anti-scalping pharmaceutical packaging film

专利摘要:
PHARMACEUTICAL PACKAGING FILMANTI-SCALPING.A film for packaging a product that has an active agentpharmaceutical includes a sealing layer contacting the product. THElayer contacting the product includes at least 90% by weight of aethylene norbornene copolymer having a transition temperaturevitreous in a range of 50 °C to 110 °C. The pharmaceutical active agentcomprises a Hansen Solubility Parameter for thesealing contacting product of 0.5 or greater.
公开号:BR112016018382A2
申请号:R112016018382-7
申请日:2015-02-10
公开日:2021-08-24
发明作者:Jennifer Riis；Yuan Liu；Lyndsey Mcmillan；Chris Osborn；Rishabh Jain
申请人:Bemis Company, Inc；
IPC主号:

专利说明:

[0001] [0001] This application claims priority over US Patent Application No. 14/178,005, filed February 11, 2014 entitled ANTI-SCALPING TRANSDERMAL PACKAGING FILM, which application is hereby incorporated herein by reference to the extent that that does not conflict with this disclosure. AREA
[0002] [0002] The present application generally relates to packaging suitable for packaging an article for collection or administration of a physiologically active substance such as transdermal drug delivery patches. TECHNICAL BACKGROUND
[0003] [0003] Pharmaceuticals such as the drugs fentanyl and nicotine are often administered through the use of transdermal patches that are applied to a patient's skin to allow administration of the drugs over time by absorption. Prior to application of a drug-containing dressing, the dressing is packaged in a pouch that is designed to be opened to allow access to the dressing by the patient or caregiver for application to a patient's skin. Proper packaging for transdermal patches should contain the patch and its drug within the package while protecting the patch from contamination and harmful effects from the external environment. Therefore, articles such as a pouch can hold a transdermal patch to protect the patch and its drug contents from contact or exposure to unwanted materials such as microbes, insects, air, moisture, sunlight, etc. The container is typically sealed, e.g., by a heat seal to provide an airtight barrier.
[0004] [0004] The materials used in the packaging construction of transdermal patches and especially the inner surface layer of the patch contact package must resist chemical migration between the patch and the packaging materials. Such migration of drug or dressing components from the dressing to the packaging structure is referred to as "scalping". A common material employed for inner surface layers of transdermal patch packaging that prevents scalping is polyacrylonitrile which is often sold under the trademark Barex® by Ineos AG. Although Barex® has superb anti-scalping properties, it is very expensive, has poor tearing properties that make opening pouches difficult, and has limited availability which creates supply chain risk due to its manufacture in a single production reactor. Other polymers used in packaging transdermal patches as a contact surface layer include polyester. Polyester suffers from the disadvantage of being less resistant to scalping from certain chemicals than desired and its tear properties are also less than desired. Accordingly, there is a need for a more cost-effective packaging material for containing articles for collection or delivery of a physiologically active substance such as transdermal drug delivery patches. BRIEF SUMMARY
[0005] [0005] This disclosure, among other things, relates to films for packaging products containing an active pharmaceutical agent. The film resists the migration of chemicals, such as active pharmacological agents or excipients, between the product and the film. Therefore, the films are 6/82 anti-scalping films. In a packaged product, the anti-scalping layer may be in contact with the active pharmaceutical agent. As used herein, "contacting pharmaceutical active agent", in the context of a layer of a film, means that under typical storage conditions some portion of the active agent will contact the layer. The active agent may be in direct contact with the layer containing the product or it may be in indirect contact with the layer. Indirect contact between the active agent and the layer contacting the product can occur, for example, due to volatilization of the active agent or an active agent carrier within the package to make the active agent, which is not stored in direct contact, with the layer containing the product, contact the layer. However, even if the active agent is not in contact with the sealing layer, it may be desirable for the sealing layer to be anti-scalping to provide assurance that if an active agent accidentally becomes exposed to the sealing layer, the layer sealant would not subject the active agent to scalping.
[0006] [0006] The product contacting layers of the films described herein include at least 90% by weight of an ethylene norbornene copolymer having a glass transition temperature in a range of 50°C to 138°C. Layers having such properties have been found to resist the migration of nicotine and fentanyl. These results were unexpected since ethylene norbornene copolymers such as polyethylene are polyolefins, and because polyethylene has previously been shown to have poor antiscalping properties.
[0007] [0007] Polymers are typically compared based on their polymer classification. Accordingly, because polyethylene was determined to be a poor choice for an anti-scalping film or layer, it would be expected that other polyolefins would also be poor choices. These expectations were reinforced by the fact that cyclic olefin copolymers (COCs), such as ethylene norbornene copolymers, perform similarly to low density polyethylene with respect to d-limonene. See, for example, 2005 PLACE Conference, September 27-29, Las Vegas, Nevada, slideshow entitled “TOPAS® Cyclic Olefin Copolymers in Food Packaging - High Aroma Barrier Combined with Low Extractables”, presented by Randy Jester, slide 10 , available at http://www.slideshare.net/TopasAdvancedPolymers/aroma-barrier-web, which states, “The scalping of d-Limonene by COC is similar to that of LLDPE, indicating that the solubility of d-Limonene in COC is similar to that of LLDPE”. That is, COCs and low density polyethylene have been determined to have poor anti-scalping performance with respect to d-limonene.
[0008] [0008] After the unexpectedly good antiscalping properties of COCs as described here with respect to nicotine and fentanyl, the antiscalping properties of COCs with respect to other pharmaceutical agents were evaluated to identify whether COCs might be useful as films or layers. antiscalping for these other active agents and to try to identify whether certain parameters can be used to predict whether COCs would be effective antiscalping layers.
[0009] [0009] Without wishing to be bound by theory it is now believed that a combination of the Hansen Solubility Parameter (HSP) of the pharmaceutical active agent and a film or layer comprising the ethylene norbornene copolymer and the glass transition temperature of the film or layer can be used to predict whether an ethylene norbornene copolymer film will have a suitable anti-scalping property for a given pharmaceutical active agent.
[0010] [0010] In various embodiments, the pharmaceutical active agent has an HSP for the film or layer of 0.5 or greater or has a glass transition temperature of 50°C or greater. The HSP is preferably 0.6 or greater, such as 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1 or greater. Preferably, the glass transition temperature is 55°C or greater, such as 60°C or greater, or 65°C or greater. In various embodiments, the glass transition temperature is 138°C or less, such as 110°C or less.
[0011] [0011] In various embodiments, the pharmaceutical active agent is selected from the group consisting of fentanyl, nicotine, lidocaine, estradiol, clonidine, ethynyl estradiol, oxybutynin, buprenorphine, granisitron, methylphenidate, and scopolamine.
[0012] [0012] In some embodiments, a flexible, multilayer packaging film suitable for packaging an article for collecting or administering a physiologically active substance such as transdermal drug delivery patches, thin oral dissolvable strips, and cassettes is provided. disposable, microfluidic test tubes having: (a) a layer containing the article having at least 90% by weight of an ethylene norbornene copolymer and a glass transition temperature of 65 to 110°C; (b) a bulk layer of polyolefin; (c) a first intermediate adhesive layer; (d) an oxygen barrier layer having an oxygen transmission rate of less than 0.01 cm 3 /100 inch 2 / 24 hours at 1 atmosphere and 23°C; (e) a second intermediate adhesive layer; and (f) an outer protective layer comprising a polymer selected from the group consisting of amorphous polyester, polyamide, polyolefin, nylon, polypropylene, or copolymers thereof, or combinations thereof; 9/82 wherein said multilayer film has the following properties: a WVTR of less than 0.01 g/100 inch 2 for 24 hours at Room Temperature (RT) (23°C) and 1 atmosphere; and a thickness of 10 mil or less. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] [0013] The following detailed description of specific embodiments of the present disclosure may be better understood when read in conjunction with the following drawings, where similar structure is indicated with similar reference numerals and in which:
[0014] [0014] FIG. 1 is a schematic cross-sectional view of a multilayer film in accordance with the embodiments shown herein; and
[0015] [0015] FIG. 2 is a schematic view of a pharmaceutical product packaged in accordance with the embodiments shown herein.
[0016] [0016] Schematic drawings are not necessarily to scale. Similar numbers used in the figures refer to similar components. However, it will be understood that the use of a number to refer to a component in a given figure is not intended to limit the component to another figure labeled with the same number. Additionally, the use of different numbers to refer to components is not intended to indicate that different numbered components cannot be the same or similar to other numbered components. DETAILED DESCRIPTION
[0017] [0017] Definitions and Nomenclature
[0018] [0018] In the discussion of combinations of polymers, plastic films and packaging, several acronyms are used here and are listed below. Also, when referring to polymer combinations, a colon (:) will be used to indicate that the left and right components of the colon are combined.
[0019] [0019] The term "nanocomposite" shall mean a mixture that includes a polymer, or copolymer having dispersed therein a plurality of individual platelets obtained from an exfoliated modified clay and having oxygen barrier properties.
[0020] [0020] The term "adhesive layer", or "bonding layer", refers to a layer or material placed in one or more layers to promote the adhesion of that layer to another surface. Preferably, the adhesive layers are positioned between two layers of a multilayer film to keep the two layers in position relative to each other and prevent undesirable delamination. In some embodiments, a disposable binding layer may be used which is designed to have cohesive failure or delamination of one or both of the adjacent layers after application in a suitable manual manner to provide an opening characteristic for a package made therefrom. film. Unless otherwise indicated, an adhesive layer can be of any suitable composition that provides a desired level of adhesion with one or more surfaces in contact with the adhesive layered material. Optionally, an adhesive layer placed between a first layer and a second layer in a multilayer film may comprise components of both the first layer and the second layer on opposite sides of the adhesive layer.
[0021] [0021] As used herein, unless otherwise noted, the phrases "sealing layer", "sealing layer", "heat sealing layer", and "sealing layer", refer to a layer, or layers, of film involved in sealing the film: to itself; the other film layer of the same film or another film; and/or to another article that is not a film, eg a tray. In general, the sealant layer is a surface layer, i.e., an outer or inner layer of any suitable thickness, which provides sealing of the film to itself or another layer. With respect to packages having only vane-type seals, as opposed to pleat-type seals, the phrase "sealing layer" generally refers to the inner surface film layer of a package. The entire layer can often also serve as an article contact layer in article packaging.
[0022] [0022] "Polyolefin" is used herein broadly to include polymers such as polyethylene, ethylene-alpha-olefin (EAO) copolymers, polypropylene, polybutene, ethylene copolymers having a majority by weight amount of ethylene polymerized with a minor amount of a comonomer such as vinyl acetate, and other polymeric resins being in the "olefin" family classification. Polyolefins can be made by a variety of processes well known in the art including batch and continuous processes using single, step or sequential reactors, slurry, solution and fluid bed processes and one or more catalysts including, for example, heterogeneous and homogeneous systems. and Ziegler, Phillips, metallocene, single-site, and constrained geometry catalysts to produce polymers having different combinations of properties. Such polymers may be highly branched or substantially linear and the branching, dispersion and average molecular weight and may vary depending on the parameters and processes chosen for their manufacture in accordance with the teachings of polymer art.
[0023] [0023] “Polyethylene” is the name of a polymer whose basic structure is characterized by the chain --(CH2--CH2--)n. Polyethylene homopolymer is generally described as being a solid having a partially amorphous phase and a partially crystalline phase with a density of between 0.915 and 0.970 g/cm 3 . It is known that the relative crystallinity of polyethylene affects its physical properties. The amorphous phase provides flexibility and high impact strength while the crystalline phase provides high softening temperature and stiffness.
[0024] [0024] Unsubstituted polyethylene is generally referred to as a high density homopolymer and has a crystallinity of 70 to 90 percent with a density of between about 0.96 to 0.97 g/cm 3 . Most commercially used polyethylenes are not unsubstituted homopolymers but instead have C2-C8 alkyl groups attached to the backbone. These substituted polyethylenes are also known as branched-chain polyethylenes. Likewise, commercially available polyethylenes often include other substituent groups produced by copolymerization. Branching with alkyl groups generally reduces crystallinity, density and melting point. The density of polyethylene is recognized as being closely connected with crystallinity. The physical properties of commercially available polyethylenes are also affected by the average molecular weight and molecular weight distribution, branch length and type of substituents.
[0025] [0025] Persons skilled in the art generally refer to several broad categories of polymers and copolymers as "polyethylene". The placement of a particular polymer in one of these categories of "polyethylene" is often based on the density of the "polyethylene" and often by further reference to the process by which it was made since the process often determines the degree of branching, crystallinity, etc. and density. In general, the nomenclature used is not specific to a compound but rather refers to a range of compositions. This range often includes both homopolymers and copolymers.
[0026] [0026] For example, "high density" polyethylene (HDPE) is ordinarily used in the art to refer to both (a) homopolymers of densities between about 0.960 and 0.970 g/cm3 and (b) copolymers of ethylene and an α-olefin (usually 1-butene or 1-hexene) having a density between 0.940 and 0.958 g/cm 3 . HDPE includes polymers made with Ziegler or Phillips-type catalysts and is said to also include high molecular weight “polyethylenes”. In contrast to IIDPE, whose polymer chain has some branching, are "ultra high molecular weight polyethylenes" which are essentially unbranched specialty polymers having a much higher molecular weight than high molecular weight HOPE.
[0027] [0027] Hereinafter, the term “polyethylene” will be used (unless otherwise indicated) to refer to homopolymers of ethylene as well as copolymers of ethylene with α-olefins and the term will be used without regard to the presence or absence of substituent branching groups. Another broad grouping of polyethylene is “low density, high pressure polyethylene” (LDPE). LDPE is used to name branched homopolymers having densities between 0.915 and 0.930 g/cm3. LDPEs typically contain long branches from the backbone (often called the “backbone”) with alkyl substituents of 2 to 8 carbon atoms.
[0028] [0028] Linear Low Density Polyethylene (LLDPE) is copolymers of ethylene with alpha-olefins having densities from 0.915 to
[0029] [0029] Ethylene α-olefin copolymers are copolymers having an ethylene as the main component copolymerized with one or more alpha-olefins such as octene-1, hexene-, or butene-1 as the secondary component. AEOs include well-known polymers such as LLDPE, VLDPE, ULDPE, and plastomers and can be made using a variety of processes and catalysts including metallocene, single-site and geometry constrained catalysts as well as Ziegler-Natta and Phillips catalysts.
[0030] [0030] Very Low Density Polyethylene (VLDPE) which is also called “Ultra Low Density Polyethylene” (ULDPE) comprises copolymers of ethylene with α-olefins, usually 1-butene, 1-hexene or 1-octene and is generally recognized by those skilled in the art as having a high degree of structure linearity with short branching rather than the long side branches characteristic of LDPE. However, VLDPEs have lower densities than LLDPEs. The densities of the VLDPEs are recognized by those skilled in the art as ranging between 0.860 and 0.915 g/cm 3 . Sometimes VLDPEs having a density less than 0.900 g/cm3 are referred to as "plastomers".
[0031] [0031] Polyethylenes can be used alone, in combinations and/or with copolymers in either single-layer or multi-layer films for packaging applications.
[0032] [0032] As used herein, the term "modified" refers to a chemical derivative, e.g., one having any form of anhydride functionality, such as maleic acid anhydride, crotonic acid, citraconic acid, itaconic acid, fumaric, etc., whether grafted onto a polymer, copolymerized with a polymer, or otherwise functionally associated with one or more polymers, and also includes derivatives of other functionalities, such as acids, esters, and metal salts derived therefrom. Another example of a common modification is acrylate-modified polyolefins.
[0033] [0033] As used herein, terms identifying polymers, such as, e.g., "polyamide" or "polypropylene", include not only polymers comprising repeating units derived from monomers known to polymerize to form a polymer of the type termed, but also include comonomers as well as both unmodified and modified polymers made by, e.g., derivatizing a polymer after its polymerization to add functional groups or moieties between the polymer chain. Furthermore, terms identifying polymers also include "combinations" of such polymers. Accordingly, the terms "polyamide polymer" and "nylon polymer" may refer to a polyamide-containing homopolymer, a polyamide-containing copolymer, or mixtures thereof.
[0034] [0034] The term "polyamide" means a high molecular weight polymer having amide bonds (--CONH--)n that occur along the molecular chain, and includes "nylon" resins which are well-known polymers having a multitude of of uses including utilities such as packaging films, bags, and pouches. See, e.g., Modern Plastics Encyclopedia, 88 Vol. 64, No. 10A, p. 34-37 and 554-555 (McGraw-Hill, Inc., 1987) which is hereby incorporated by reference. Polyamides are preferably selected from nylon compounds approved for use in the production of articles intended for use in processing, handling, and packaging of food or drugs.
[0035] [0035] The term "nylon" as used herein refers more specifically to synthetic, aliphatic or aromatic polyamides, in crystalline, semi-crystalline, or amorphous form characterized by the presence of the amide group --CONH. It is intended to refer to both polyamides and copolyamides.
[0036] [0036] Accordingly, the terms "polyamide" or "nylon" encompass both polymers comprising repeating units derived from monomers, such as caprolactam, which polymerize to form a polyamide, as well as copolymers derived from the copolymerization of caprolactam with a comonomer that when polymerized alone does not result in the formation of a polyamide. Preferably, the polymers are selected from compositions approved as safe to produce articles intended for use in food or drug processing, handling and packaging, such as US Food and Drug Administration approved nylon resins provided in 21 CFR § 177.1500 (" Nylon resins"), which is incorporated herein by reference. Examples of these polymeric nylon resins for use in food or drug packaging and processing include: nylon 66, nylon 610, nylon 66/610, nylon 6/66, nylon 11, nylon 6, nylon 66T, nylon 612, nylon 12, nylon 6/12, nylon 6/69, nylon 46, nylon 6-3-T, nylon MXD-6, nylon MXDI, nylon 12T and nylon 61/6T disclosed in 21 CFR §177.1500. Examples of such polyamides include nylon homopolymers and copolymers such as those selected from the group consisting of nylon 4,6 (poly(tetramethylene adipamide)), nylon 6 (polycaprolactam), nylon 6,6 (poly(hexamethylene adipamide)), nylon 6.9 (poly(hexamethylene nonanediamide)), nylon 6.10 (poly(hexamethylene sebacamide)), nylon 6.12 (poly(hexamethylene dodecanediamide)), 18/82 nylon 6/12 (poly(caprolactam) -cododecanediamide)), nylon 6,6/6 (poly(hexamethylene adipamide-co-caprolactam)), nylon 66/610 (e.g., made by condensation of mixtures of nylon 66 salts and nylon 610 salts) , nylon 6/69 resins (eg, made by the condensation of epsilon-caprolactam, hexamethylenediamine, and azelaic acid), nylon 11 (polyundecanolactam), nylon 12 (polylaurillactam) and copolymers or mixtures thereof.
[0037] [0037] In the use of the term "amorphous nylon copolymer", the term "amorphous" as used herein denotes an absence of a regular three-dimensional arrangement of molecules or subunits of molecules extending over distances that are large relative to atomic dimensions. . However, structure regularity can exist on a local scale. See, “Amorphous Polymers,” Encyclopedia of Polymer Science and Engineering, 2nd Ed., p. 789-842 (J. Wiley & Sons, Inc. 1985). In particular, the term "amorphous nylon copolymer" refers to a material recognized by one skilled in the art of differential scanning calorimetry (DSC) as having no measurable melting point (less than 0.5 cal/g) or no heat of fusion as measured by DSC using ASTM 3417-83. The amorphous nylon copolymer can be manufactured by the condensation of hexamethylenediamine, terephthalic acid, and isophthalic acid according to known processes. Amorphous nylons also include those amorphous nylons prepared from condensation polymerization reactions of diamines with dicarboxylic acids. For example, an aliphatic diamine is combined with an aromatic dicarboxylic acid, or an aromatic diamine is combined with an aliphatic dicarboxylic acid, to give suitable amorphous nylons.
[0038] [0038] As used herein, "EVOH" refers to ethylene vinyl alcohol copolymer. EVOH is otherwise known as saponified or hydrolyzed ethylene vinyl acetate copolymer, and refers to a vinyl alcohol copolymer having an ethylene comonomer. EVOH is prepared by the hydrolysis (or saponification) of an ethylene-vinyl acetate copolymer. The degree of hydrolysis is preferably from about 50 to 100 percent by mole, more preferably from about 85 to 100 percent by mole, and most preferably at least 97%. It is well known that to be a highly effective oxygen barrier, hydrolysis-saponification must be almost complete, i.e., to the extent of at least 97%. EVOH is commercially available in resin form with various percentages of ethylene and there is a direct relationship between ethylene content and melting point. For example, EVOH having a melting point of about 175°C or lower is characteristic of EVOH materials having an ethylene content of about 38% by mole or greater. EVOH having an ethylene content of 38% by mole has a melting point of about 175°C. With increasing ethylene content, the melting point is lowered. Also, EVOH polymers having increasing percentages by mole of ethylene have higher gas permeabilities. A melting point of about 158°C corresponds to an ethylene content of 48% by mole. EVOH copolymers having lower or higher ethylene contents may also be employed. Processability and orientation are expected to be facilitated to higher contents; however, gas permeabilities, particularly with respect to oxygen, can become undesirably high for certain packaging applications that are sensitive to microbial growth in the presence of oxygen. Conversely, lower contents may have lower gas permeabilities, but processability and orientation may be more difficult.
[0039] [0039] As used herein, the term "polyester" refers to synthetic homopolymers and copolymers having ester linkages between 20/82 monomer units that can be formed by condensation polymerization methods. Polymers of this type are preferably aromatic polyesters, and more preferably homopolymers and copolymers of poly(ethylene terephthalate), poly(ethylene isophthalate), poly(butylene terephthalate), poly(ethylene naphthalate) and combinations thereof. Suitable aromatic polyesters may have an intrinsic viscosity between 0.60 and 1.0, preferably between 0.60 and 0.80.
[0040] [0040] The terms "heat seal layer" or "seal layer" are used interchangeably to refer to a layer that is heat sealable, ie, capable of fusion bonding by conventional indirect heating means that generate sufficient heat in at least one film contact surface for conducting to the adjoining film surface and forming a bonding interface therebetween without loss of film integrity. The connecting interface between contiguous inner layers preferably has sufficient physical strength to withstand the packaging process and subsequent handling. Advantageously, the bonding interface is preferably sufficiently thermally stable to prevent leakage of gases or liquids therethrough when exposed to above or below ambient temperatures, e.g. during one or more of the following: packaging, storage, handling operations , and transport. Heat seals can be designed to meet different conditions of expected use and various heat seal formulations are known in the art and can be employed with the present invention. Preferably, the article contacting layer or heat seal is heat sealable to itself, but may be sealable to other objects, films or layers, e.g., to a tray when used as a release film, or to a outer layer in a pleat seal or in certain full tray wrapping embodiments.
[0041] [0041] As used here, the singular forms "a", "a", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "structured-background surface" includes examples having two or more such "structured-background surfaces" unless the context clearly indicates otherwise.
[0042] [0042] As used herein, the term "or" is generally used in its sense including "and/or" unless the context clearly dictates otherwise. The term "and/or" means one or all of the listed elements or a combination of any two or more of the listed elements. The use of “and/or” in certain cases here does not imply that the use of “or” in other cases does not mean “and/or”.
[0043] [0043] As used herein, “has”, “has”, “having”, “includes”, “includes”, “including”, “comprises”, “comprises”, “comprising” or similar are used in their inclusive sense open, and generally mean "includes but not limited to", "includes but not limited to", or "including but not limited to".
[0044] [0044] “Optional” or “optionally” means that the event, circumstance, or component subsequently described may or may not occur, and that the description includes cases where the event, circumstance, or component occurs, and cases where it does not.
[0045] [0045] The words “preferred” and “preferably” refer to embodiments of disclosure that may yield certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the inventive technology.
[0046] [0046] For purposes of the present disclosure, recitations of number ranges by endpoints include all subsumed numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3 .80, 4, 5, etc.). Where a value range is “greater than”, “less than”, etc. a particular value, that value is included within the range.
[0047] [0047] Any direction referred to here, such as “top”, “bottom”, “left”, “right”, “top”, “bottom”, “up”, “bottom”, and other directions and orientations are described here for clarity in reference to the figures and not to be limiting of an actual device or system or use of the device or system. Many of the devices, articles or systems described here can be used in a number of directions and orientations.
[0048] [0048] Unless otherwise expressly stated, it is in no way intended that any method presented herein be interpreted as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not in fact recite an order to be followed by its steps or is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that any particular order is inferred. Any single or multiple feature or feature recited in any one claim may be combined or interchanged with any other feature or feature recited in any other claim or claims.
[0049] [0049] It is also noted that the recitations here refer to a component being "configured" or "adapted to" function in a particular way. In this regard, such a component is "configured" or "adapted to" embody a particular property, or function, or in a particular way, where such recitations are structural recitations as opposed to recitations of intended use. More specifically, the references herein to the way in which a component is "configured" or "adapted to" denote an existing physical condition of the component and, as such, are to be taken as a definitive recitation of the component's structural features.
[0050] [0050] While various features, elements or steps of particular embodiments may be disclosed using the transitional phrase "comprising" it is to be understood that alternative embodiments, including those that may be described using the transitional phrases "consisting" or " consisting essentially of” are implied. Thus, for example, alternative embodiments implied by a product contacting layer comprising an ethylene norbornene copolymer include embodiments where a product contacting layer consists of an ethylene norbornene copolymer, and embodiments where a product contacting layer consists of an ethylene norbornene copolymer. with the product essentially consists of an ethylene norbornene copolymer. Article Contact Layers/Heat Sealing
[0051] [0051] The films described here have a product contact layer containing ethylene norbornene copolymer, which is a cyclic olefin copolymer (COC). COCs are commercially available from Topas as a clear, amorphous copolymer of ethylene and norbornene made by polymerization with a metallocene catalyst. These commercially available COCs reportedly have high transparency and gloss, excellent moisture barrier and aroma barrier properties, a variable glass transition point between 50 and 178 °C (such as 65 to 178 °C), high rigidity, high strength , excellent biocompatibility and inertia and easy to exclude and thermoform. COCs have previously been used for pharmaceutical, medical and food packaging applications including use in co-extruded 24/82 molded films for blister packaging and can be combined with polyethylene.
[0052] [0052] The product contacting layers of the films described here include ethylene norbornene copolymers having a glass transition temperature (Tg) of 50-138 °C (such as 65-138 °C), an ethylene- norbornene of 20-40% by mole of ethylene and 30-60% by mole of norbornene, or a glass transition temperature (Tg) of 50-138°C (such as 65-138°C) and a comonomer content of ethylene-norbornene of 20-40% per mole of ethylene and 30-60% per mole of norbornene. In some embodiments, the product-contacting layers of the films described herein comprise polymer units derived from comonomers essentially solely of ethylene and norbornene.
[0053] [0053] In some embodiments, the product contacting layers of the films described herein include one or more of the following properties: a density (Δ) of 1.02 g/cm3; a molten volume ratio (MVR) of 1.0 - 12.0 cm 3 /10 min. at 230 °C, 2.16 kg load, and 1.0 – 2.0 at 190 °C, 2.16 kg load (ISO 1133); a melt index of 0.1 to 1.9 at 190°C, load 2.16 kg (reported as calculated from ISO 1133 MVR using a melt density of 0.92). The product-contacting layers of the films described here may also include one or more other properties of the Topas cyclic olefin copolymer described in a March 2006 brochure “Topas® Cylcic Olefin Copolymers” available from Topas Advanced Polymers on its website, whose leaflet is hereby incorporated by reference in its entirety.
[0054] [0054] In various embodiments, the contact layer may also function as a heat-sealing or heat-sealable layer to facilitate the formation of hermetically sealed packages. The article contact layer comprises at least 90% by weight of 25/82
[0055] [0055] The terms “heat seal layer” or “seal layer” are used interchangeably to refer to a layer that is heat sealable, ie, capable of fusion bonding by conventional indirect heating means that generates sufficient heat in at least one film contact surface for conducting to the adjoining film surface and forming a bonding interface therebetween without loss of film integrity. The connecting interface between contiguous inner layers preferably has sufficient physical strength to withstand the packaging process and subsequent handling. Advantageously, the bonding interface is preferably sufficiently thermally stable to prevent leakage of gases or liquids therethrough when exposed to above or below ambient temperatures, e.g. during one or more of the following: packaging, storage, handling operations , and transport.
[0056] [0056] The films and packaging described herein may include one or more optional layers, such as one or more barrier layers, an outer layer which may be an abuse resistant outer layer, one or more intermediate layers, and a or more binding layers. barrier layers
[0057] [0057] If included, a barrier layer functions preferentially as both a gas barrier layer and a moisture barrier layer, although these functions can be provided by separate layers. A gas barrier layer is preferably an oxygen barrier layer, and is preferably a core layer positioned between and protected by surface layers. For example, an oxygen barrier layer may be in contact with a first surface layer and an adhesive layer or may be sandwiched between two bonding layers and/or two surface layers.
[0058] [0058] An oxygen barrier is preferably selected to provide a sufficiently low oxygen permeability to protect the packaged article from deterioration or undesirable oxidative processes. For example, a film may comprise an oxygen barrier having an oxygen permeability that is low enough to prevent oxidation of oxygen-sensitive articles and substances to be packaged in the film, e.g., oxygen-sensitive articles such as napkins. transdermal patches, eg, nicotine or fentanyl patches, or oxygen-sensitive collection samples such as blood that can be collected, eg, on a microcassette device. Preferably, a multilayer packaging film according to the present invention will have an oxygen barrier of less than or equal to 10 cm 3 /100 inch 2 /24 hours at 1 atmosphere and 23°C, more preferably less than 0.016 cm 3 /m2 for 24 hours at 1 atmosphere. To protect oxygen-sensitive articles from deterioration from oxygen contact over time, films in accordance with the present invention will have a preferred oxygen transmission rate (O2TR) of less than 1, preferably less than 0.1, more preferably less than 0.01, and most preferably less than 0.001 g/100 inch 2 at 24 hours at Room Temperature (RT) (~23°C) and 1 atmosphere (<0.001 g/m 2 at 24 hours at Room Temperature (RT) (~23 °C)) and 1 atmosphere).
[0059] [0059] A moisture barrier is preferably selected to provide sufficiently low moisture permeability to protect the packaged article from undesirable spoilage. For example, a film may comprise a water barrier having a moisture permeability that is low enough to prevent deleterious effects on packaged articles such as transdermal drug patches or other moisture sensitive products. A preferred film in accordance with various embodiments will have a water or moisture transmission rate (WVTR) of less than 0.01 g/100 inch2 for 24 hours at Room Temperature (RT) (23°C) and 1 atmosphere . In some embodiments, a film has a WVTR of less than 0.01 g/100 inch2 per 24 hours at Room Temperature (RT) (23°C) and 1 atmosphere, or less than 0.001 g/100 inch2 per 24 hours at Room Temperature (RT) (23 °C) and 1 atmosphere.
[0060] [0060] A barrier layer may comprise any suitable material. An oxygen barrier layer may comprise EVOH, polyvinylidene chloride, polyamide, polyester, polyalkylene carbonate, polyacrylonitrile, nanocomposite, a metallized film such as aluminum vapor deposited on a polyolefin, etc., as known to those skilled in the art. Suitable moisture barrier layers include aluminum foil, PVDC, or polyolefins such as LDPE or LLDPE. It is desirable that the thickness of the barrier layer be selected to provide the desired combination of intended performance properties, e.g. with respect to oxygen permeability, and delamination resistance, and water barrier properties. . Suitable thicknesses in multilayer films are less than 15%, eg 3 to 13% of the total film thickness and preferably less than about 10% of the total thickness of the multilayer film. Greater thicknesses can be employed, however, oxygen barrier polymers tend to be relatively expensive and therefore it is expected that cheaper resins will be used in other layers to provide desirable properties once a suitable thickness is used to achieve the barrier property. to the desired gases for the combination of film layers. For example, the thickness of a nuclear oxygen barrier layer can advantageously be less than about 0.45 mil (10.16 microns) and greater than about 0.05 mil (1.27 microns), including thickness. of 0.10, 0.20, 0.25, 0.30, 0.40, or 0.45 mil.
[0061] [0061] An oxygen barrier layer of a film may comprise aluminum foil, or EVOH, although oxygen barrier layers comprising polyvinylidene chloride-vinyl chloride copolymer (PVDC or VDC-VC) or vinylidene chloride copolymer - methylacrylate (VDC-MA), as well as its combinations, can also be used. A suitable EVOH barrier material is a 44% by mol EVOH resin E151B sold by the Eval Company of America under the tradename Evai®LC-E151B. Another example of an EVOH that may be acceptable can be purchased from Nippon Gohsei under the trade name Soarnol® AT (EVOH with 44% ethylene by mol).
[0062] [0062] For packaging oxygen sensitive articles such as drug dressings, an oxygen permeability (O2) of less than about 310 cm3/m2 over a 24 hour period at 1 atmosphere, 0% relative humidity and 23 °C, and preferably less than 75 29/82 cm 3 /m 2 , more preferably less than 20 cm 3 /m 2 . The thickness of the core layer can be varied and beneficially can be from about 0.05 to about 0.60 mils (1.3 - 15.2 microns).
[0063] [0063] A bulk layer may be provided to provide functionality such as rigidity or heat sealability or to improve machinability, cost, flexibility, barrier properties, etc. Preferred bulk layers comprise one or more polyolefins such as polyethylene, ethylene-alpha-olefin (EAO) copolymers, polypropylene, polybutene, ethylene copolymers having a majority by weight amount of ethylene polymerized with a minor amount of a comonomer such as vinyl acetate, and other polymeric resins being in the "olefin" family classification. The bulk layer can be any suitable thickness from 0.1 to 7 mils or even omitted for use in certain applications, but is preferably present to improve especially stiffness/flexibility and heat sealability properties. Abuse Resistant Outer Layer
[0064] [0064] The films described here may include an outer layer. As it is viewed by the user/consumer, in both single-layer and multi-layer embodiments, the outer surface of the film preferably has desirable optical properties and may preferably have high gloss. It also preferentially supports contact with sharp objects and provides abrasion resistance, and for these reasons it is often called an abuse resistant layer. This outer abuse resistant layer may or may not also be used as a heat sealable layer. As the outer surface layer of the film, this layer is most often also the outer layer of any package, bag, pouch or other container made from the inventive film, and is therefore subject to handling and abuse, e.g. 30/82 equipment during packaging, and smearing against other packages and shipping containers and storage shelves during transport and storage.
[0065] [0065] An intermediate layer is any layer between the outer layer and the inner layer and may include oxygen barrier layers, bonding layers or layers having functional attributes useful to the structure of the film or its intended uses. Intermediate layers can be used to provide, provide or otherwise modify a multitude of features; e.g., printability for compartment-printed structures, machinability, tensile properties, flexibility, stiffness, modulus, designated delamination, easy-open characteristics, tear-off properties, strength, elongation, optics, moisture barrier, oxygen barrier, or other gases, radiation or barrier selection, eg to ultraviolet wavelengths, etc. Suitable intermediate layers may include: adhesives, adhesive polymers, paper, oriented polyester, amorphous polyester, polyamide, polyolefin, nylon, polypropylene, or copolymers thereof, or combinations. Suitable polyolefins may include: polyethylene, ethylene-alpha-olefin (EAO) copolymers, polypropylene, polybutene, ethylene copolymer having a major by weight amount of ethylene polymerized with a minor amount of a comonomer such as vinyl acetate, and others polymeric resins being in the family classification of “olefins”, LDPE, HDPE, LLDPE, EAO, ionomer, ΕΜΑ, ΕΑΑ, modified polyolefins, eg, eg anhydride grafted ethylene polymers, etc. Link Layers 32/82
[0066] [0066] In addition to the outer layer, the inner layer, and the intermediate layer such as a barrier layer, a multilayer packaging film may additionally comprise one or more adhesive layers, also known in the art as "bonding layers", which can be selected to promote adhesion of adjacent layers to each other in a multilayer film and prevent undesirable delamination. A multifunctional layer is preferably formulated to assist in the adhesion of one layer to another layer without the need to use separate adhesives due to the compatibility of the materials in that layer to the first and second layers. In some embodiments, the adhesive layers comprise materials found in both the first and second layers. The adhesive layer may suitably be less than 10% and preferably between 2% and 10% of the overall thickness of the multilayer film. Adhesive resins are often more expensive than other polymers, so the thickness of the bonding layers is usually kept to a minimum consistent with the desired effect. In one embodiment, a multilayer film comprises a multilayer structure comprising a first adhesive layer positioned between and in direct contact with the outer layer and a nuclear oxygen barrier layer; and preferably and optionally has a second bonding layer to produce a five-layer film. Adhesive layers may include modified polymers, e.g., anhydride-modified, e.g., polyolefins such as polyethylenes or ethylene copolymers such as EVA, and may also be specialty adhesive resins or initiators.
[0067] [0067] Multilayer films may comprise any suitable number of bonding or adhesive layers of any suitable composition. Various adhesive layers are formulated and positioned to provide a desired level of adhesive between specific layers of the film according to the composition of the layers contacted by the bonding layers.
[0068] [0068] For example, adhesive layers in contact with a layer comprising a polyester, such as PET, preferably comprise a suitable combination of polyolefins with other adhesive polymers. A preferred component of an adhesive layer in contact with a PET polyester is EMAC SP 1330 (which reportedly has: a density of 0.948 g/cm3; melt index of 2.0 g/10 min.; a melting point of 93 °C; it is at the softening point of 49 °C; and a methylacrylate (MA) content of 22%).
[0069] [0069] The inner, outer, intermediate or binding layers may be formed of any suitable thermoplastic materials, for example polyamides, polystyrenes, styrenic copolymers, e.g. styrene-butadiene copolymer, polyolefins, and in particular members of the polyethylene family such as LLDPE, VLDPE, HOPE, LDPE, ethylene vinyl ester copolymer or ethylene alkyl acrylate copolymer, polypropylenes, ethylene-propylene copolymers, ionomers, polybutylenes, alpha-olefin polymers, polyesters, polyurethanes, polyacrylamides , anhydride-modified polymers, acrylate-modified polymers, polylactic acid polymers, or various combinations of two or more of these materials.
[0070] [0070] In another embodiment, the outer, inner and/or one or more intermediate layers may comprise or consist essentially of a nylon blend composition. Preferably, the nylon blend composition comprises at least one amorphous nylon such as 6I/6T nylon copolymer, in combination with at least one semicrystalline nylon homopolymer or copolymer such as 6/12, 6/69, 6 nylon. /66, MXD6, 6, 11, or 12.
[0071] [0071] In another embodiment of the invention, one or more of the outer, inner and/or one or more intermediate layers comprise at least one polyester polymer. Preferred polyester polymers comprise aromatic polyesters and, more preferably, are homopolymers or copolymers of poly(ethylene terephthalate) (PET), poly(ethylene naphthalate) and combinations thereof. Suitable polyesters may have an intrinsic viscosity of from about 0.60 to about 1.2, preferably between 0.60 and 0.80. The polyester may be an aliphatic polyester resin, but is preferably an aromatic polyester resin. For example, polyester materials can be derived from dicarboxylic acid components, including terephthalic and isophthalic acid as preferred examples, and also dimers of unsaturated aliphatic acids. Examples of a diol component as another component for polyester synthesis may include: polyalkylene glycols, such as ethylene glycol, propylene glycol, tetramethylene glycol, neopentyl glycol, hexamethylene glycol, diethylene glycol, polyethylene glycol and polytetramethylene glycol oxide; 1,4-cyclohexane-dimethanol, and 2-alkyl-1,3-propanediol. More specifically, examples of dicarboxylic acids constituting the polyester resin may include: terephthalic acid, isophthalic acid, phthalic acid, 5-t-butylphthalic acid, naphthalenedicarboxylic acid, diphenyl ether dicarboxylic acid, cyclohexane-dicarboxylic acid, adipic acid, oxalic, malonic acid, succinic acid, azelaic acid, sebacic acid, and dimer acids comprising dimers of unsaturated fatty acids. These acids can be used singly or in combination of two or more species. Examples of diols constituting the polyester resin may include: ethylene glycol, propylene glycol, tetramethylene glycol, neopentyl glycol, hexamethylene glycol, diethylene glycol, polyalkylene glycol, 1,4-cyclohexane-dimethanol, 1,4-butanediol, and 2-alkyl-1,3-propane diol. These diols can be used singly or in combination of two or more species.
[0072] [0072] Polyester compositions comprising an aromatic polyester resin comprising an aromatic dicarboxylic acid component may be preferred in some respects, including, e.g., polyesters between terephthalic acid (as a dicarboxylic acid) and diols having at most 10 carbon atoms, such as polyethylene terephthalate and polybutylene terephthalate. Particularly preferred examples thereof may include: copolyesters obtained by replacing a portion, preferably at most 30% by mol, more preferably at most 15% by mol, of the terephthalic acid with another dicarboxylic acid, such as isophthalic acid; copolymers obtained by replacing a portion of the diol component such as ethylene glycol with another diol, such as 1,4-cyclohexane-dimethanol (e.g., "Voridian 9921", made by the Voridian division of Eastman Chemical Co.); and polyester-polyether copolymers comprising polyester as a predominant component (e.g. polyester-ether between a dicarboxylic acid component comprising primarily terephthalic acid and/or its ester derivative and a diol component primarily comprising tetramethylene glycol and oxide of tetramethylene glycol, preferably containing the residue of polytetramethylene glycol oxide in a proportion of 10 - 15% by weight). It is also possible to use two or more different polyester resins in a mixture. Examples of preferred polyesters are available under the tradenames Voridian 9663, Voridian 9921 and EAST AR® 6763 copolyester, all from Eastman Chemical Company, Kingsport, Tenn., USA Optional Layer Additives
[0073] [0073] Various additives may be included in the polymers used in one or more outer, inner and intermediate or packaging binding layers comprising the same. For example, a layer may be coated with an anti-blocking powder. Likewise, antioxidants, anti-blocking additives, polymeric plasticizers, acid, moisture or gas scavengers (such as oxygen), gliding agents, dyes, inks, pigments, conventional organoleptic agents may be added to one or more layers of film or may be exempt. of such additional ingredients. If the outer layer is corona treated, preferably no gliding agent will be used, but will contain or be coated with a powder or anti-blocking agent such as silica or starch. Processing aids are typically used in amounts less than 10%, less than 7% and preferably less than 5% of the layer weight. A preferred processing aid for use in the outer layer of the film includes one or more of fluoroelastomers, stearamides, erucamides, and silicates.
[0074] [0074] Preferred films may also provide a beneficial combination of one or more of or all of the properties including low haze, high gloss, good machinability, good mechanical strength and good barrier properties including high oxygen barriers and water permeability. Similar barrier properties may have WVTR values less than or equal to 0.03 g/100 inch 2 for 24 hours at 1 atmosphere and RT; and/or O2TR values less than or equal to 10 cm3/100 inch2 for 24 hours at 1 atmosphere and RT. Preferred barrier property values are WVTR =< 0.001 g/100 inch2 for 24 hours at 1 atmosphere and RT, and/or O2TR values less than or equal to 0.001 cm3/100 inch2 for 24 hours at 1 atmosphere and RT. Manufacturing Methods 37/82
[0075] [0075] The inventive single-layer or multi-layer film can be made by conventional processes. These processes for producing flexible films may include, e.g., molded or blown film processes.
[0076] [0076] In some embodiments, the polymers described herein are "unmodified" by any intentional grafting or copolymerization with modifying moieties such as dienes, rubber moieties, or acrylic acids. However, polymers may contain chemicals or additives in small amounts (typically below 1% by weight based on polymer weight) that are present as by-products of the polymer manufacturing process or otherwise added by polymer manufacturers including, e.g., catalyst residues, antioxidants, stabilizers, anti-blocking materials and the like. In some embodiments, the polymers are "modified" or "derivatized" by grafting or copolymerization with modification moieties. For purposes of the present disclosure, such modified or derivatized polymers are considered a subset of the polymer being modified. For example, a modified or derivatized polyethylene is considered a polyethylene.
[0077] [0077] Exact and Escorene polymers are the tradenames of polymers available from the Exxon Chemical Company of Houston, Tex., USA. Afinity and Attane polymers are the tradenames of polymers available from the Dow Chemical Company of Midland, Mich., USA Surlyn and Elvax are the trade names for polymers available from Dupont, USA
[0078] [0078] Metal sheets and metallized films are also contemplated. One or more functional properties may be contributed by one or more layers including desired levels of heat sealability, optical properties, e.g., transparency, gloss, haze, abrasion resistance, coefficient of friction, tensile strength, flex crack resistance, puncture resistance, abrasion resistance, printability, color fastness, flexibility, dimensional stability, barrier properties to gases such as oxygen, or moisture, broad or narrow spectrum light including, eg. , UV resistance, etc.
[0079] [0079] In some embodiments, a packaging film as described herein may utilize a gas barrier layer such as aluminum foil, polyvinylidene chloride copolymers such as saran, or ethylene vinyl alcohol copolymers that provide high barriers. to gas permeability.
[0080] [0080] In some embodiments, a packaging film as described herein may utilize a moisture barrier layer such as aluminum foil, polyvinylidene chloride copolymers such as saran, or polyolefin materials such as LDPE that prevent permeation. to the moisture of the steam.
[0081] [0081] Adhesives useful in the present invention include permanent adhesives, polymer modified adhesives and polymer resins commonly available from many commercial sources. It is contemplated that acrylic and anhydride modified polymers may be employed as well as many adhesives which may be selected depending on other material selections for other functional layers such as the oxygen and/or moisture barrier layer(s) as well as the abuse-resistant or protective outer layer as well as the required COC layer.
[0082] [0082] Additives and processing aids; natural and synthetic dyes, pigments and inks; fillers such as calcium carbonate or carbon black, antimicrobial agents may be incorporated into or coated onto one or more layers of the multilayer films of the present invention. Film Thickness 40/82
[0083] [0083] Preferably, the packaging film has a total thickness of less than about 10 mils, more preferably the film has an overall thickness of about 1.0 to 10 mils (25-250 microns (μ)). Advantageously, many embodiments can be from about 1 to 5 mils thick, with certain typical embodiments being from about 2 to 3.5 mils. For example, entire multilayer films or any single layer of a multilayer film may have suitable thicknesses, including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mils, or any increment of 0.1 or 0.01 thousand between them. Although films suitable for packaging pharmaceutical dressings as thick as 4 mils (101.6 microns) or higher, or as thin as 1 mils (25.4 microns) or lower, can be made between about 2-4 mil (51-102 microns). Films where the multilayer film has a thickness of between about 2 and 3 mils (50.8-76.2 microns) are especially preferred for use as films for packaging transdermal patches. Such films may have good abuse resistance and machinability.
[0084] [0084] Typical contents for various embodiments of the inventive container may include, for example, transdermal patches, thin strips of dissolvable material for oral administration, as well as articles for collecting or administering a physiologically active substance, e.g., a microdiffusion cassette.
[0085] [0085] Example of commercially available LDPE resin for use in the present invention includes, but is not limited to, Equistar's LDPE 216-000 resin. Examples of commercially available EAA resin for use in the present invention include, but are not limited to, 3990-L from Dupont, which is supplied by Dupont de Nemours. Examples of commercially available ionomer resins for use in the present invention include, but are not limited to, Dupont's Surlyn 1652-1, which is supplied by 41/82
[0086] [0086] The mLLDPE layer used in the examples was a combination of 80% comprising LDPE and 20% mLLDPE.
[0087] [0087] Example of commercially available LDPE resin for use in the present invention includes, but is not limited to, LDPE 4012 from Dow which is supplied by Dow Chemical Co. of Midland, Michigan, USA.
[0088] [0088] Example of commercially available mLLDPE resin for use in the present invention includes, but is not limited to, Exxon's mLLDPE 3040 Exact resin, which is supplied by Exxon.
[0089] [0089] Example commercially available COC resin for use in the present invention includes, but is not limited to, 8007F-400 from Topas, which is supplied by Topas Advanced Polymers.
[0090] [0090] The containers, e.g., a pouch, may additionally include a tear aid or tear initiator such as a notch. Examples of tear aids or tear initiators such as notches, slits, perforations, rough surface portions, etc., are described in U.S. Patent Nos. 4, 778,058; 3,608,815; 4,834,245; 4,903,841; 5,613,779; 5,988,489; 6,102,571; 6,106,448; 6,541,086; 7,470,062; and 7,481,581. Such tear initiators may be used at one or more ends of the inventive pouch and package.
[0091] [0091] Advantageously, the tear initiator can be used with grooving, e.g. mechanical or laser grooving of one or more layers, in preference to another abuse-resistant layer, to create a tear guide line that facilitates tearing. opening. Prior art films used for packaging transdermal patches that utilize polyacrylonitrile as the patch-contacting surface layer (sealant layer) have undesirably poor tear properties, being very susceptible to delamination after attempts to open even with ridges. . These packages typically have to use scissors or a knife for opening. Beneficially, the present invention has excellent tearing properties and when used with a furrow line it can be manually opened in a clean, non-delaminating manner without the use of scissors or other cutting implements. This easy-to-open feature of the present invention may be coupled with child-resistant packaging technology such as that described in pending patent application number PCTIUS2013/022101, which is hereby incorporated by reference in its entirety, to provide a tamper-resistant package. children that is simultaneously easy to open by an adult. Relationship between pharmaceutical active and layer contacting the product
[0092] [0092] As indicated above it is proposed here that both the glass transition temperature of the layer comprising ethylene norbornene copolymer and the Hansen Solubility Parameter (HSP) of the active pharmaceutical agent to be stored in contact (direct or indirect) with the layer contacting product comprising ethylene norbornene copolymer can be factors in determining whether the product contacting layer can serve as an effective anti-scalping layer.
[0093] [0093] Based on the experiments described here we now believe that the HSP provides a thermodynamic indication of whether the active agent will migrate to the layer contacting the product, with higher HSPs favoring lower amounts of migration. We now also believe that the glass transition temperature provides a kinetic indication of the rate at which the active agent will migrate into the layer contacting the product, with higher glass transition temperatures tending to result in slower kinetics and thus antiscalping properties. best.
[0094] [0094] In various embodiments, the pharmaceutical active agent has an HSP for the film or layer of 0.5 or greater and has a glass transition temperature of 50°C or greater. The HSP is preferably 0.6 or greater, such as 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1 or greater. Preferably, the glass transition temperature is 55°C or greater, such as 60°C or greater, 65°C or greater, or 75°C or greater. In various embodiments, the glass transition temperature is 138°C or lower. Preferably, the glass transition temperature is 110°C or lower. In some embodiments, the glass transition temperature of the layer contacting the product is in a range of 50 °C to 138 °C, such as in a range of 55 °C to 138 °C, in a range of 50 °C C to 110 °C, in a range of 65 °C to 110 °C, or the like.
[0095] [0095] The HSP of a pharmaceutical active agent for a layer comprising an ethylene norbornene copolymer as described herein can be determined as described in Hansen, CM, Hansen Solubility Parameters a User's Handbook 2nd Ed., CRC Press, Boca Raton, 2007. According to Hansen, the total cohesion energy (E) of a liquid is defined by the energy required to convert a liquid into a gas. This can be experimentally measured by the heat of vaporization. Hansen described the total cohesion energy as being comprised of three main intermolecular forces: atomic dispersion forces (ED), permanent molecular dipole-dipole (EP) interactions, and molecular hydrogen bonding (EH) interactions. When the cohesion energy is divided by the molar volume (V), the total cohesion energy density of the liquid is given by: E/V = ED/V + EP/V + EH/V. (1) 44/82
[0096] [0096] The solubility parameter (δ) of the liquid is related to the cohesive energy density by: δ = (E/V)1/2. (2) where δ is the Hildebrand solubility parameter. The three components of the Hansen solubility of a liquid are thus given by: δ2 = δD2 + δΡ2 + δΗ2. (3)
[0097] [0097] These three parameters have been tabulated for thousands of solvents and can be used to describe polymer-solvent interactions (see, eg, Hansen, 2007).
[0098] [0098] There are solubility parameters for solid polymers as well as liquid solvents (see, eg, Hansen, 2007). Polymer-solvent interactions are determined by comparing the Hansen Solubility parameters of the polymer with those of a solvent or solvent mixture defined by the term Ra as Ra2 = 4(δD2-δD1)2 + (δΡ2-δP1)2 + (δΗ2 -δH1)2 (4) where the subscripts 1 and 2 refer to the solvent or mixture of solvents and polymer, respectively. Ra is the distance in three-dimensional space between the Hansen Solubility parameters of a polymer and those of a solvent. A "good" solvent for a particular polymer has a small Ra value. This means that the solubility parameters of the polymer and solvent are closely matched and the solvent will rapidly dissolve the polymer. Ra will increase as the Hansen Solubility parameters of a solvent become more dissimilar to those of the polymer.
[0099] [0099] The solubility of a particular polymer is not technically described only by the three parameters in Equation (3). A good solvent does not have to have parameters that perfectly match those of the polymer. There is a range of solvents that will work to dissolve the polymer. The Hansen solubility parameters of a polymer are 45/82 defined by δD, δP, and δH which are coordinates of the center of a solubility sphere that has a radius (Ro). Ro defines the maximum distance from the center of the sphere that a solvent can be and still dissolve the polymer.
[0100] [0100] The strength of a solvent to a polymer is determined by comparing Ra with Ro. A term called Relative Energy Difference (RED) is given by: RED = Ra/Ro. (5)
[0101] [0101] Using RED values is a simple way to assess how “good” a solvent or active agent will be for a given polymer. Solvents or active agents that have a RED number much less than 1 will have Hansen solubility parameters close to those of the polymer and will dissolve. Solvents or active agents that have RED numbers much greater than 1 will have Hansen solubility parameters far from the polymer and will have little or no ability to dissolve the polymer. Solvents or active agents that have RED numbers close to one will be on the boundary between good and weak solvents and will partially dissolve.
[0102] [0102] The HSP values given here are RED values. RED values for a pharmaceutical active agent and a layer comprising ethylene norbornene copolymer can be determined experimentally or by identifying Ra values in existing databases, such as the HSPiP Datasets available at http://hansen-solubility.com /HSPiPDatasets.html. For polymer blends, the Ra values of the various polymers forming the blend can be averaged. If a polymer blend contains 90% or more of a polymer, e.g., at least 90% of an ethylene norbornene copolymer, then, for purposes of the present disclosure, the value of Ra for the polymer blend may be 46 /82 assumed to be the Ra value of the polymer constituting 90% or more of the blend.
[0103] [0103] For purposes of the present disclosure, a pharmaceutical composition is considered to be a pharmaceutical "product". Preferably, the RED values of one or more of the excipients for the ethylene norbornene copolymer are 0.5 or greater. More preferably, the RED values are 0.6, 0.7, 0.8, 0.9, or 1 or greater. RED values for excipients can be obtained generally as described above with respect to active pharmaceutical agents.
[0104] [0104] Excipients that may be included in various types of pharmaceuticals are generally known to those of ordinary skill in the pharmaceutical arts and may be provided in Remington: The Science and Practice of Pharmacy, 22nd edition, Loyd V. Allen, Jr. ( editor), Pharmaceutical Press, September 2012.
[0105] [0105] A film packaging pharmaceutical described herein may include any suitable pharmaceutical active agent. In some embodiments, the pharmaceutical active agent is selected from the group consisting of fentanyl, nicotine, lidocaine, estradiol, clonidine, ethynyl estradiol, oxybutynin, buprenorphine, granisitron, methylphenidate, and scopolamine. In some embodiments, one or more of the listed pharmaceutical active agents are included in a transdermal patch.
[0106] [0106] Examples of some excipients that may be present in a transdermal patch include solvents, preservatives, and permeation enhancers. Examples of some particular excipients include isopropyl myristate, ethyl lactate, lauryl lactate, dimethyl sulfoxide (DMSO), capric acid, dipropylene glycol, ethanol, oleic acid, triacetin, isopropyl palmitate, water, tetradecane and the like.
[0107] [0107] HSP (RED) values of various active pharmaceutical agents and excipients for various sealant film polymers are listed below in Table 1. Table 1: HSP Data Comparing Various Seal Films HSP Data RED Values Barex CXB Drugs PE PET EVOH Fentanyl 0.51 1.04 2.34 0.32 1.38 Nicotine 1.33 0.86 2.93 0.19 1.03 Lidocaine 1.32 0.9 2.85 0.23 1, 12 Phenylethylamine 1.03 1.14 21.4 0.28 1.31 Estradiol 1.62 0.97 3.12 0.46 0.93 Clonidine 2.2 0.39 4.52 0.83 0.62 Estradiol of Ethynyl 1.38 0.92 0.37 3.01 0.98 Oxybutyn 0.79 1.28 1.52 0.41 1.57 Buprenorphine 1.18 1.08 2.42 0.29 1.19 Granisitron 1.74 0.63 3.8 0.61 0.98 D-Limonene 0.61 1.56 0.55 0.81 2.02 Methylphenidate 0.71 1.2 1.79 0.35 1.47 Scopalamine 1.65 0.97 3.01 0.35 0.97 Excipients Isopropyl Myristate 0.83 1.63 0.41 0.91 2.14 Ethyl Lactate 2.7 1.21 4.22 1.06 1 .18 Lauryl Lactate 1.23 1.36 1.7 0.55 1.61 Dimethylsulfoxide 3.15 0.65 5.6 1.33 1.03 Capric Acid 1.47 1.37 2.01 0.61 1.57 Dipropylene Glycol 3, 38 1.23 1.44 5.35 1.23 Ethanol 3.77 1.52 1.73 5.76 1.63 Oleic Acid 0.6 1.42 0.6 1.2 1.75
[0108] [0108] In Table 1, CXB is a copolymer of ethylene norbornene from 35% by weight of ethylene monomers and 65% by weight of norbornene monomers; PE is a polyethylene homopolymer; PET is poly(ethylene terephthalate); and EVOH is an ethylene vinyl alcohol copolymer formed from 24 to 48% by weight ethylene.
[0109] [0109] As shown in Table 1, all drugs (active agents) and excipients listed have an HSP to CXB of more than 0.5. All listed drugs and excipients, except fentanyl, have an HSP to CXB of 0.6 or greater. All listed drugs and excipients, except fentanyl, D-limonene, and oleic acid, have an HSP to CXB of 0.7 or greater. All listed drugs and excipients, except fentanyl, D-limonene, oleic acid, methylphenidate, and oxybutynin, have an HSP to CXB of 0.8 or greater. All drugs and excipients listed except fentanyl, D-limonene, oleic acid, methylphenidate, oxybutynin, isopropyl myristate and isopropyl palmitate have an HSP to CXB of 0.9 or greater. The remaining drugs and excipients have CXB HSPs of 1 or greater.
[0110] [0110] A pharmaceutical product may be packaged in a film described herein in any suitable manner. In some embodiments, a pharmaceutical is packaged such that the pharmaceutical active agent is not in contact with a sealing layer of the film. In some embodiments, the pharmaceutical is packaged such that the pharmaceutical active agent is in contact with the sealing layer of the film. The active agent can be in direct contact with the sealing layer or in indirect contact with the sealing layer.
[0111] [0111] In some embodiments, the pharmaceutical product comprises a gel, paste, solution or the like, where the gel, paste, solution, etc. contains the active ingredient and is in direct contact with the sealing layer.
[0112] [0112] In some embodiments, the pharmaceutical product includes an active agent or excipient that acts as a carrier for the active agent where the active agent or carrier has a sufficiently high vapor pressure to cause volatilization of the active agent or carrier to causing the active agent to contact the sealing layer after storage, although the product is initially packaged in such a way that the active agent is not in direct contact with the sealing layer.
[0113] [0113] In some embodiments, the pharmaceutical product includes a transdermal patch. Transdermal patches typically have a release liner covering a matrix comprising a pharmaceutical active agent. Accordingly, the pharmaceutical active agent and excipients of a transdermal patch having a release liner may not be in direct contact with the sealing film layer in which they are packaged. However, at one end of the release liner, some of the matrix may be in direct contact with the sealing layer and may allow the active agent to be deflected towards the sealing layer. Alternatively or additionally, the vapor pressure of the active agent or a carrier excipient may be high enough to cause the active agent to contact the sealing layer after storage. By way of example, nicotine, which is often included in transdermal patches, is relatively volatile and has a vapor pressure of 5.65 Pa at 25°C.
[0114] [0114] In some embodiments, the pharmaceutical is packaged in a film described herein such that the active pharmaceutical agent is not in contact with the sealant layer. For example, the active agent may be surrounded by a liner and release liner or may be otherwise contained such that the active agent is not in contact with the sealing layer. In such cases it may still be desirable to have a sealing layer that would be anti-scalping if the active agent came into contact with the sealing layer. For example, if the pharmaceutical product includes a release liner configured to prevent contact of the active agent with the sealing layer, the release liner may slip or otherwise partially release during packaging, shipping, storage, or the like for display. the active agent to the sealing layer. Even if there is little or no risk that the active agent could be exposed to the sealing layer it may be desirable for the sealing layer to be anti-scalping for escrow, reinsurance, or similar purposes.
[0115] [0115] When a pharmaceutical product is packaged in a film such that the sealing layer contacting the product of the film is in indirect contact with an active pharmaceutical agent in the product, detectable amounts of the pharmaceutical agent are present on a surface of the layer contacting the product. the product or migrate to the layer contacting the product after storing the product in the packaging film. Any suitable technique can be employed to determine whether a pharmaceutical agent in a pharmaceutical product indirectly contacts a layer of a package in which the product is sealed. That is, if a detectable amount of the agent is present on a surface of a layer or a layer of the film, then the pharmaceutical agent is "in contact" with the layer of the film for purposes of the present disclosure. Examples of suitable techniques that can be employed to determine whether a pharmaceutical agent in a pharmaceutical product indirectly contacts a layer of a package in which the product is sealed include Raman spectroscopy, gas chromatography, gas chromatography-mass spectrometry (GCMS), liquid chromatography-mass spectrometry (LCMS), high performance liquid chromatography (HPLC) and the like.
[0116] [0116] To determine whether a pharmaceutical active agent in a pharmaceutical product is in indirect contact with a sealing layer of a film, the presence of the active agent in or on a sealing layer of the film can be evaluated after the pharmaceutical product has been wrapped in film under storage conditions for a period of time. Storage conditions and time can be standard storage conditions. Default storage conditions can be accelerated storage conditions; eg at temperatures above room temperature. For example, storage conditions might be 20% relative humidity and a temperature of 100°F for 1, 7, 15, or 31 days.
[0117] [0117] Alternatively or additionally, to determine whether a pharmaceutical active agent of a pharmaceutical product could be in indirect contact with a sealing layer of a film described herein, the presence of the active agent in or on a replacement sealing layer of the film can be evaluated after the pharmaceutical product has been packaged in the replacement film under standard storage conditions for a standard period of time. Preferably, the substituent film is not anti-scalping or is not anti-scalping like a film as described herein. The product may be packaged and stored in the film containing the replacement sealing layer in a manner similar to how the pharmaceutical packaged in film as described herein would be packaged and stored. If the active agent migrates to the replacement sealing layer, then the active agent can be considered to be "in contact" with the replacement layer and would be considered to be "in contact" with a sealing layer of any film on the surface. which it was stored, such as a movie as described here. anti-scalping
[0118] [0118] Whether a layer contacting the product of a film effectively performs as an anti-scalping layer can be a subjective determination, with different amounts of migration of an active pharmaceutical agent into a layer of a film being considered acceptable depending on, among other things , the active agent, the amount that the active agent migrates in layers of other films, and the like.
[0119] [0119] For purposes of the present application a layer contacting the product of a film is considered to serve as an effective anti-scalping layer if (i) a lower amount of the active agent migrates to the layer contacting the product of the film (the film test) than migrates to a substantially similar film having a PE, such as a linear low density polyethylene homopolymer, the layer contacting the product (the reference film) when a product containing the pharmaceutical active agent is positioned relative to the product. to the test and reference films such that the pharmaceutical active agent is in direct contact with the layers contacting the product of the test and reference films; or (ii) an amount of the active agent migrating to the layer contacting the film product (the test film) is not more than 15% greater than that migrating to a substantially similar film having a layer contacting the Barex® product (the reference film) when a product containing the active pharmaceutical agent is positioned relative to the test and reference films such that the active pharmaceutical agent is in direct contact with the layers contacting the product from the test and reference films . Preferably, the product is sealed in a cavity formed at least in part by the test film and the product is sealed in a cavity formed at least in part by the reference film. The sealed product can be stored under identical conditions prior to testing to determine whether less active agent has migrated into the layer contacting the test film product than the reference film. Storage conditions may be accelerated storage conditions as described above.
[0120] [0120] Any technique may be employed to determine whether less active agent has migrated into the layer contacting the test film product than the reference film. For example, Raman spectroscopy or gas chromatography can be used.
[0121] [0121] In some embodiments, the amount of a pharmaceutical agent that migrates to a film having a linear low density polyethylene homopolymer as a product contacting layer (as described above) will be 1.5 times or more than the amount of pharmaceutical active agent that migrates to an anti-scalping product contact layer of a film as described herein. In some embodiments, the amount of a pharmaceutical agent that migrates to a film having a linear low density polyethylene homopolymer as a product contacting layer (as described above) will be 2 times or more, 3 times or more, or 4 times or more, or 5 times or more, the amount of pharmaceutical active agent that migrates to an anti-scalping product contact layer of a film as described herein.
[0122] [0122] In preferred embodiments, an amount of an active pharmaceutical agent that migrates to a film having an ethylene norbornene copolymer as described herein as a sealing layer will be no more than 10% more than the amount of the pharmaceutical active agent that migrates to film having Barex® as a sealing layer. More preferably, the amount of an active pharmaceutical agent that migrates in a film having an ethylene norbornene copolymer as described herein as a sealing layer will be no more than 9% (no more than 8%, no more than 7% , not more than 6%, not more than 5%, not more than 4%, not more than 3%, not more than 2%, or not more than 1%) more than the amount of pharmaceutical active agent that migrates to film having Barex® as a sealing layer.
[0123] [0123] A preferred method for determining whether a film is anti-scalping is to compare active agent uptake against a linear low density polyethylene homopolymer or Barex® as described above. In preferred embodiments, a drug uptake test is performed generally as follows:
[0124] [0124] Ten pouches are made with each test film by heat sealing together two pieces of the sample film each measuring 3 x 3.5 inches on three sides with the same surface contacting the article aimed at the others. Next, a standard amount of the drug being tested is placed on a 1 x 1.25 inch piece of drying paper and the drying paper is placed inside the pouch which is then heat sealed.
[0125] [0125] Bags are stored at 100°F and 20% RH and three bags of each film frame are tested at reported intervals, e.g., days 1, 7, 15, and 31. After the time allowed, three pouches are opened by cutting an end seal, and stains removed. The unstained pouches are rinsed with distilled water to remove any drug residue that could be present on the surface of the sealant and excess water is removed from the pouches by agitation. Next, 5 ml of 55/82 isopropanol enriched with an internal standard (propylene glycol n-propyl ether) is placed in each pouch which is then resealed with heat seals. The resealed pouches are placed in a shaker tube for 90 minutes to facilitate drug extraction from the sealant. Finally, extracts from the bags are analyzed by gas chromatography and the amount of eluted drug is calculated for each bag. figures
[0126] [0126] Referring now to the Drawings, FIG. 1 is a schematic cross-sectional drawing of a multilayer film 10 in accordance with an embodiment described herein. In the illustrated embodiment, the film 10 includes six layers. On one surface is the layer contacting product 1, which comprises an ethylene norbornene copolymer. Adjacent and in contact with the product contacting layer 1 is a polyolefin bulk layer 2. Adjacent and contacting the polyolefin bulk layer 2 is a first intermediate adhesive layer 3. Adjacent and contacting the first adhesive layer Intermediate 3 is an oxygen barrier layer
[0127] [0127] Referring now to FIG. 2, a schematic view of a packaged pharmaceutical product 100 is shown. In the illustrated embodiment, the packaged pharmaceutical product includes a pharmaceutical product 20 sealed in a packaging film 10 as described 56/82 herein. The dotted lines in FIG. 2 represent the boundaries of a sealed interior volume 15 formed by the film 10 (in this case, wrapped around the product 20 and sealed).
[0128] [0128] In some embodiments, a single web of rolls of pouch film can be placed in a packaging machine and folded together and heat sealed and cut to form heat sealed pouches. Two-sided sealed pouches with a folded third side can be used to package an article by a manufacturer or packer who places a product in the pouch, and completes the final seal to produce a hermetically sealed package containing for example: a transdermal patch delivery drugs; an orally soluble thin strip containing a drug, flavoring, antimicrobial agent, odorant, and/or microbiologically active ingredient or combination thereof; or an article for collecting or administering a physiologically active substance.
[0129] [0129] Experimental results and reported properties are based on the following test methods or substantially similar test methods unless otherwise noted Oxygen Gas Transmission Rate (O2GTR): ASTM D-3985-81 Transmission Rate Water Vapor (WVTR): ASTM F 1249-90 Caliber: ASTM D-21 03 Melt Index (MI): ASTM D-1238, Condition E (190 °C.) (except for propylene-based polymers (> 50% C3 content) tested at TL Condition (230 °C.)) Melting point: ASTM D-3418, DSC with heating rate 5 °C/min Glass Transition Temperature Tg ASTM D3418 Brightness: ASTM D- 2457, 45° angle Direct Contact Test with Nicotine 57/82
[0130] [0130] Ten pouches are made with each test film by heat sealing together two pieces of the sample film each measuring 3 x 3.5 inches on three sides with the same surface contacting the article aimed at the others. Next, 50 µL of pure nicotine is placed on a 1 x 1.25 inch piece of drying paper and the drying paper is placed inside the pouch which is then heat sealed.
[0131] [0131] Bags are stored at 100°F and 20% RH and two bags of each film structure are tested at reported intervals eg days 1, 2, 8, 15 and 31. After the time allowed , two pouches are opened by cutting an end seal, and the stains removed. The unstained pouches are rinsed with distilled water to remove any liquid nicotine that could be present on the surface of the sealant and excess water is removed from the pouches by shaking. Next, 5 ml of isopropanol enriched with an internal standard (propylene glycol n-propyl ether) is placed in each pouch which is then resealed with heat seals. The resealed pouches are placed in a shaker tube for 90 minutes to facilitate extraction of nicotine from the sealant. Finally, extracts from the pouches are analyzed by gas chromatography and the amount of eluted nicotine is calculated for each pouch. Nicotine Vapor Test
[0132] [0132] Ten pouches are made with each test film by heat sealing together two pieces of the sample film each measuring 3 x 3.5 inches on three sides with the same contacting surface with the article aimed at the others. Next, 50 µL of pure nicotine is placed on a 1 x 1.25 inch piece of drying paper. The drying paper is then wound on perforated sheet having approximately 20 needle punctures per side. The sheet-wrapped drying paper is placed inside the pouch which is then hermetically sealed. The perforated 58/82 foil wrapping prevents direct contact of the nicotine absorbed in the paper with the sealing layer of the film.
[0133] [0133] Bags containing stains are stored at 100°F and 20% Relative Humidity (RH). Two pockets of each film structure are tested at reported intervals, e.g., days 1, 2, 8, 15, and 31 as follows. After the time allowed, two pouches are opened by cutting an end seal, and the foil-covered papers are removed. Then, 5 ml of isopropanol, enriched with an internal standard (propylene glycol n-propyl ether), is placed in each pouch and each paperless pouch is resealed with heat seals. The resealed pouches are then placed in a shaker tube for 90 minutes to facilitate extraction of nicotine from the sealant. Finally, extracts from the pouches are analyzed by gas chromatography and the amount of eluted nicotine is calculated for each pouch.
[0134] [0134] Eluted nicotine values are measured by the methods described above or tests similar to them, unless otherwise specified. Drug uptake test
[0135] [0135] Ten pouches are made with each test film by heat sealing together two pieces of the sample film each measuring 3 x 3.5 inches on three sides with the same surface contacting the article aimed at the others. Next, a standard amount of the drug being tested is placed on a 1 x 1.25 inch piece of drying paper and the drying paper is placed inside the pouch which is then heat sealed.
[0136] [0136] Bags are stored at 100°F and 20% RH and three bags of each film structure are tested at reported intervals, e.g., days 1, 7, 15, and 31. After the time allowed, three pouches are opened by cutting an end seal, and stains removed. The unstained pouches are rinsed with distilled water to remove any drug residue that could be present on the surface of the sealant and excess water is removed from the pouches by agitation. Next, 5 ml of isopropanol enriched with an internal standard (propylene glycol n-propyl ether) is placed in each pouch which is then resealed with heat seals. The resealed pouches are placed in a shaker tube for 90 minutes to facilitate drug extraction from the sealant. Finally, extracts from the bags are analyzed by gas chromatography and the amount of eluted drug is calculated for each bag. Drug Vapor Test
[0137] [0137] Ten pouches are made with each test film by heat sealing together two pieces of the sample film each measuring 3 x 3.5 inches on three sides with the same surface contacting the article aimed at the others. Next, a standard amount of the drug being tested is placed on a 1 x 1.25 inch piece of drying paper. The drying paper is then wound on perforated sheet having approximately 20 needle punctures per side. The sheet-wrapped drying paper is placed inside the pouch which is then hermetically sealed. Perforated foil wrapping prevents direct contact of the drug absorbed on the paper with the sealant layer of the film.
[0138] [0138] Bags containing stains are stored at 100°F and 20% Relative Humidity (RH). Three pockets of each film structure are tested at reported intervals, e.g., days 1, 7, 15, and 31 as follows. After the time allowed, three pouches are opened by cutting an end seal, and the foil-covered stains are removed. Then, 5 ml of isopropanol, enriched with an internal standard (propylene glycol n-propyl ether), is placed in each pouch and each spotless pouch is resealed with heat seals. The resealed pouches are then placed in a shaker tube for 90 minutes to facilitate 60/82 drug extraction from the sealant. Finally, extracts from the bags are analyzed by gas chromatography and the amount of eluted drug is calculated for each bag.
[0139] [0139] Eluted drug values are measured by the methods described above or tests similar thereto, unless otherwise specified. Raman spectroscopy
[0140] [0140] For purposes of illustration a method of Raman Spectroscopy is now described for samples in direct contact with a nicotine composition. It will be understood that the method can be readily modified for use with indirect drug contact or for use with other drugs.
[0141] [0141] Film samples in direct contact with nicotine for a specified time were analyzed using a Raman Confocal microscope (Thermo Fisher DXRxi) using a 100x objective (numerical aperture: 0.90), a laser wavelength of 532 nm (10 mW of power at the sampling point) and an exposure time of 0.04 seconds per spectrum. The estimated spot size in the sample was 0.2 μm and the confocal aperture used was 25 μm. Spectra between wave numbers 500-3500 cm-1 were collected. The spectra were collected in the form of a depth profile from a section of film (100 x 100 μm) as a Raman image pixel size specified as 2 µm and the total number of scans was 10. As a result, each Raman image is a composite of results from 25,000 spectra. The Raman image was generated using proprietary software (Thermo Fisher Scientific) included in the Raman microscope used. The area under the peaks (wavenumber range: 1004-1064 cm-1) was used to indicate the relative concentration of nicotine at each point in the Raman 61/82 image generated on a rainbow scale (low: blue , raised: red). Pure nicotine peaks at 1026 cm-1 and 1042 cm-1.
[0142] [0142] The following are examples given to illustrate the invention, but these examples should not be taken as limiting the scope. All percentages are by weight unless otherwise indicated.
[0143] [0143] Films with 6, 7, 8, 9 or more layers are contemplated. The inventive multilayer films may include additional layers or polymers to add or modify various properties of the desired film such as heat sealability, interlayer adhesion, crease resistance, puncture resistance, printability, hardness, gas barrier properties, and/or water, abrasion resistance, printability, and optical properties such as gloss, haze, freedom from lines, streaks or gels. These layers may be formed by any suitable method including coextrusion, extrusion coating and lamination.
[0144] [0144] Unless otherwise noted, the thermoplastic resins used in the present invention are generally commercially available in pellet form and, as generally recognized in the art, can be melt-combined or mechanically blended by well-known methods using commercially available equipment. available including drums, mixers or combiners. Also, if desired, well-known additives such as processing aids, glidants, anti-blocking agents and pigments, and mixtures thereof, can be incorporated into the film or applied to one or more surfaces thereof, e.g., by blending prior to extrusion. , dusting, spraying, application on contact rollers, etc. Typically, the resins and any desired additives are blended and fed into an extruder where the resins are melt plasticized by heating and then transferred to an extrusion (or coextrusion) die. Extruder and spinner temperatures will depend on the particular resin or resin-containing mixtures being processed and suitable temperature ranges for commercially available resins are generally known in the art, or are provided in technical bulletins made available by resin manufacturers. Processing temperatures may vary depending on other processing parameters chosen. EXAMPLES 1-5
[0145] [0145] Examples 1-4 are comparative examples (not of the invention). Example 5 is an example according to the present invention. In all examples a multilayer film is provided having a base film and sealing film attached. The sealant film has a surface layer that is designed to contact the article to be packaged, e.g., a transdermal patch article, and to allow heat sealing of the film in multiple layers to form a container such as a pouch. . The EAAILDPE/COC sealant layer of the invention and the comparative sealant layers were extrusion coated or adhesively laminated. In all examples 1-5 a multi-layer base film was made having the following structure: OPET / Primer / PE / EAA / Sheet and only the bonded sealant film was varied. base film
[0146] [0146] The base film was comprised of five layers having an ordered structure of: /Layer 1/ Layer 2/ Layer 3/Layer 4/Layer 5/ corresponding to: /outer layer 1/initiator layer 2/volume layer 3 /adhesive layer 4/layer 0 2 5/; or more particularly, /OPET/PEI/LDPE/EVA/Al Sheet/.
[0147] [0147] Layer 1 was a 0.92 mil, biaxially oriented polyethylene terephthalate (OPET) film with corona treatment on one side. The treated OPET film received a second corona treatment on the previously treated side before receiving an anchor coat of a water-based polyethyleneimine (PEI) initiator (Layer 2) that was contact coated on the corona treated side of the OPET film and dried immediately prior to laminating the OPET film onto 0.35 mil aluminum foil (Layer 5) using a coextrusion of LDPE (Layer 3) and EAA (Layer 4). Layers 3 and 4 were produced by co-extruding two layers of LDPE and EAA. The anchor coated side of the OPET film was laminated to 0.35 mil aluminum foil with a coextrusion of LDPE and EAA. LDPE was a combination of 87.5% by weight of LDPE laminate resin and 12.5% by weight of a white dye in a carrier resin. The barrier to oxygen and moisture was provided by a commercially available aluminum foil. Comparative Example 1
[0148] [0148] In example 1, an ionomer sealant film was extrusion coated onto a five layer base film made as described above. The aluminum foil surface of the multilayer base film having the structure OPET/initiator/LDPE/EAA/foil underwent corona treatment and then was extrusion coated with ionomer. The ionomer used was a zinc salt of ethylene acid methacrylate copolymer commercially available under the tradename Surlyn® 1652-1 and having a reported density of 0.940 g/cm3 and meh index of 4.5 g/10 min.
[0149] [0149] The resulting six-layer, multilayer film had the following structure: OPET with 0.92 mil / initiator / coex (LDPE with 0.42 mil / EAA with 0.1 mil) / sheet with 0.35 mil 1.0 mil, and had a nominal total thickness of 2.8 mils (71 microns).
[0150] [0150] The base film for example 2 was produced in the same manner as for example 1 except that the aluminum foil was not corona treated prior to the addition of the sealant film. In comparative example 2, a three-layer coextrusion of: EAA; LDPE; and an 80:20% by weight blend of LDPE:mLLDPE was extrusion coated onto the aluminum foil surface of the multi-layer base film with the EAA layer adhered to and in direct contact with the aluminum foil. The resulting multilayer film had the following structure: OPET with 0.92 mil / initiator / (LDPE with 0.42 mil / EAA with 0.1 mil) / sheet with 0.35 mil / EAA with 0.17 mil / LDPEI with 0.65 mil LDPE:mLLDPE with 0.43 mil and a total thickness of 3.04 mils (77.2 microns). Comparative Example 3
[0151] [0151] The base film for example 3 was produced in the same manner as for example 2. In comparative example 3, the sealant film was a commercially available corona treated molded APET film. The APET film received an additional corona treatment prior to adhesive lamination. The base films and sealant were laminated by coating the aluminum foil surface of the base film in multiple layers having the OPET/initiator/LDPE/EAA/foil structure with a 2-part urethane adhesive using an analox winder followed by contact of lamination on an APET film with corona retreatment. The 7 layer film had the following structure: OPET with 0.92 mil / initiator / LDPE with 0.42 mil / EAA with 0.1 mil / sheet with 0.35 mil / adhesive with 0.08 mil / APET with 2 mil (inside) and a total thickness of 3.9 mils (99 microns). Comparative Example 4 65/82
[0152] [0152] The base film for example 4 was produced in the same manner as for example 2, except that the LDPE/EAA coextrusion was applied slightly thicker. In comparative example 4, the sealing film was a corona treated polyacrylonitrile film. The polyacrylonitrile film received an additional corona treatment immediately before lamination. The aluminum foil surface of the multilayer base film having the structure OPET/initiator/LDPE/EAA/foil was then coated with a 2-part urethane adhesive using an analox winder and the structure was adhesively laminated onto the polyacrylonitrile film. with corona retreatment. The resulting multilayer film had the following structure (outside) OPET with 0.92 mil / initiator / LDPE with 0.56 mil / EAA with 0.1 mil / sheet with 0.35 mil / Adhesive with 0.07 mil / Barex with 1.5 mil (inside) and a total thickness of 3.5 mil. Example 5 (Of the Invention)
[0153] [0153] The film structure in Example 5 is exemplary of a film in accordance with the present invention. The base film for example 5 was produced in the same manner as for comparative example 2. In this example, the sealant film was a three-layer coextrusion of EAA, LDPE and Ethylene-norbornene copolymer (COC) that was coated with extrusion on the aluminum foil surface of the base film in multiple layers to produce an eight layer film having the structure: OPET with 0.92 mil/initiator/LDPE with 0.42 mil/EAN with 0.1 mil sheet with 0 .35 mils/EAA with 0.17 mils/LDPE with 0.65 mils/COC with 0.43 mils COC and a total thickness of 3.0 mils (76 microns). The inventive film is well suited for packaging articles for collecting or administering a physiologically active substance such as transdermal drug delivery patches, or thin oral dissolvable strips and has moisture barrier, oxygen barrier, and low scalping properties as discussed in low. The resulting 66/82 multilayer film was tested for the various properties which are reported below. Scalping Tests for Examples 1-5
[0154] [0154] Each of the films made in Examples 1-5 were tested for nicotine scalping by a “Nicotine Direct Contact Test” and a “Nicotine Vapor Test”. The properties are reported in Table 2 below. Table 2 Ex. Layer Thickness Direct Contact Test with Nicotine Vapor Test No. Sealant Average Nicotine Amount of Eluted Nicotine Sealant Amount of Eluted Nicotine (mg) (mil) (mg) Day Day Day Day Day Day Day Day 8 Day Day 1 2 8 15 31 1 2 15 31 1 Ionomer 1.0 17.1 15.3 16.7 24.0 22.0 8.5 11.9 15.8 25.2 23.7 2 Combination 0.43 10.5 10.8 13.3 17.0 15.8 5.76 7.85 11.5 17.2 16.2 80:20% by weight LDPE:mLLDPE 3 APET 2 12.6 10.5 12 0 .49 0.70 1.08 COC 0.43 2.08 3.47 1.42 3.12 2.03 0.94 1.26 1.95 2.42 1.26 Example 6 - Testing of additional agents
[0155] [0155] Tested Structures: APET: OPET 92 ga / PE White 7.5# Coex / Sheet 35 ga / Ad. 1.7# / APET with 2 mil (35680-G) CXB™: OPET 92 ga / PE White 9.6# Coex / Sheet 35 ga / Ad. 1.7# / CXB with 2 mil (LLDPE-COC) (35694-G) Barex®: OPET 92 ga / White PE 9.6# Coex / Sheet 35 ga / Ad. 1.7# / Barex® with 2 mil ( 35434-G) 67/82
[0156] [0156] When choosing the test materials, PE-based sealants were chosen as a negative control and Barex® was chosen as a positive control. The purpose of an anti-scalping sealant is to perform better than PE and show performance close to (if not matched to) Barex®.
[0157] [0157] With Barex® being the gold standard for uptake, a goal of at least 85% Barex® performance was set. While each application will differ in barrier requirements, those that do require minimal uptake and are currently on Barex® will require performance close to that of Barex® to minimize the risk of packaging.
[0158] [0158] In the case of the Nicotine Uptake Test, CXB™ performed at 95.2% of the performance of Barex® with direct contact and 98% of the performance of Barex® with indirect contact. In subsequent nicotine uptake studies, CXB™ performed greater than 98% of the performance of Barex®. Estradiol uptake, and HSP
[0159] [0159] Direct contact day Ionomer Barex APET 35775-PE CXB 1 0.0000 0.0000 0.0000 0.0000 0.0000 7 0.0000 0.0000 0.0000 0.0000 0.0000 18 0.0073 0 .0000 0.0000 0.0048 0.0055 30 0.0051 0.0000 0.0137 0.0000 0.0088 60 0.0029 0.0000 0.0161 0.0058 0.0132 68/82
[0160] [0160] Very small amounts of estradiol can be detected in several of the samples. It is unclear at this point whether the values are indicative of a precise uptake trend.
[0161] [0161] Indirect Contact (steam contact) day Barex APET 35775-PE CXB ionomer 1 0.00000 0.00000 0.00000 0.00000 0.00000 7 0.00000 0.00000 0.00000 0.00000 0.00000 17
[0162] [0162] In the indirect uptake test, PE and APET show detectable amounts of Estradiol while the other materials showed no uptake. Estradiol values in this case remain very low.
[0163] [0163] HSP: (no RED value for the lonomer) RED values CXB Barex PE (low Tg) PET Estradiol 1.62 0.97 3.12 0.46
[0164] [0164] Raman: No penetration of Estradiol could be detected with Raman Spectroscopy in the uptake samples. Lidocaine, HSP, and Raman Uptake
[0165] [0165] Direct Contact Direct Contact (average mg of Lidocaine) day Ionomer Barex APET 35775-PE CXB 0 0.0000 0.0000 0.0000 0.0000 0.000 1 0.3283 0.0467 0.0693 0.1559 0, 0124 7 1.8896 0.1055 0.2392 0.5739 0.0214 18 1.9872 0.5642 0.3339 0.6513 0.0473 30 2.7984 0.1328 0.6924 0.8306 0.1347 60 2.85 0.43 1.19 0.72 0.25 69/82
[0166] [0166] Direct contact shows CXB as the best performance, even exceeding the performance of Barex®.
[0167] [0167] Indirect Contact (Steam Contact) Steam Contact (average mg of Lidocaine) day Barex APET 35775-PE CXB Ionomer 0 0.0000 0.0000 0.0000 0.0000 0.0000 0.0000 1 0.0125 0.0090 0.0083 0.0137 0.0055 7 0.0400 0.0199 0.0194 0.0276 0.0075 14 0.0492 0.0352 0.0272 0.0536 0.0107 30 0.0664 0.0719 0, 0506 0.0809 0.0209 60 0.3570 0.2999 0.1717 0.2452 0.1389
[0168] [0168] Again with steam contact, CXB™ is the best performer.
[0169] [0169] HSP: RED CXB Barex PE (Low Tg) PET Lidocaine Values 1.32 0.9 2.85 0.23
[0170] [0170] Raman: Lidocaine permeation could only be seen in Ionomer and PE after 28 days of direct contact. PE permeation resulted in Lidocaine diffusing through the sealant layer and settling at the sealant/sheet interface.
[0171] [0171] Based on the results of the above examples, the inventors now believe that two factors play a role in permeation characteristics; namely, thermodynamic and kinetic interactions. Again, based on the results presented here, the inventors believe that both of these interactions will together provide a more complete understanding of the permeation properties of a sealant film in relation to any of the factors in isolation. Thermodynamic interactions can be predicted through solubility modeling. Kinetic interactions are based on the structure of the polymer and the molecular weight of the active agent in the product. Assuming that all transdermal drugs are of low molecular weight, polymer characteristics can be used to predict the kinetic interaction. In this case, the Tg can be used as a factor in determining the rate at which a drug will diffuse through a polymer, with a higher Tg resulting in a lower diffusion rate. However, the Tg must be low enough to allow the polymer to be heat sealable. Therefore, the RED value of the HSP can be factored, with higher RED values indicating lower solubilities (thermodynamic factor). The more soluble the drug is in the sealant, the more permeation will occur. Antiscalping heat sealable films or layers with low permeation can be obtained by balancing RED (thermodynamics) and Tg (kinetic factors).
[0172] [0172] Based on the results presented here, the inventors believe that films or layers comprising 90% or more of an ethylene norbornene copolymer and having a glass transition temperature of 50-138 °C, an ethylene-norbornene comonomer content of 20-40% by mole of ethylene and 30-60% by mole of norbornene, or a glass transition temperature of 50-138 °C and an ethylene-norbornene comonomer content of 20-40% by mole of ethylene and 30-60% by mole of norbornene can provide a heat sealable film or layer that is anti-scalping with respect to a number of pharmaceutical agents, particularly those having HPS RED values of 0.5 or greater, such as 0, 6 or greater, 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1 or greater.
[0173] [0173] Various embodiments have been described above. While the invention has been described with reference to these specific embodiments, the descriptions are intended to be illustrative and not intended to be limiting. Various modifications and applications may occur to those skilled in the art without departing from the true spirit and scope of the invention as defined in the appended claims.
72/82

权利要求:
Claims (12)
[1]
1. A film for packaging a product comprising a pharmaceutical active agent, the film comprising: a sealing layer contacting the product comprising at least 90% by weight of an ethylene norbornene copolymer or having a glass transition temperature in a range from 50°C to 110°C; wherein the pharmaceutical active agent comprises a Hansen Solubility Parameter for the product-contacting seal layer of 0.5 or greater.
[2]
A film according to claim 1, wherein the pharmaceutical active agent is selected from the group consisting of fentanyl, nicotine, lidocaine, estradiol, clonidine, ethynyl estradiol, oxybutynin, buprenorphine, granisitron, methylphenidate, and scopolamine.
[3]
A film according to claim 1, wherein the pharmaceutical active agent is selected from the group consisting of nicotine, lidocaine, estradiol, clonidine, ethynyl estradiol, buprenorphine, granisitron, and scopolamine.
[4]
A film according to any one of claims 1, 2 or 3, wherein the pharmaceutical active agent comprises a Hansen Solubility Parameter for the polymeric sealant layer of 1 or greater.
[5]
A film according to any one of claims 1, 2, 3 or 4, wherein the sealing layer consists essentially of ethylene norbornene copolymer.
[6]
A film according to any one of claims 1, 2, 3, 4 or 5, wherein the product comprising the pharmaceutical active agent comprises a transdermal patch comprising the pharmaceutical active agent.
5/7
[7]
A packaged pharmaceutical product, comprising: a film according to any one of claims 1, 2, 3, 4, 5 or 6, wherein the sealing layer contacting the product defines a sealed interior volume; and the product containing a pharmaceutical active agent disposed in the interior volume of the sealed package, wherein the pharmaceutical agent is in contact with the sealing layer.
[8]
8. A method for packaging a pharmaceutical product comprising a pharmaceutical active agent, the method comprising: sealing the pharmaceutical product within a packaging film, wherein the film comprises a sealing layer comprising at least 90% by weight of an ethylene norbornene copolymer having a glass transition temperature in a range of 65°C to 110°C, wherein sealing the pharmaceutical within the packaging film comprises bringing the pharmaceutical agent into contact with the sealing layer, and wherein the pharmaceutical active agent comprises a Hansen Solubility Parameter for the polymeric seal layer of 0.5 or greater.
[9]
9. A flexible, drug resistant, multilayer packaging film comprising: (a) a drug contact layer having at least 90% by weight of an ethylene norbornene copolymer having a glass transition temperature of 65°C to 110°C; (b) a bulk layer of polyolefin; (c) a first intermediate adhesive layer; 6/7
(d) an oxygen barrier layer having an oxygen transmission rate of less than 0.01 cm 3 /100 inch 2 / 24 hours at 1 atmosphere and 23°C; (e) a second intermediate adhesive layer; and (f) an outer protective layer comprising a polymer selected from the group consisting of paper, oriented polyester, amorphous polyester, polyamide, polyolefin, nylon, polypropylene, or copolymers thereof, or combinations thereof, wherein said multilayer film has the following properties: a water vapor transmission rate (WTVR) of less than 0.01 g/100 square inches for 24 hours at 23 °C and 1 atmosphere.
[10]
10. A flexible, drug resistant, multilayer packaging film comprising a drug contact layer having at least 90% by weight of an ethylene norbornene copolymer having a glass transition temperature of 55°C to 110°C .
[11]
A packaged pharmaceutical product comprising: a film according to claim 10, wherein the film is formed in a flexible container; and a product comprising a pharmaceutical active agent, wherein the pharmaceutical active agent is in contact with the drug-contacting layer of the film.
[12]
A packaged pharmaceutical product according to claim 11, wherein the product comprising the pharmaceutical active agent comprises a transdermal patch comprising the pharmaceutical active agent, wherein the patch is a nicotine or fentanyl drug delivery patch.
7/7

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同族专利:

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公开号 | 公开日

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MY179541A|2020-11-10|

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US20170174405A1|2017-06-22|

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EP3848195A1|2021-07-14|

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US20150225151A1|2015-08-13|

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CN106457759B|2021-02-26|

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DK3105049T3|2021-01-11|

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US20210147129A1|2021-05-20|

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PL3105049T3|2021-06-28|

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ES2834377T3|2021-06-17|

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WO2015123211A1|2015-08-20|

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CN112895648A|2021-06-04|

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EP3105049A1|2016-12-21|

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CN106457759A|2017-02-22|

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US10934070B2|2021-03-02|

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EP3105049B1|2020-10-21|

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WO2015123211A8|2016-05-26|

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法律状态:
2018-12-26| B25G| Requested change of headquarter approved|Owner name: BEMIS COMPANY, INC (US) |

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2019-12-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-04-13| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-08-31| B15I| Others concerning applications: loss of priority|Free format text: PERDA DA PRIORIDADE US 14/178,005 REIVINDICADA NO PCT/US2015/015246, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 167O, ITEM 28 DO ATO NORMATIVO 128/97 E NO ART. 29 DA RESOLUCAO INPI-PR 77/2013. ESTA PERDA SE DEU PELO FATO DE O DEPOSITANTE CONSTANTE DA PETICAO DE REQUERIMENTO DO PEDIDO PCT SER DISTINTO DAQUELES QUE DEPOSITARAM A PRIORIDADE REIVINDICADA E NAO APRESENTOU DOCUMENTO DE CESSAO REGULARIZADO DENTRO DO PRAZO DE 60 DIAS A CONTAR DA DATA DA PUBLICACAO DA EXIGENCIA, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 166O, ITEM 27 DO ATO NORMATIVO 128/97 E NO ART. 28 DA RESOLUCAO INPI-PR 77/2013. |

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2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

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2021-11-09| B12F| Other appeals [chapter 12.6 patent gazette]|Free format text: RECURSO: 870210100395 - 29/10/2021 |

优先权:

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申请号 | 申请日 | 专利标题

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US14/178,005|US20150225151A1|2014-02-11|2014-02-11|Anti-Scalping Transdermal Patch Packaging Film|

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PCT/US2015/015246|WO2015123211A1|2014-02-11|2015-02-10|Anti-scalping pharmaceutical packaging film|

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