hydrochloride, lofexidine hydrochloride, lom mine, iocarmic acid, iocetamic acid, iodamide, iodine, iodi bricine, lomefloxacin, lomerizine, lometraline hydrochlo US 2014/005 1771 A1 Feb. 20, 2014 ride, lometrexol, lomitapide, lomofungin, lomoxicam, mianserin hydrochloride, mibefradil, mibefradil dihydro lomustine, lonapalene, lonazolac, lonidamine, loperamide chloride, mibolerone, michellamine B, miconazole, micro hydrochloride, loracarbef, lorajmine hydrochloride, lorata colin A, midaflur, midazolam hydrochloride, midodrine, dine, lorazepam, lorbamate, lorcamide hydrochloride, lore mifepristone, mifobate, miglitol, millacemide, milameline, clezole, lorglumide, lormetazepam, lornoxicam, lornoxicam, mildronate, milemperone, millipertine, milnacipran, mil lortalamine, lorZafone, losartan (commercially available as rinone, miltefosine, mimbane hydrochloride, minaprine, COZAARR) from Merck), losigamone, losoxantrone, losula minaxolone, minocromil, minocycline, minoxidil, miofla Zine hydrochloride, loteprednol, lovastatin, loviride, loxap Zine hydrochloride, miokamycin, mipragoside, mirfentanil, ine, loxoribine, lubeluzole, lucanthone hydrochloride, mirimoStim, mirincamycin hydrochloride, mirisetron male lufironil, lurosetron mesylate, lurtotecan, luteinizing hor ate, mirtazapine, mismatched double stranded RNA, mis mone, lutetium, lutrelin acetate, luZindole, lyapolate Sodium, onidazole, misoprostol, mitindomide, mitocarcin, mitocro lycetamine, lydicamycin, lydimycin, lynestrenol, lypressin, min, mitogillin, mitoguaZone, mitolactol, mitomalcin, lysine, lysofylline, lysostaphin, lytic peptides, maduramicin, mitomycin, mitonafide, mitosper, mitotane, mitoxantrone, mafenide, magainin 2 amide, magnesium salicylate, magne mivacurium chloride, mivaZerol, mixanpril, mixidine, mizo sium Sulfate, magnolol, maitansine, malethamer, malloto lastine, mizoribine, moclobemide, modafinil, modaline Sul chromene, mallotojaponin, malotilate, mangafodipir, manid fate, modecamide, moexipril, mofarotene, mofegiline hydro ipine, maniwamycin A, mannitol, mannostatin A, chloride, mofeZolac, molgramoStim, molinaZone, molindone manumycin E, manumycin F, MAPK/ERK kinase (MEK) hydrochloride, molsidomine, mometasone, monatepil male inhibitors, mapinastine, maprotiline, marimastat, masopro ate, monensin, monoctanoin, montelukast sodium (commer col, maspin, massetolide, matrilysin inhibitors, maytansine, cially available as SINGULAIRR) available from Merck), maZapertine Succiniate, mazindol, mebendazole, mebeverine montirelin, mopidamol, moracizine, morantel tartrate, mori hydrochloride, mebrofenin, mebutamate, mecamylamine cizine, morniflumate, morphine, morphine Sulfate, morrhuate hydrochloride, mechlorethamine hydrochloride, meclocy Sodium, mosapramine, mosapride, motilide, motretinide, cline, meclofenamate Sodium, mecloqualone, meclorisone moxalactam disodium, moxazocine, moxiraprine, moxnida dibutyrate, medazepam hydrochloride, medorinone, Zole, moXonidine, mumps skin testantigen, mustard antican medrogestone, medroxalol, medroxyprogesterone (commer cer agent, muZolimine, mycaperoxide B, mycophenolic acid, cially available as DEPO-PROVERAR) from Pfizer, Inc.), myriaporone, nabazenil, nabilone, nabitan hydrochloride, medrysone, meelizine hydrochloride, mefenamic acid, naboctate hydrochloride, nabumetone, n-acetyldinaline, mefenidil, mefenorex hydrochloride, mefexamide, meflo nadide, nadifloxacin, nadolol, nadroparin calcium, nafadot quine hydrochloride, mefruside, megalomicin potassium ride, nafamo.stat, nafarelin, nafcillin sodium, nafenopin, phosphate, megestrol acetate, meglumine, meglutol, nafimidone hydrochloride, naflocort, nafomine malate, melengestrol acetate, melitracen hydrochloride, melphalan, nafoxidine hydrochloride, nafronyl oxalate, naftifine hydro memotine hydrochloride, menabitan hydrochloride, menoc chloride, naftopidil, naglivan, nagreStip, nalbuphine hydro tone, menogaril, menotropins, meobentine Sulfate, mepartri chloride, nalidixate Sodium, nalidixic acid, nalmefene, cin, mepenZolate bromide, meperidine hydrochloride, nalmexone hydrochloride, naloxone/pentazocine, naltrex mephentermine Sulfate, mephenyloin, mephobarbital, mepi one, namoxyrate, nandrolone phenpropionate, nantradol vacaine hydrochloride, meprobamate, meptazinol hydrochlo hydrochloride, napactadine hydrochloride, napadisilate, ride, medulidox, meralein sodium, merbarone, mercaptopu napamezole hydrochloride, napavin, naphazoline hydro rine, mercufenol chloride, mercury, meropenem, chloride, naphterpin, naproxen, naproXol, napsagatran, nara mesalamine, meseclaZone, mesoridazine, mesterolone, nol hydrochloride, narasin, naratriptan, nartograstim, nasaru mestranol, meSuprine hydrochloride, metalol hydrochloride, plase, natamycin, nateplase, naxagolide hydrochloride, metaproterenol polistirex, metaraminol bitartrate, metaxa nebivolol, nebramycin, medaplatin, nedocromil, nefazodone lone, meteneprost, meterelin, metformin, methacholine chlo hydrochloride, neflumozide hydrochloride, nefopam hydro ride, methacycline, methadone hydrochloride, methadyl chloride, neleZaprine maleate, nemazoline hydrochloride, acetate, methalthiazide, methamphetamine hydrochloride, nemorubicin, neomycin palmitate, neostigmine bromide, methaqualone, methazolamide, methdilazine, methenamine, neridronic acid, netilmicin Sulfate, neutral endopeptidase, methenolone acetate, methetoin, methicillin Sodium, methi neutramycin, nevirapine, nexeridine hydrochloride, niacin, mazole, methioninase, methionine, methisaZone, methixene nibroxane, nicardipine hydrochloride, nicergoline, niclosa hydrochloride, methocarbamol, methohexital sodium, mide, nicorandil, nicotinyl alcohol, nicotine (commercially methopholine, methotrexate, methotrimeprazine, meth available as NICOTROL(R) NS from Pfizer, Inc.), nifedipine, Oxatone, methoxyflurane, methSuximide, methyclothiazide, nifirmerone, nifluridide, nifuradene, nifuraldezone, nifuratel, methyl 10 palmoxirate, methylatropine nitrate, methylbenze nifuratrone, nifurdazil, nifurimide, nifurpirinol, thonium chloride, methyldopa, methyldopate hydrochloride, nifurquinazol, nifurthiazole, nilutamide, nilvadipine, nima methylene blue, methylergonovine maleate, methylhista Zone, nimodipine, niperotidine, niravoline, niridazole, nisa mine, R-alpha, methylinosine monophosphate, methylpheni mycin, nisbuterol mesylate, nisin, nisobamate, nisoldipine, date hydrochloride, methylprednisolone, methyltestosterone, nisoxetine, nisterime acetate, nitarSone, nitaZoxamide, nite methynodiol diacelate, methysergide, methysergide maleate, capone, nitrafudam hydrochloride, nitralamine hydrochlo metiamide, metiapine, metioprim, metipamide, metipra ride, nitramisole hydrochloride, nitrazepam, nitrendipine, nolol, metizoline hydrochloride, metkephamid acetate, meto nitrocycline, nitrodan, nitrofurantoin, nitrofuraZone, nitro clopramide, metocurine iodide, metogest, metolaZone, glycerin, nitromersol, nitromide, nitromifene citrate, nitrous metopimazine, metoprine, metoprolol, metoquizine, metri oxide, nitroxide antioxidant, nitrullyn, nivaZol. nivimedone fonate, metrizamide, metrizoate Sodium, metronidazole, Sodium, nizatidine, noberastine, nocodazole, nogalamycin, meturedepa, metyrapone, metyrosine, mexiletine hydrochlo nolinium bromide, nomifensine maleate, noracymethadol ride, mexrenoate potassium, meZlocillin, mfonelic acid, hydrochloride, norbolethone, norepinephrinebitartrate, nore US 2014/005 1771 A1 Feb. 20, 2014 thindrone, norethynodrel, norfloxacin, norflurane, norgesti ride, phendimetrazine tartrate, phenelzine Sulfate, phenindi mate, norgestomet, norgestrel, nortriptyline hydrochloride, one, phenmetrazine hydrochloride, phenobarbital, phenoxy noscapine, novobiocin Sodium, N-Substituted benzaimides, benzamine hydrochloride, phenprocoumon, phenserine, nufenoXole, nylestriol, nystatin, O6-benzylguanine, obi phensuccinal, phensuximide, phentermine, phentermine doXime chloride, ocaperidone, ocfentanil hydrochloride, oci hydrochloride, phentolamine mesilate, phentoxifylline, phe naplon, octanoic acid, octaZamide, octenidine hydrochloride, nyl aminosalicylate, phenylacetate, phenylalanine, phenyla octodrine, octreotide, octriptyline phosphate, ofloxacin, lanyl ketoconazole, phenylbutaZone, phenylephrine hydro oformine, okicenone, olanzapine (commercially available as chloride, phenylpropanolamine hydrochloride, ZYPREXAR) from Eli Lilly and Company), oligonucle phenylpropanolamine polistirex, phenyramidol hydrochlo otides, olopatadine, olprinone, olsalazine, olsalazine Sodium, ride, phenyloin, phosphatase inhibitors, physostigmine, olvanil, omeprazole, onapristone, ondansetron, ontazolast, picenadol, picibanil, picotrin diolamine, picroliv, picume oocyte maturation inhibitor, opipramol hydrochloride, ora terol, pidotimod, pifamine, pilocarpine, pilsicamide, pimage cin, orconazole nitrate, orgotein, orlislat, ormaplatin, orme dine, pimetime hydrochloride, pimilprost, pimobendan, toprim, ornidazole, orpanoxin, orphenadrine citrate, osater pimozide, pinacidil, pinadoline, pindolol, pinnenol, pinoce one, otenZepad, oxacillin Sodium, oxagrelate, oxaliplatin, brin, pinoxepin hydrochloride, pioglitaZone (commercially oXamarin hydrochloride, oxamisole, oxamniquine, oxan available as ACTOSR) from Takeda Pharmaceuticals), pipam drolone, oxantel pamoate, oxaprotiline hydrochloride, perone, pipazethate, pipecuronium bromide, piperacetazine, oxaprozin, oxarbazole, Oxatomide, oxaunomycin, oxazepam, piperacillin Sodium, piperamide maleate, piperazine, pipo oXcarbazepine, Oxendolone, oxethazaine, oxetorone fuma broman, piposulfan, pipotiazine palmitate, pipoxolan hydro rate, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, chloride, piprozolin, piquindone hydrochloride, piquizil oxidopamine, oxidronic acid, oxifungin hydrochloride, hydrochloride, piracetam, pirandamine hydrochloride, pira oXilorphan, oximonam, oximonam sodium, OXiperomide, rubicin, piraZmonam Sodium, piraZolac, pirbenicillin oxiracetam, oxiramide, Oxisuran, oxmetidine hydrochloride, Sodium, pirbuterol acetate, piremperone, pirenzepine hydro oXodipine, oxogestone phenpropionate, oxolinic acid, Oxpre chloride, piretanide, pirfenidone, piridicillin Sodium, piridr nolol hydrochloride, oxtriphylline, oxybutynin chloride, oxy onate Sodium, piriprost, piritrexim, pirlimycin hydrochloride, chlorosene, oxycodone, oxymetazoline hydrochloride, pirlindole, pirmagrel, pirmenol hydrochloride, pirnabine, oxymetholone, oxymorphone hydrochloride, oxypertine, piroctone, pirodavir, pirodomast, pirogliride tartrate, pirolate, oxyphenbutaZone, oxypurinol, oxytetracycline, oxytocin, pirolaZamide, piroXantrone hydrochloride, piroxicam, oZagrel, oZolinone, paclitaxel, palauamine, paldimycin, pali piroximone, pirprofen, pirquinozol, pirsidomine, preny navir, paliperidone (commercially available as INVEGAR) lamine, pitavastatin (commercially available as LIVALOAR) from Janssen Pharmaceuticals, Inc.), paliperidone palmitate from Eli Lilly and Company), pituitary, posterior, pivampi (commercially available as INVEGAR SUSTENNAR) from cillin hydrochloride, pivopril, pizotyline, placetin A, plati Janssen Pharmaceuticals, Inc.), palmitoylrhizoxin, palmox num compounds, platinum-triamine complex, plicamycin, irate Sodium, pamaqueside, pamatolol Sulfate, pamicogrel, plomestane, pobilukast edamine, podofilox, poisonoak pamidronate disodium, pamidronic acid, panadiplon, pan extract, poldine methylsulfate, poliglusam, polignate Sodium, amesine, panaxytriol, pancopride, pancuronium bromide, polymyxin B sulfate, polythiazide, ponalrestat, porfimer panipenem, pannorin, panomifene, pantethine, pantoprazole, Sodium, porfiromycin, potassium chloride, potassium iodide, papaverine hydrochloride, parabactin, parachlorophenol, potassium permanganate, povidone-iodine, practolol, prali paraldehyde, paramethasone acetate, paranyline hydrochlo doXime chloride, pramiracetam hydrochloride, pramoxine ride, parapenzolate bromide, pararosaniline pamoate, par hydrochloride, pranolium chloride, prasugrel (commercially bendazole, parconazole hydrochloride, paregoric, pareptide available as EFFIENTR) from Eli Lilly and Company), pra Sulfate, pargyline hydrochloride, parnaparin Sodium, paro Vadoline maleate, pravastatin, prazepam, praZosin, praZosin momycin Sulfate, paroxetine (commercially available as hydrochloride, prednazate, prednicarbate, prednimustine, PAXILR) from GlaxoSmithKlein), parthenolide, partricin, prednisolone, prednisone, prednival, pregabalin (commer paulomycin, paZelliptine, paZinaclone, paZoxide, paZufloxa cially available as LYRICAR) from Pfizer, Inc.), preg cin, pefloxacin, pegaspargase, pegorgotein, pelanserin hydro nenolone Succiniate, prenalterol hydrochloride, pridefine chloride, peldesine, peliomycin, pelretin, pelrinone hydro hydrochloride, prifelone, prilocalne hydrochloride, prilosec, chloride, pemedolac, pemerid nitrate, pemetrexed, primaquine phosphate, primidolol, primidone, prinivil, pri pemirolast, pemoline, penamecillin, penbutolol sulfate, pen nomide tromethamine, prinoXodan, prizidilol hydrochloride, ciclovir, penfluridol, penicillin G benzathine, penicillin G proadifen hydrochloride, probenecid, probicromil calcium, potassium, penicillin G procaine, penicillin G Sodium, peni probucol, procainamide hydrochloride, procaine hydrochlo cillin V, penicillin V benzathine, penicillin V hydrabamine, ride, procarbazine hydrochloride, procaterol hydrochloride, penicillin V potassium, pentabamate, pentaerythritol tetrani prochlorperazine, procinonide, proclonol, procyclidine trate, pentafuside, pentamidine, pentamorphone, bentamus hydrochloride, prodilidine hydrochloride, prodolic acid, prof tine, pentapiperium methylsulfate, pentazocine, pentetic adol hydrochloride, progabide, progesterone, proglumide, acid, pentiapine maleate, pentigetide, pentisomicin, pentizi proinsulin human, proline, prolintane hydrochloride, pro done sodium, pentobarbital, pentomone, pentopril, pentosan, mazine hydrochloride, promethazine hydrochloride, pro pentostatin, pentoxifylline, pentrinitrol, pentroZole, peplo pafenone hydrochloride, propagermanium, propanidid, pro mycin Sulfate, pepstatin, perflubron, perfof amide, perfosfa pantheline bromide, proparacaine hydrochloride, propatyl mide, pergolide, perhexyline maleate, perillyl alcohol, perin nitrate, propentofylline, propenZolate hydrochloride, dopril, perindoprilat, perlapine, permethrin, peroSpirone, propikacin, propiomazine, propionic acid, propionylcar perphenazine, pethidine, phenacemide, phenaridine, phena nitine, propiram, propiram-paracetamol, propiverine, propo Zinomycin, phenazopyridine hydrochloride, phenbutaZone fol, propoxycaine hydrochloride, propoxyphene hydrochlo Sodium glycerate, phencarbamide, phencyclidine hydrochlo ride, propranolol hydrochloride, propulsid, propyl bis US 2014/005 1771 A1 Feb. 20, 2014

acridone, propylhexedrine, propyliodone, propylthiouracil, fide, selenomethionine se 75, selfotel, sematilide, semdu produaZone, prorenoate potassium, proroxan hydrochloride, ramicin, semotiadil, Semustine, sense oligonucleotides, sepa proscillaridin, prostalene, prostratin, protamine Sulfate, pro Zonium chloride, Seperidol hydrochloride, Seprilose, tegrin, protirelin, protoSufloxacin, protriptyline hydrochlo seproxetine hydrochloride, seractide acetate, Sergolexole ride, proxazole, proxazole citrate, proxicromil, proXorphan maleate, serine, sermetacin, sermorelin acetate, Sertacona tartrate, prulifloxacin, pseudoephedrine hydrochloride, Zole, sertindole, Sertraline, Setiptiline, Setoperone, Sevirumab, desloratadine/pseudoephedrine Sulfate (commercially avail sevoflurane, Sezolamide, Sibopirdine, sibutramine hydrochlo able as CLARINEX-DR) from Merck), puromycin, purpu ride, signal transduction inhibitors, silandrone, Sildenafil rins, pyrabrom, pyrantel, pamoate, pyrazinamide, pyrazofu (commercially available as VIAGRAR) from Pfizer Inc.), sil rin, pyrazoloacridine, pyridostigmine bromide, pyrilamine ipide, silteplase, silver nitrate, Simendan, SimtraZene, simv maleate, pyrimethamine, pyrinoline, pyrithione sodium, astatin (commercially available as ZOCORR) from Merck), pyrithione Zinc, pyrovalerone hydrochloride, pyroxamine sincalide, sinefungin, sinitrodil, sinnabidol, sipatrigine, maleate, pyrrocaine, pyrroliphene hydrochloride, pyrrolini Sirolimus, Sisomicin, Sitogluside, sizofuran, Sobuzoxane, trin, pyrvinium pamoate, quadazocine mesylate, quazepam, Sodium amylosulfate, Sodium iodide I 123, Sodium nitroprus quaZinone, quaZodine, quaZolast, quetiapine (commercially side, Sodium oxybate, Sodium phenylacetate, sodium salicy available as SEROQUEL(R) available from AstraZenica), qui late, Solverol, Solypertine tartrate, Somalapor, Somantadine flapon, quinagolide, quinaldine blue, quinapril, quinaprilat, hydrochloride, Somatomedin B, Somatomedin C, somatrem, quinaZosin hydrochloride, quinbolone, quinctolate, quinde Somatropin, somenopor, somidobove, Sonermin, Sorbinil, camine acetate, quindonium bromide, quinelorane hydro Sorivudine, Sotalol, Soterenol hydrochloride, sparfloxacin, chloride, quinestrol, quinfamide, quingestanol acetate, sparfosate sodium, Sparfosic acid, sparsomycin, Sparteine quingestrone, quinidine gluconate, quinielorane hydrochlo Sulfate, spectinomycin hydrochloride, spicamycin D, spiper ride, quinine Sulfate, quinpirole hydrochloride, quinterenol one, spiradoline mesylate, spiramycin, spirapril hydrochlo Sulfate, quinuclium bromide, quinupristin, quipazine male ride, spiraprilat, spirogermanium hydrochloride, Spiromus ate, rabeprazole Sodium, racephenicol, racepinephrine, raf tine, Spironolactone, Spiroplatin, spiroXasone, splenopentin, antagonists, rafoxamide, ralitoline, raloxifene, raltitrexed, spongistatin 1, Sprodiamide, squalamine, stallimycin hydro ramatroban, ramipril, ramoplanin, ramosetron, ranelic acid, chloride, Stannous pyrophosphate, Stannous Sulfur colloid, ranimycin, ranitidine, ranolazine, rauwolfia Serpentina, stanozolol, statolon, staurosporine, stavudine, Steffimycin, recainam, recainam hydrochloride, reclazepam, Stenbolone acetate, Stepronin, Stilbazium iodide, stilonium regavirumab, regramostim, relaxin, relomycin, remacemide iodide, stipiamide, stiripentol, stobadine, streptokinase, hydrochloride, remifentanil hydrochloride, remiprostol, streptomycin Sulfate, Streptonicozid, streptonigrin, Streptozo remoxipride, repirinast, repromicin, reproterol hydrochlo cin, stromelysin inhibitors, strontium chloride Sr 89, succi ride, reserpine, resinferatoxin, resorcinol, retelliptine dem bun, Succimer, Succinylcholine chloride, Sucralfate. Sucrosof ethylated, reticulon, reviparin Sodium, revizinone, rhenium re ate potassium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, 186 etidronate, rhizoxin, ribaminol, ribavirin, riboprine, Sulbactam pivoxil, Sulconazole nitrate, Sulfabenz, Sulfaben ribozymes, ricasetron, ridogrel, rifabutin, rifametane, Zamide, Sulfacetamide, Sulfacytine, Sulfadiazine, Sulfadox rifamexil, rifamide, rifampin, rifapentine, rifaximin, retina ine, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, mide, rilopiroX, riluzole, rimantadine, rimcazole hydrochlo Sulfamethizole, Sulfamethoxazole, Sulfamonomethoxine, ride, rimexolone, rimiterol hydrobromide, rimoprogin, rio Sulfamoxole, Sulfanilate Zinc, Sulfanitran, Sulfasalazine, Sul dipine, rioprostil, ripazepam, ripisartan, risedronate Sodium, fasomizole, Sulfazamet, Sulfinalol hydrochloride, Sulfinosine, risedronic acid, risocaine, risotilide hydrochloride, rispen Sulfinpyrazone, Sulfisoxazole, Sulfomyxin, Sulfonterol hydro Zepine, risperdal, risperidone, ritanserin, ritipenem, ritodrine, chloride, Sulfoxamine, Sulinldac, Sulmarin, Sulnidazole, ritolukast, ritonavir, rizatriptan benzoate, rocastine hydro Suloctidil, Sulofenur, Sulopenem, Suloxifen oxalate, Sulpiride, chloride, rocuronium bromide, rodocaine, roflurane, Sulprostone, Sultamicillin, Sulthiame, Sultopride, Sulukast, rogletimide, rohitukine, rokitamycin, roletamicide, rolgami Sumarotene, Sumatriptan, Suncillin Sodium, Suproclone, dine, rolicyprine, rolipram, rollitetracycline, rolodine, romaz Suprofen, Suradista, Suramin, Surfomer, Suricamide maleate, arit, romurtide, ronidazole, ropinirole (commercially avail SuritoZole, Suronacrine maleate, Suxemerid Sulfate, Swainso able as REQUIPR) from GlaxoSmithKline), ropitoin nine, Symakalim, symclosene, Symetine hydrochloride, Syn hydrochloride, ropivacaine, ropizine, roquinimex, rosarami thetic glycosaminoglycans, tadalafil (commercially available cin, roSoxacin, rotoxamine, rosuvastatin (commercially as CIALISR) and ACIRCAR) from from Eli Lilly and Com available as CRESTORR) available from AstraZeneca), pany), taciamine hydrochloride, tacrine hydrochloride, tac roXaitidine, roXarsone, roXindole, roXithromycin, rubiginone rolimus, talampicillin hydrochloride, taleranol, talisomycin, B1, ruboxyl, rufloxacin, rupatidine, rutamycin, ruzadolane, tallimustine, talmetacin, talniflumate, talopram hydrochlo sabeluzole, Safingol, Safironil, Saintopin, Salbutamol, sal ride, talosalate, tametraline hydrochloride, tamoxifen (com colex, Salethamide maleate, salicyl alcohol, salicylamide, mercially available as NOLVADEXR) from AstraZeneca), salicylate meglumine, Salicylic acid, Salmeterol, Salnacedin, tampramine fumarate, tamsulosin hydrochloride, tandamine Salsalate, sameridine, Sampatrilat, Sancycline, Sanfetrinem, hydrochloride, tandospirone, tapgen, taprostene, tasosartan, sanguinarium chloride, Saperconazole, saprisartan, saprop tauromustine, taxane, taxoid, tazadolene Succinate, tazano terin, saquinavir, Sarafloxacin hydrochloride, Saralasin last, tazarotene, tazifylline hydrochloride, taZobactam, acetate, SarCNU, sarcophytol A, SargramoStim, Sarmoxicil tazofelone, tazolol hydrochloride, tebufelone, tebuquine, lin, Sarpicillin, Sarpogrelate, Saruplase, Saterinone, satigrel, technetium Tc 99 m bicisate, teclozan, tecogalan Sodium, Satumomab pendetide, Schick test control, scopafungin, Sco teecleukin, teflurane, tegafur, tegretol, teicoplanin, telen polamine hydrobromide, ScraZaipine hydrochloride, Sdi 1 Zepine, tellurapyrylium, telmesteine, telmisartan, telomerase mimetics, secalciferol, secobarbital. Seelzone, seglitide inhibitors, teloxantrone hydrochloride, teludipine hydrochlo acetate, selegiline, selegiline hydrochloride, selenium Sul ride, temafloxacin hydrochloride, tematropium methyl Sul US 2014/005 1771 A1 Feb. 20, 2014 fate, temazepam, temelastine, temocapril, temocillin, hydrochloride, trimegestone, trimeprazine tartrate, tri temoporfin, temozolomide, tenofovir, tenidap, teniposide, methadione, trimethaphan camsylate, trimethobenzamide tenosal, tenoxicam, tepirindole, tepoxalin, teprotide, tera hydrochloride, trimethoprim, trimetozine, trimetrexate, Zosin, terbinafine, terbutaline sulfate (commercially available trimipramine, trimoprostil, trimoxamine hydrochloride, tri as BRICANYL(R) from AstraZeneca), terconazole, terfena olein 1 125, triolein 1131, trioxifene mesylate, tripamide, dine, terflavoxate, terguride, teriparatide acetate, terlakiren, tripelennamine hydrochloride, triprolidine hydrochloride, terlipressin, terodiline, teroxalene hydrochloride, teroxirone, triptorelin, trisulfapyrimidines, troclosene potassium, trogli tertatolol, terutroban, tesicam, tesimide, testolactone, test taZone, trolamine, troleandomycin, trombodipine, trometa osterone, tetracaine, tetrachlorodecaoxide, tetracycline, tet mol, tropanserin hydrochloride, tropicamide, tropine ester, rahydrozoline hydrochloride, tetramisole hydrochloride, tet tropisetron, trospectomycin, trovafloxacin, troVirdine, tryp razolast meglumine, tetraZomine, tetrofosmin, tetroquinone, tophan, tuberculin, tubocurarine chloride, tubulozole hydro tetroxoprim, tetrydamine, thaliblastine, thalidomide, theofi chloride, tucarcsol, tulobuterol, turosteride, tybamate, tylo brate, theophylline, thiabendazole, thiamiprine, thiampheni genin, tyropanoate Sodium, tyrosine, tyrothricin, tyrphostins, col, thiamylal, thiazesim hydrochloride, thiazinamium chlo ubenimex, uldazepam, undecylenic acid, uracil mustard, ura ride, thiazolidinedione, thiethylperazine, thimerfonate pidil, urea, uredepa, uridine triphosphate, urofollitropin, Sodium, thimerosal, thiocoraline, thiofedrine, thioguanine, urokinase, ursodiol, Valaciclovir, Valine, Valnoctamide, Val thiomarinol, thiopental Sodium, thioperamide, thioridazine, proate Sodium, Valproic acid, Valsartan (commercially avail thiotepa, thiothixene, thiphenamil hydrochloride, thiphencil able as DIOVANR) from Novartis Pharmaceuticals), vamica lin potassium, thiram, thozalinone, threonine, thrombin, mide, Vanadeine, Vancomycin, Vaminolol, Vapiprost thrombopoietin, thrombopoietin mimetic, thromboxane Syn hydrochloride, vapreotide, Vardenafil (commercially avail thase inhibitors, thromboxane receptor, antagonists, thymal able as LEVITRAR) from GlaxoSmithKline), variolin B, fasin, thymopoietin receptor agonist, thymotrinan, thyrom vasopressin, Vecuronium bromide, Velaresol, Velnacrine edan hydrochloride, thyroxine 1 125, thyroxine 1 131, maleate, Venlafaxine, Veradoline hydrochloride, Veramine, tiacrilast, tiacrilast sodium, tiagabine, tiamenidine, tianept Verapamil hydrochloride, verdins, verilopam hydrochloride, ine, tiapafant, tiapamil hydrochloride, tiaramide hydrochlo Verlukast, Verofylline, Veroxan, Verteporfin, Vesnarinone, ride, tiazofurin, tibenelast sodium, tibolone, tibric acid, tica vexibinol, Vidarabine, vigabatrin, viloxazine hydrochloride, besone propionate, ticarbodine, ticarcillin cresyl Sodium, vinblastine Sulfate, vinburnine citrate, Vincofos, Vinconate, ticagrelor, ticlopidine, ticlatone, ticlopidine, ticrynafen, Vincristine Sulfate, vindesine, vindesine Sulfate, vinepidine tienoxolol, tifurac sodium, tigemonam dicholine, tigestol, sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorel tiletamine hydrochloride, tilidine hydrochloride, tilisolol, til bine, Vinpocetine, Vintoperol, Vinxaltine, Vinzolidine Sulfate, noprofen arbamel, tillorone hydrochloride, tiludronate diso Viprostol, Virginiamycin, viridofulvin, ViroXime, vitaxin, dium, tiludronic acid, timefurone, timobesone acetate, Volazocine, Voriconazole, Vorozole, VOXergolide, warfarin timolol, tin ethyl etiopurpurin, tinabinol, tinidazole, tinza Sodium, Xamoterol, Xanomeline, XanoXate Sodium, Xanthinol parin Sodium, tioconazole, tiodaZosin, tiodonium chloride, niacinate, Xemilofiban, Xenalipin, Xenbucin, Xilobam, Ximo tioperidone hydrochloride, tiopinac, tioSpirone hydrochlo profen, Xipamide, Xorphanol mesylate, Xylamidine tosylate, ride, tiotidine, tiotropium bromide, tioxidazole, tipentosin xylazine hydrochloride, Xylometazoline hydrochloride, hydrochloride, tipredane, tiprenolol hydrochloride, tiprinast Xylose, yangambin, Zabicipril, Zacopride, Zafirlukast, Zalcit meglumine, tipropidil hydrochloride, tiqueside, tiquinamide abine, Zaleplon, Zalospirone, Zaltidine hydrochloride, Zalto hydrochloride, tirandalydigin, tirapazamine, tirilazad, profen, Zanamivir, Zankiren, Zanoterone, Zantac, Zarirlukast, tirofiban, tiropramide, titanocene dichloride, tixanox, tiXo Zatebradine, Zatosetron, Zatosetron maleate, Zenarestat, Zena cortol pivalate, tizanidine hydrochloride, tobramycin, tocam Zocine mesylate, Zeniplatin, Zeranol, Zidometacin, Zidovu ide, tocamphyl, tofenacin hydrochloride, tolamolol, tolaza dine, Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine mide, tolazoline hydrochloride, tolbutamide, tolcapone, hydrochloride, Zinc undecylenate, Zindotrine, Zinoconazole tolciclate, tolfamide, tolgabide, lamotrigine, tolimidone, hydrochloride, Zinostatin, Zinterol hydrochloride, Zin tolindate, tolmetin, tolnaftate, tolpovidone 1 131, tolpyrra ViroXime, Ziprasidone, Zobolt, Zofenopril calcium, Zofenop mide, tolrestat, tomelukast, tomoxetine hydrochloride, tona rilat, Zolamine hydrochloride, Zolazepam hydrochloride, Zocine mesylate, topiramate, topotecan, topotecan hydro Zoledronie acid, Zollertine hydrochloride, Zolmitriptan, Zolpi chloride, top sentin, topterone, toguizine, torasemide, dem, Zomepirac sodium, Zometapine, ZonicleZole hydrochlo toremifene, torsemide, tosifen, to Sufloxacin, totipotent stem ride, Zonisamide, Zopiclone, Zopolrestat, Zorbamycin, Zoru cell factor, tracazolate, trafermin, tralonide, tramadol hydro bicin hydrochloride, Zotepine, Zucapsaicin, JTT-501 (PNU chloride, tramazoline hydrochloride, trandolapril, tranex 182716) (reglitazar), AR-HO39122, MCC-555 amic acid, tranilast, transcamide, translation inhibitors, tras (netoglitazone), AR-HO49020 (tesaglitazar), CS-011 (CI tuzumab (commercially available as HERCEPTINR) from 1037), GW-409544x, KRP-297, RG-12525, BM-15.2054, Genentech), traXanox, traZodone hydrochloride, traZodone CLX-0940, CLX-0921, DRF-2189, GW-1929, GW-9820, hcl, trebenzomine hydrochloride, trefentanil hydrochloride, LR-90, LY-510929, NIP-221, NIP-223, JTP-20993, LY treloxinate, trepipam maleate, trestolone acetate, tretinoin, 29311 Na, FK 614, BMS 298.585, R 483, TAK 559, DRF triacetin, triacetyluridine, triafungin, triamcinolone, triampy 2725 (ragaglitazar), L-686398, L-168049, L-805645, Zine Sulfate, triamterene, triazolam, tribenoside, tricaprilin, L-054852, demethyl asteriquinone B1 (L-783281), tricetamide, trichlormethiazide, trichohyalin, triciribine, L-363586, KRP-297, P32/98, CRE-16336, EML-1625, phar tricitrates, triclofenol piperazine, triclofos sodium, triclonide, maceutically acceptable salts thereof (e.g., Zn, Fe,Mg, K, Na, trientine, trifenagrel, triflavin, triflocin, triflubazam, triflumi F, CI, Br, I, acetate, diacetate, nitrate, nitrite, sulfate, sulfite, date, trifluoperazine hydrochloride, trifluperidol, triflupro phosphate, and phosphite salts), pharmaceutically acceptable mazine, triflupromazine hydrochloride, trifluridine, trihex forms thereof with acid associates (e.g. HCl), and any com yphenidyl hydrochloride, triloStane, trimaZosin bination thereof. US 2014/005 1771 A1 Feb. 20, 2014

0096 Suitable antibiotics for use in conjunction with the 0.098 Suitable active biologicals for use in conjunction molded polyethylene components of the present invention with the molded polyethylene components of the present may include, but are not limited to, to B-lactam antibiotics invention may include, but are not limited to, hormones (Syn (e.g., benZathine penicillin, benzylpenicillin (penicillin G). thetic or natural and patient derived or otherwise), DNAS phenoxymethylpenicillin (penicillin V), procaine penicillin, (synthetic or natural and patient derived or otherwise), RNAs methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flu (synthetic or natural and patient derived or otherwise), siR cloxacillin, temocillin, amoxicillin, amplicillin, co-amoxiclav NAs (synthetic or natural and patient derived or otherwise), (amoxicillin+clavulanic acid), azlocillin, carbenicillin, ticar proteins and peptides (e.g., albumin, atrial natriuretic factor, cillin, mezlocillin, piperacillin, cephalosporin, cephalexin, renin, Superoxide dismutase, C.-1-antitrypsin, lung Surfactant cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, proteins, bacitracin, bestatin, cydosporine, delta sleep-induc cefotetan, cefoxitin, ceftriaxone, cefotaxime, cefpodoxime, ing peptide (DSIP), endorphins, glucagon, gramicidin, mel cefixime, ceftazidime, cefepime, cefpirome, carbapenem, anocyte inhibiting factors, neurotensin, oxytocin, Somostatin, imipenem (with cilastatin), meropenem, ertapenem, faro terprotide, serum thymide factor, thymosin, DDAVP, dermor penem, doripenem, aztreonam (commercially available as phin, Met-enkephalin, peptidoglycan, Satietin, thymopentin, AZACTAM(R) from Bristol-Myers Squibb), tigemonam, fibrin degradation product, des-enkephalin-C-endorphin, nocardicinA, tabtoxinine-B-lactam, clavulanic acid, taZobac gonadotropin releasing hormone, leuprolide, C-MSH, and tam, and Sulbactam); aminoglycoside antibiotics (e.g., ami metkephamid), enzymes, nucleotides, oligionucleotides, noglycoside, amikacin, apramycin, arbekacin, astromicin, antibodies, monoclonal antibodies, growth factors (e.g., epi bekanamycin, capreomycin, dibekacin, dihydrostreptomy dermal growth factor (EGF), fibroblast growth factors, basic cin, elsamitrucin, G418, gentamicin, hygromycin B, isepami fibroblast growth factor (bFGF), nerve growth factor (NGF), cin, kanamycin, kasugamycin, micronomicin, neomycin, bone derived growth factor (BDGF), transforming growth netilmicin, paromomycin Sulfate, ribostamycin, sisomicin, factors, transforming growth factor-B1 (TGF-B1), and human streptoduocin, streptomycin, tobramycin, Verdamicin; Sul growth hormone (hGH)), viral Surface antigens (e.g., aden fonamides such as Sulfamethoxazole, Sulfisomidine (also oviruses, epstein-barr virus, hepatitis. A virus, hepatitis B known as Sulfaisodimidine), Sulfacetamide, Sulfadoxine, virus, herpes viruses, HIV-1, HIV-2, HTLV-III, influenza dichlorphenamide (DCP), and dorzolamide); quinolone anti viruses, Japanese encephalitis virus, measles virus, papilloma biotics (e.g., cinobac, flumequine, nalidixic acid, oxolinic viruses, paramyxoviruses, polio virus, rabies virus, rubella acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxa virus, vaccinia (Smallpox) viruses, and yellow fever virus), cin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, nor bacterial Surface antigens (e.g., bordetella pertussis, helico floxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gre bacter pylorn, clostridium tetani, corynebacterium diphthe pafloxacin, levofloxacin, paZufloxacin, sparfloxacin, ria, escherichia coli, haemophilus influenza, klebsiella spe temafloxacin, to Sufloxacin, clinafloxacin, gatifloxacin, gemi cies, legionella pneumophila, mycobacterium bovis, floxacin, moxifloxacin, sitafloxacin, trovafloxacin, pruli mycobacterium leprae, mycrobacterium tuberculosis, neis floxacin, garenoxacin, and delafloxacin); oxazolidone antibi seria gonorrhoeae, neisseria meningitidis, proteus species, otics (e.g., lineZolid, toreZolid, eperezolid, posiZolid, and pseudomonas aeruginosa, Salmonella species, Shigella Spe radeZolid), and any combination thereof. cies, Staphylococcus aureus, Streptococcus pyogenes, vibrio cholera, and versinia pestis), parasite Surface antigens (e.g., 0097 Suitable antifungals for use in conjunction with the plasmodium viva-malaria, plasmodium falciparum-malaria, molded polyethylene components of the present invention plasmodium ovale-malaria, plasmodium malariae-malaria, may include, but are not limited to, polyene antifungals (e.g., leishmania tropica-leishmaniasis, leishmania donovani, natamycin, rimocidin, filipin, nystatin, amphotericin B, can leishmaniasis, leishmania branziliensis-leishmaniasis, trypa dicin, and hamycin; imidazole antifungals such as micona nosoma rhodescense—sleeping sickness, trypanosoma gam zole (commercially available as MICATINR) from Well biense—sleeping sickness, trypanosoma Cruzi—Chagas Spring Pharmaceutical Corporation), ketoconazole disease, Schistosoma mansoni-Schistosomiasis, schistoso (commercially available as NIZORAL(R) from McNeil con moma haematobium-schistomiasis, Schistosoma japonicum Sumer Healthcare), clotrimazole (commercially available as shichtomiasis, trichinella spiralis-trichinosis, stronglyloides LOTRAMIN(R) and LOTRAMINAF(R) available from Merck duodenale hookworm, ancyclostoma duodenale hook and CANESTENR) available from Bayer), econazole, omo worm, necator americanus—hookworm, wucheria ban conazole, bifonazole, butoconazole, fenticonazole, isocona crofti-filariasis, brugia malaya-filariasis, loa loa-filariasis, Zole, oxiconazole, Sertaconazole (commercially available as dipetalonema perstaris-filariasis, dracuncula medimensis-fi ERTACZOR) from OrthoDematologics), sulconazole, and lariasis, and Onchocerca volvulus-filariasis), immunogobu tioconazole; triazole antifungals such as fluconazole, itra lins (e.g., IgG, IgA, IgM, antirabies immunoglobulin, and conazole, isaVuconazole, raVuconazole, posaconazole, Vori antivaccinia immunoglobulin), and any combination thereof. conazole, terconazole, and albaconazole), thiazole antifun gals (e.g., abafungin), allylamine antifungals (e.g., 0099 Suitable antitoxins for use in conjunction with the terbinafine (commercially available as LAMISIL(R) from molded polyethylene components of the present invention Novartis Consumer Health, Inc.), naftifine (commercially may include, but are not limited to, botulinum antitoxin, available as NAFTINR) available from Merz Pharmaceuti diphtheria antitoxin, gas gangrene antitoxin, tetanus anti cals), and butenafine (commercially available as LOTRA toxin, and any combination thereof. MINULTRAR) from Merck), echinocandinantifungals (e.g., 0100 Suitable antigens for use in conjunction with the anidulafungin, caspofungin, and micafungin), polygodial, molded polyethylene components of the present invention benzoic acid, ciclopirox, tolnaftate (e.g., commercially avail may include, but are not limited to, hormones and growth able as TINACTINR) from MDS Consumer Care, Inc.), unde factors (e.g., follicle stimulating hormone, prolactin, angio cylenic acid, flucytosine, 5-fluorocytosine, griseofulvin, genin, epidermal growth factor, calcitonin, erythropoietin, haloprogin, and any combination thereof. thyrotropic releasing hormone, insulin, growth hormones, US 2014/005 1771 A1 Feb. 20, 2014

insulin-like growth factors 1 and 2, skeletal growth factor, 0.108 D: a method that comprises providing a polyethyl human chorionic gonadotropin, luteinizing hormone, nerve ene composition melt that comprises polyethylene having a growth factor, adrenocorticotropic hormone (ACTH), lutein melt flow index of about 3.5 g/10 minor greater as measured izing hormone releasing hormone (LHRH), parathyroid hor by ASTM D1238 at 190° C./21.5 kg weight and having anash mone (PTH), thyrotropin releasing hormone (TRH), vaso content of about 500 ppm or less; and injection molding the pressin, cholecystokinin, and corticotropin releasing polyethylene composition melt to form a molded polyethyl hormone), cytokines (e.g., interferons, interleukins, colony ene component of a biomedical device; stimulating factors, and tumor necrosis factors: fibrinolytic 0109 E: a method that comprises providing a component enzymes, such as urokinase, kidney plasminogen activator), of a biomedical device; and Substantially encasing the com clotting factors (e.g., Protein C, Factor VIII, Factor IX, Factor ponent in polyethylene having a melt flow index of about 3.5 VII and Antithrombin III), and any combination thereof. g/10 min or greater as measured by ASTM D1238 at 190° 0101 Suitable nutritional supplements for use in conjunc C./21.5 kg weight and having an ash content of about 500 tion with the antigents present invention may include, but are ppm or less; not limited to, vitamins, minerals, herbs, botanicals, amino 0110 F: a method that comprises providing a sheet com acids, steroids, and the like. prising a polyethylene composition that comprises polyeth 0102 Suitable nutraceuticals for use in conjunction with ylene having a melt flow index of about 3.5 g/10 min or the molded polyethylene components present invention may greater as measured by ASTM D1238 at 190° C./21.5 kg include, but are not limited to, dietary Supplements, botani weight and having an ash content of about 500 ppm or less; cals, functional foods and extracts thereof, medicinal foods and thermoforming the sheet into a molded polyethylene and extracts thereof, vitamins, minerals, co-enzyme Q, car component of a biomedical device; and nitine, multi-mineral formulas, gingseng, gingko biloba, saw 0111 G: a method that comprises providing a sheet com palmetto, other plant-based Supplements, probiotics, omega prising a polyethylene composition that comprises polyeth 3, canola and other oils, plant stanols, natural Sweeteners, ylene having a melt flow index of about 3.5 g/10 min or mushroom extracts, chocolate, chocolate extracts, grape greater as measured by ASTM D1238 at 190° C./21.5 kg extracts, berry extracts, Super food extracts, quillaja molina weight and having an ash content of about 500 ppm or less; extracts, plant extracts, yucca Schidigera extract, bran, ala and shrink wrapping the sheet onto a portion of a biomedical nine, beta-carotene, carotenoids, arginin, vitamin A, aspar device or component thereof, and agine, Vitamin B-complex, aspartate, vitamin C, leucine, iso 0112 H: a method that comprises polymerizing at least leucine, valine, Vitamin D, citrulline, vitamin E, cysteine, one olefin in the presence of a catalyst so as to form polyeth Vitamin K, glutamine, minerals, micro-nutrients, glutamic ylene having a melt flow index of about 3.5 g/10 min or acid, calcium, glycine, chromium, histidine, copper, lysine, greater as measured by ASTM D1238 at 190° C./21.5 kg iodine, methionine, iron, ornithine, magnesium, phenylala weight, the at least one olefin being selected from the group nine, potassium, proline, selenium, serine, Zinc, taurine, consisting of ethylene, propylene, and/or butylene, and any threonine, alpha lipoic acid, tryptophan, green tea extracts, combination thereof, and treating the polyethylene to yield a tyrosine, essential fatty acids (EFA), whey protein, flaxseed treated polyethylene having an ash content of about 500 ppm oil, and any combination thereof. or less. 0103) A typical dosage of APIs may range from about 0113. Each of embodiments A-G may independently have 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 one or more of the following additional elements in any mg/kg to about 100 mg/kg, and more preferably from about combination: Element 1: the polyethylene having a specific 0.10 mg/kg to about 20 mg/kg, relative to weight of the gravity of about 0.93 g/cm3 to about 0.97 g/cm; Element 2: patient. In some embodiments, an API may be used alone or the polyethylene having an average molecular weight of in combination with another API. One skilled in the art should about 30,000 g/mol to about 2,500,000 g/mol; Element 3: the understand the dose and/or combination of agents should be polyethylene comprising a copolymer of ethylene and at least chosen so as to minimize adverse interactions. one monomer selected from the group consisting of propy 0104 Embodiments disclosed herein include: lene, butylene, and any combination thereof; Element 4: the 0105 A: a biomedical device that comprises a molded polyethylene being crosslinked; Element 5: the polyethylene polyethylene component that comprises a polyethylene com composition being foamed; Element 6: the molded polyeth position that comprises polyethylene having a melt flow ylene component is nonload-bearing; Element 7: the bio index of about 3.5 g/10 minor greater as measured by ASTM medical device being nonload-bearing or load-bearing; Ele D1238 at 190° C./21.5 kg weight and having anash content of ment 8: the polyethylene composition further comprising an about 500 ppm or less; active pharmaceutical ingredient; Element 9: the polyethyl 0106 B: a biomedical device that comprises a conduit that ene composition further comprising an imaging agent; Ele comprises at least one wall defining an internal Volume, the at ment 10: the polyethylene composition further comprising at least one wall comprising: polyethylene having a melt flow least one selected from the group consisting of a second index of about 3.5 g/10 minor greater as measured by ASTM polymer, a plasticizer, a compatibilizer, an antioxidant, a D1238 at 190° C./21.5 kg weight and having anash content of reinforcing filler, a pigment, a dye, a radioopaque filler, a about 500 ppm or less; lubricant, a processing aid, a light stabilizer, a neutralizer, an 0107 C: a method that comprises providing a polyethyl antiblock, and any combination thereof; Element 11: the ene composition melt that comprises polyethylene having a molded polyethylene component (or the like, e.g., a sheet) melt flow index of about 3.5 g/10 minor greater as measured further comprising a reinforcing structure, wherein the poly by ASTM D1238 at 190° C./21.5 kg weight and having anash ethylene composition is disposed on at least a portion of a content of about 500 ppm or less; and extruding the polyeth surface of the reinforcing structure; Element 12: the biomedi ylene composition melt to form a molded polyethylene com cal device further comprising other components, and wherein ponent of a biomedical device; the molded polyethylene component Substantially encases US 2014/005 1771 A1 Feb. 20, 2014

the other components: Element 13: the biomedical device ous components or steps, the compositions and methods can being at least one selected from the group consisting of a chip, also “consist essentially of or “consist of the various com an RFID tag, tubing, a pump, a feeding tube, a catheter, a ponents and steps. All numbers and ranges disclosed above vascular catheter, a prosthetic, an inflatable balloon, a stent, a may vary by some amount. Whenever a numerical range with heart valve, a neurostimulator, a cochlear implant, a cranio a lower limit and an upper limit is disclosed, any number and maxillofacial implant, synthetic cartilage, a stomach ring, a any included range falling within the range is specifically Surgical instrument, a blood vessel clamp, an aneurysm clip, disclosed. In particular, every range of values (of the form, a spinal plug for use in conjunction with a joint fusion system, “from about a to about b,” or, equivalently, “from approxi a base-plate stem cap for an artificial joint, a muscle implant, mately a to b, or, equivalently, “from approximately a-b) a nasopharyngeal implant, and a laryngeal implant, a drug disclosed herein is to be understood to set forth every number delivery device, a transdermal patch, a Subdermal implant, an and range encompassed within the broader range of values. oromucosal insert, an intrauterine device, an intravaginal Also, the terms in the claims have their plain, ordinary mean ring, and a dental fiber; Element 14: the biomedical device ing unless otherwise explicitly and clearly defined by the being in a kit with a set of instructions: Element 15: implant patentee. Moreover, the indefinite articles “a” or “an,” as used ing the biomedical device in a patient; and Element 16: treat in the claims, are defined hereinto mean one or more than one ing a patient with the biomedical device. Embodiment H may of the element that it introduces. If there is any conflict in the have one or more of the following additional elements in any usages of a word or term in this specification and one or more combination: Element 17: the treated polyethylene having a patent or other documents that may be incorporated herein by specific gravity of about 0.93 g/cm3 to about 0.97 g/cm; reference, the definitions that are consistent with this speci Element 18: the treated polyethylene having an average fication should be adopted. molecular weight of about 30,000 g/mol to about 2,500,000 1. A biomedical device comprising: g/mol; Element 19: treating involves exposing the polyethyl a molded polyethylene component that comprises a poly ene concurrently or in series to at least one selected from the ethylene composition that comprises polyethylene hav group consisting of steam, an inert Solvent the catalyst is at ing a melt flow index of about 3.5 g/10 minor greater as least partially soluble in, an acid, acetone, water, a haloge measured by ASTM D1238 at 190° C./21.5 kg weight nated solvent, and any combination thereof; Element 20: and having an ash content of about 500 ppm or less. treating involves increased temperature and/or decreased 2. The biomedical device of claim 1, wherein the polyeth pressure; and Element 21: forming a molded polyethylene ylene has a specific gravity of about 0.93 g/cm to about 0.97 component of a biomedical device from the treated polyeth g/cm. ylene. 3. The biomedical device of claim 1, wherein the polyeth 0114. By way of non-limiting example, exemplary com ylene has an average molecular weight of about 30,000 g/mol binations independently applicable to embodiments A-G to about 2,500,000 g/mol. include: at least two of Elements 1-6 in combination; Element 4. The biomedical device of claim 1, wherein the polyeth 8 in combination with at least one of Elements 1-6: Element ylene comprises a copolymer of ethylene and at least one 9 in combination with at least one of Elements 1-6: Element monomer selected from the group consisting of propylene, 10 in combination with at least one of Elements 1-6: Element butylene, and any combination thereof. 13 incombination with at least one of Elements 1-6: Elements 5. The biomedical device of claim 1, wherein the polyeth 8 and 13 in combination with at least one of Elements 1-6. ylene is crosslinked. Elements 9 and 13 in combination with at least one of Ele 6. The biomedical device of claim 1, wherein the polyeth ments 1-6: Element 1 in combination with Element 4: Ele ylene composition is foamed. ments 10 and 13 in combination with at least one of Elements 7. The biomedical device of claim 1, wherein the molded 1-6: Element 13 in combination with at least two of Elements polyethylene component is nonload-bearing. 8-10 and at least one of Elements 1-6: Element 14 in combi 8. The biomedical device of claim 1, wherein the biomedi nation with the foregoing any of the combinations; Element cal device is nonload-bearing. 15 in combination with the foregoing any of the combina 9. The biomedical device of claim 1, wherein the biomedi tions: Element 16 in combination with the foregoing any of cal device is load-bearing. the combinations; and so on. 10. The biomedical device of claim 1, wherein the molded 0115 Therefore, the present invention is well adapted to polyethylene component has been formed into a desired attain the ends and advantages mentioned as well as those that shape from a polyethylene composition melt that comprises are inherent therein. The particular embodiments disclosed the polyethylene. above are illustrative only, as the present invention may be 11. The biomedical device of claim 1, wherein the poly modified and practiced in different but equivalent manners ethylene composition further comprises an active pharma apparent to those skilled in the art having the benefit of the ceutical ingredient. teachings herein. Furthermore, no limitations are intended to 12. The biomedical device of claim 1, wherein the poly the details of construction or design herein shown, other than ethylene composition further comprises an imaging agent. as described in the claims below. It is therefore evident that 13. The biomedical device of claim 1, wherein the poly the particular illustrative embodiments disclosed above may ethylene composition further comprises at least one selected be altered, combined, or modified and all such variations are from the group consisting of a second polymer, a plasticizer, considered within the scope and spirit of the present inven a compatibilizer, an antioxidant, a reinforcing filler, a pig tion. The invention illustratively disclosed herein suitably ment, a dye, a radioopaque filler, a lubricant, a processing aid, may be practiced in the absence of any element that is not a light stabilizer, a neutralizer, an antiblock, and any combi specifically disclosed herein and/or any optional element dis nation thereof. closed herein. While compositions and methods are described 14. The biomedical device of claim 1, wherein the molded in terms of "comprising.” “containing,” or “including vari polyethylene component further comprises a reinforcing US 2014/005 1771 A1 Feb. 20, 2014 20 structure, wherein the polyethylene composition is disposed 31. A method comprising: on at least a portion of a surface of the reinforcing structure. treating a patient with the biomedical device of claim 21. 15. The biomedical device of claim 14, wherein the rein 32. A method comprising: forcing structure comprises at least one selected from the providing a polyethylene composition melt that comprises group consisting of ultra high molecular weight polyethyl polyethylene having a melt flow index of about 3.5 g/10 ene, a metal, a metal alloy, a ceramic, and any combination min or greater as measured by ASTM D1238 at 190° thereof. C./21.5 kg weight and having an ash content of about 16. The biomedical device of claim 1, wherein the bio 500 ppm or less; and medical device further comprises other components, and extruding the polyethylene composition melt to form a wherein the molded polyethylene component substantially molded polyethylene component of a biomedical encases the other components. device. 17. The biomedical device of claim 1 being at least one 33. The method of claim 32, wherein the polyethylene selected from the group consisting of a chip, an RFID tag, composition melt further comprises an additive that com tubing, a pump, a feeding tube, a catheter, a vascular catheter, prises at least one selected from the group consisting of a a prosthetic, an inflatable balloon, a stent, a heart valve, a plasticizer, a compatibilizer, an active pharmaceutical ingre neurostimulator, a cochlear implant, a cranio-maxillofacial dient, a contrast agent, an antioxidant, a reinforcing filler, a implant, synthetic cartilage, a stomach ring, a Surgical instru pigment, a dye, a radioopaque filler, a lubricant, a processing ment, a blood vessel clamp, an aneurysm clip, a spinal plug aid, a light stabilizer, a neutralizer, an antiblock, and any for use in conjunction with a joint fusion system, a base-plate combination thereof. stem cap for an artificial joint, a muscle implant, a nasopha 34. The method of claim 32, wherein the polyethylene ryngeal implant, a laryngeal implant, a drug delivery device, composition melt further comprises at least one second poly a transdermal patch, a Subdermal implant, an oromucosal mer selected from the group consisting of a polyethylene, insert, an intrauterine device, an intravaginal ring, and aden linear low density polyethylenes, low density polyethylenes, tal fiber. a polypropylene, a graft-modified olefin polymer, a chlori 18. A kit comprising the biomedical device of claim 1 and nated polyethylene, a thermoplastic Vulcanizate, a polyether a set of instructions. ether ketone, a polyisoprene, a polyester, a polyamide, an 19. A method comprising: ethylene vinyl acetate copolymer, an ethylene vinyl-meth implanting the biomedical device of claim 1 into a patient. acrylate copolymer, a silicone, a polyethylene glycol, poly 20. A method comprising: lactic acid, poly glycolic acid, polyethylene imine, a polyure treating a patient with the biomedical device of claim 1. thane, polyacrylonitrile, a styrene block copolymer, a rubber, 21. A biomedical device comprising: an ethylene-carboxylic acid copolymer, an ethylene acrylate a conduit that comprise at least one wall defining an inter copolymer, polybutylene, polybutadiene, a nylon, a polycar nal Volume, the at least one wall comprising: bonate, an ethylene ethylacrylate polymer, an ethylene Sty polyethylene having a melt flow index of about 3.5 g/10 rene interpolymer, any derivative thereof, any copolymer minor greater as measured by ASTM D1238 at 190° thereof, and any combination thereof. C./21.5 kg weight and having an ash content of about 35. The method of one claim 32, wherein the polyethylene 500 ppm or less. composition is extruded onto at least a portion of a Surface of 22. The biomedical device of claim 21, wherein the poly the reinforcing structure. ethylene has a specific gravity of about 0.93 g/cm to about 36. The method of claim 32 further comprising: 0.97 g/cm. applying to the molded polyethylene component at least 23. The biomedical device of claim 21, wherein the poly one selected from the group consisting of an active phar ethylene has an average molecular weight of about 30,000 maceutical ingredient, a contrast agent, an antioxidant, a g/mol to about 2,500,000 g/mol. pigment, a dye, a radioopaque filler, a lubricant, a pro 24. The biomedical device of one claim 21, wherein the cessing aid, a light stabilizer, a neutralizer, an antiblock, polyethylene is crosslinked. and any combination thereof. 25. The biomedical device of claim 21, wherein the poly 37. The method of claim 32 further comprising: ethylene comprises a copolymer of ethylene and at least one assembling the biomedical device comprising the molded monomer selected from the group consisting of propylene, polyethylene component. butylene, and any combination thereof. 38. The method of claim32, wherein the biomedical device 26. The biomedical device of claim 21 being at least one is at least one selected from the group consisting of a chip, an selected from the group consisting of a pump, tubing, a feed RFID tag, tubing, a pump, a feeding tube, a catheter, a vas ing tube, a catheter, a vascular catheter, a stent, a heart valve, cular catheter, a prosthetic, an inflatable balloon, a stent, a a stomach ring, a Surgical instrument, a nasopharyngeal heart valve, a neurostimulator, a cochlear implant, a cranio implant, and a laryngeal implant, a drug delivery device, an maxillofacial implant, synthetic cartilage, a stomach ring, a intrauterine device, and an intravaginal ring. Surgical instrument, a blood vessel clamp, an aneurysm clip, 27. The biomedical device of claim 21 further comprising: a spinal plug for use in conjunction with a joint fusion system, at least one wire disposed within the internal volume. a base-plate stem cap for an artificial joint, a muscle implant, 28. The biomedical device of claim 27 being at least one a nasopharyngeal implant, a laryngeal implant, a drug deliv selected from the group consisting of a pacemaker, a neuro ery device, a transdermal patch, a Subdermal implant, an stimulator, and a cochlear implant. oromucosal insert, an intrauterine device, an intravaginal 29. A kit comprising the biomedical device of claim 21 and ring, and a dental fiber. a set of instructions. 39. A method comprising: 30. A method comprising: providing a polyethylene composition melt that comprises implanting the biomedical device of claim 21 into a patient. polyethylene having a melt flow index of about 3.5 g/10 US 2014/005 1771 A1 Feb. 20, 2014 21

min or greater as measured by ASTM D1238 at 190° 44. The method of claim 43 further comprising: C./21.5 kg weight and having an ash content of about forming a molded polyethylene component of a biomedi 500 ppm or less; and cal device from the treated polyethylene. injection molding the polyethylene composition melt to 45. The method of claim 43 whereintreating involves form a molded polyethylene component of a biomedical exposing the polyethylene concurrently Or 1n Series to at least device. one selected from the group consisting of steam, an inert Solvent the catalyst is at least partially soluble in, an acid, 40. A method comprising: acetone, water, a halogenated solvent, and any combination providing a component of a biomedical device; and thereof. Substantially encasing the component in polyethylene hav- 46. The method of claim 45, wherein treating further ing a melt flow index of about 3.5 g/10 minor greater as involves increased temperature and/or decreased pressure. measured by ASTM D1238 at 190° C./21.5 kg weight 47. A method comprising: and having an ash content of about 500 ppm or less. providing a sheet comprising a polyethylene composition 41. The method of claim 40, wherein substantially encas- that comprises polyethylene having a melt flow index of ing involves over molding. about 3.5 g/10 min or greater as measured by ASTM D1238 at 190° C./21.5 kg weight and having an ash 42. The method of claim 40, wherein the component is a content of about 500 ppm or less; and W1e. thermoforming the sheet into a molded polyethylene com 43. A method comprising: ponent of a biomedical device. polymerizing at least one olefinin the presence of a catalyst 48. A method comprising: so as to form polyethylene having a melt flow index of providing a sheet comprising a polyethylene composition about 3.5 g/10 min or greater as measured by ASTM that comprises polyethylene having a melt flow index of D1238 at 190°C./21.5 kg weight, the at least one olefin about 3.5 g/10 min or greater as measured by ASTM comprising ethylene and optionally at least one selected D1238 at 190° C./21.5 kg weight and having an ash from the group consisting of propylene, butylene, and content of about 500 ppm or less; and any combination thereof, and shrink wrapping the sheet onto a portion of a biomedical treating the polyethylene to yield a treated polyethylene device or component thereof. having an ash content of about 500 ppm or less. k . . . .