Patent Grant
11097035
The availability of oils that may be cured and used to develop biocompatible materials (e.g., for use as drug delivery vehicles, stand-alone films, or as coatings on medical devices) remains limited. Depending on the intended application of the cured oil composition (e.g., as a coating on a substrate such as a medical device) the physical properties of the oil used to prepare such cured oil composition may render it unsuitable for its intended application.
Cured oils that have been successfully developed have relied predominantly on fish oil triglyceride esters as the starting oil composition. In addition to fish oil, there are numerous other oils that may have potential applicability in the development of biocompatible products such as cured coatings and materials, however many of these oils may not be suitable for specific applications because of their inherent physical and chemical properties. For example, some oils may not effectively form solid gels, materials or coatings upon exposure to appropriate curing conditions. Similarly, some oils that are capable of forming solid coatings, materials or gels may not readily dissolve or hydrolyze upon exposure to appropriate conditions (e.g., in aqueous fluids), thereby making their use unsuitable for certain applications (e.g., as a vehicle or matrix with which to deliver a therapeutic agent to an intended site of action).
Novel methods and compositions for tailoring or otherwise altering the physical characteristics of cured oils are needed. Particularly needed are means of tailoring the properties of cured oils (e.g., viscosity and hydrophilicity) such that they may be rendered suitable for use, for example, as gels, materials and/or coatings useful for delivering one or more therapeutic agents. Also needed are methods and compositions useful for altering the polarity and/or hydrolysis rate of a cured oil coating, material or gel as a means to control the rate of release of a therapeutic agent to a target organ.
The present invention provides novel methods and compositions that may be used to tailor the physical characteristics of cured oils, such as marine and plant oils, to render such cured oils suitable for use, for example, as a biocompatible material for use as or with a medical device or as a coating capable of eluting one or more therapeutic agents. In certain embodiments, the methods and compositions disclosed herein identify and exploit the chemical properties of oils, both in native and synthetic form, that influence their ability to form both hydrolyzable and non-hydrolyzable cured oil based products or materials (e.g., a biocompatible material or coating, including a gel, or films, particles, or other structures or formations). In other embodiments, the methods and compositions disclosed herein relate to modifying and/or enhancing the physical and/or chemical characteristics of the oils that are used to prepare such cured oil materials or coatings, and include modifications or enhancements made to enhance the probability that such oils will form a biocompatible cured oil material or coating. Also disclosed are correlations to altering starting oil compositions (e.g., by blending of different oils) and the resulting cured coating prepared therefrom and methods of modifying or enriching such oil compositions such that the characteristics of the cured coatings prepared therefrom are modified. The methods and compositions of the present invention expand the population of oils that upon curing may be used as a stand-alone film, particle, as a coating on medical devices, or the like, and thereby enhance the ability to customize oil coatings based upon desired physical characteristics (e.g., release of a therapeutic agent, resorption kinetics and/or rate of coating hydrolysis in vivo).
Disclosed herein are cured oil based products or materials capable of use on or within a medical device and which comprise one or more cross-linked fatty acids, wherein the oils used to prepared such cross-linked fatty acids have been structurally modified from their native form to be enriched with one or more fatty acid alkyl esters (e.g., lower alkyl esters of fatty acids) prior to curing. In one embodiment, the esterified fatty acid used to enrich the oil is a lower alkyl ester of a fatty acid (e.g., an ethyl ester of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA)). Contemplated lower alkyls esters may be selected from the group consisting of linear and branched C1-C6 alkyls and include, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl (e.g., in both linear and branched forms) and combinations thereof. Preferred fatty acid alkyl esters include, for example, the ethyl esters of eicosapentaenoic acid (EPA), ethyl esters of docosahexaenoic acid (DHA) and combinations thereof.
In certain embodiments, the inventions relate to cured coatings (e.g., coatings that may be disposed or otherwise applied onto a medical device) or materials that are prepared using an enriched oil composition (e.g., blended oil compositions). Such enriched oil compositions may generally comprise one or more oils (e.g., a native oil such as fish oil triglycerides or a plant oil such as flaxseed oil) to which is added one or more fatty acid alkyl esters (e.g., lower alkyl esters of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA)). In some embodiments, the enriched oil comprises flaxseed oil and ethyl esters of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA). In other embodiments, the enriched oil comprises native fish oil triglycerides and ethyl esters of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA). The enriched oil compositions used to form such cured oil coatings and materials may comprise between about 1% to about 99% fatty acid alkyl esters (e.g., about 10-90% or about 25-75% fatty acid alkyl esters).
In certain embodiments, the enriched oils may be prepared by blending or otherwise combining one or more marine or plant oils with a second oil (e.g., fish oil ethyl esters) to form a blended oil compositions. In certain embodiments, the enriched oils may be prepared by blending or otherwise combining one or more marine or plant oils with a second, third or fourth oil. Suitable plant oils may include, for example, flaxseed oil, grapeseed oil, safflower oil, soybean oil, corn oil, echium oil, hempseed oil, walnut oil, olive oil and combinations thereof.
The coatings disclosed herein may be prepared from oils or enriched oils comprising at least about 50% polyunsaturated fatty acids. For example, the coatings may be prepared by curing (e.g., thermally curing) an enriched oil comprising at least about 60-65% polyunsaturated fatty acids (e.g., at least about 60-65% EPA and/or DHA).
In certain embodiments, the cured coatings and materials disclosed herein are hydrolyzable. Where such cured coatings are applied onto a substrate such as a medical device (e.g., a surgical mesh, a graft, a catheter balloon, a stand-alone film or a stent) they may be hydrolyzable in vivo. Disclosed are cured coatings and materials that undergo complete hydrolysis in a 0.1M NaOH solution in less than about 60 minutes at 37° C. (e.g., in about 30-45 minutes). Preferably, such cured coatings completely hydrolyze in vivo into substantially non-inflammatory compounds (e.g., free fatty acids, monoglycerides, diglycerides and glycerol). Also disclosed are cured coatings and materials that are porous or that otherwise comprise one or more voids.
In certain embodiments, the cured coatings and materials disclosed herein are non-hydrolyzable. Where such cured coatings are applied onto a substrate such as a medical device (e.g., a surgical mesh, a graft, a catheter balloon, a stand-alone film or a stent) or used to form a stand alone material they may not be hydrolyzable or absorbable in vivo, however, they may still maintain low to substantially non-inflammatory properties.
The coatings disclosed herein may be prepared such that they are hydrophilic in nature. For example, such coatings may be characterized as having a contact angle of less than about 90° (e.g., a contact angle less than 87.5°, 85°, 80°, 75°, 70°, 65°, 60°, 55°, 50°, 45°, or less). In other embodiments, the coatings described herein are characterized as having one or more polar functional groups (e.g., hydroxyl functional groups, as indicated by an infrared absorption spectrum having a peak absorbing at approximately 3300-3600 cm−1). The presence of such polar groups render such coatings more hydrophilic and thereby increase the likelihood that such coatings will hydrolyze following exposure to polar solvents (e.g., water) in vitro or in vivo.
In certain embodiments, the cured coatings and/or materials may be prepared such that they comprise one or more therapeutic agents. Such cured coatings or materials may be prepared to elute or otherwise release such therapeutic agents from the cured coatings or materials over a pre-determined period of time in vivo (e.g., at least one, two, three, four, five, six, seven, fourteen, twenty-one, thirty, sixty, ninety, one hundred and twenty days or more). Examples of contemplated therapeutic agents include, but are not limited to, anti-proliferative agents, anti-inflammatory agents, antimicrobial agents, antibiotic agents and combinations thereof.
Also disclosed are methods of altering (e.g., increasing or decreasing) the hydrolysis rate of a cured or cross-linked oil coating or material by enriching or supplementing that oil with one or more alkyl-esterified fatty acids prior to curing. Such methods generally comprise the steps of enriching one or more oils (e.g., a native plant triglyceride oil) used to form the cured oil coating with one or more oil or fatty acid alkyl esters (e.g., linear or branched C1-C6 lower alkyl esters) thereby forming a blended or enriched oil composition. The blended or enriched oil may be exposed to curing conditions (e.g., thermal curing condition) to form the cured oil material or coating. In certain embodiments, the hydrolysis rate of such cured oil coating or material is increased relative to the coating or material formed from the un-enriched or native triglyceride oil. In other embodiments, the hydrolysis rate of such cured oil coating or material is decreased relative to the coating or material formed from the un-enriched or native triglyceride oil (e.g., such that the biocompatible coating is non-absorbable).
In an example embodiment, the cured oil based products or materials are prepared using oil blends that impart different physical characteristics (e.g., exhibit faster or slower hydrolysis rates) to such cured oil based products or materials relative to the cured native or non-enriched oil. In accordance with the present invention, suitable native or non-enriched triglyceride oils may include, but are not limited to fish oil, flaxseed oil, grapeseed oil, safflower oil, soybean oil, corn oil, olive oil and combinations thereof. In one embodiment of the present invention, the cured oil based products or materials may be prepared by enriching or supplementing the native triglyceride oil used to prepared such cured oil based product, coating or material with between about 1% and about 99% fatty acid alkyl esters prior to curing, (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, about 95%, about 99% or more fatty acid alkyl esters) depending upon the desired physical characteristics of the final cured oil.
The above discussed, and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention when taken in conjunction with the accompanying examples.
The present invention is based on the discovery that the chemical properties of oils may be used to predict the physical properties of a resulting cured oil based product or material that is prepared therefrom, and in some instances the ability of the cured oil or material to form a biocompatible gel, material or coating, which may for example, be used as a standalone article, such as a film, particle or alternatively as coating on a medical device. The present invention is also based upon the finding that the chemical and physical properties of cured oil based products or materials that are prepared from native or non-enriched oils (e.g., properties such as the rate of hydrolysis of the cured oils in vitro or in vivo) may be modified by enriching such native or non-enriched oils with fatty acid alkyl esters prior to exposure to curing conditions. For example, in certain embodiments, the rate of hydrolysis of cured oils may be modified (e.g., increased or decreased) by blending such triglyceride oils with fatty acid alkyl ester oils prior to curing. In other embodiments, cured oil materials can be produced which are biocompatible, but are not hydrolyzable in-vivo. Additionally, the polarity as well as the cross-linked structure of cured oil materials can be altered as a means of controlling the release of therapeutic agents to a target organ or tissue.
In various embodiments, the cured oil based coatings and materials described herein are formed from or otherwise derived from oils (e.g., marine oils and/or plant oils), and in particular from the constituent fatty acids (e.g., polyunsaturated fatty acids) that comprise such oils. Generally, such fatty acids may be present in the oil in their native triglyceride form and/or as free fatty acids, fatty acid alkyl esters, monoglycerides and/or diglycerides. Also disclosed herein is the exposure of such oils to curing conditions (e.g., thermal curing conditions) such that cured or cross-linked oil based materials and/or coatings are formed. In certain embodiments, such cured or cross-linked oil based materials, and/or coatings are formed without the use of chemical cross-linking agents or additives. Such cured or cross-linked oil based materials may be used for a variety of applications. For example, in certain embodiments a homogeneous solid cured oil material may be useful as a dissolvable barrier or a drug delivery matrix or coating (e.g., as a coating on a medical device). In other embodiments, the materials or coatings are porous (e.g., coatings on a medical device comprising one or more voids).
As used herein to qualify the oil-derived coatings, materials, gels, films, particles and any other partially solidified compositions of the present invention, the term “cured” means that the oil has been subjected or exposed to some degree of processing, for example thermal or ultraviolet light exposure, such that some degree of oxidative cross-linking (e.g., partial or complete non-polymeric cross-linking) of the constituent fatty acids present in such oils is catalyzed. Contemplated methods for curing oils (e.g., native and/or enriched oils) to produce a cured or partially-cured material or coating include, but are not limited to, heating (e.g., by employing an oven, a broadband infrared light source, a coherent infrared light source such as a laser, and combinations of the foregoing) and ultraviolet (UV) irradiation. The exposure of such oils to curing conditions (e.g., thermal curing at 200° F. in the presence of oxygen) catalyzes the oxidation of the constituent fatty acids in the oil, thereby resulting in the cross-linking of such fatty acids (i.e., oxidative cross-linking). In certain embodiments, such cross-linking of fatty acids is achieved without reliance upon external cross-linking agents. In accordance with some embodiments of the present invention, the cured oils are characterized by an increase in viscosity relative to the uncured oils.
In various embodiments, increases in viscosity observed upon curing some oils may occur as a result of the cross-linking of one or more fatty acids (e.g., fatty acid alkyl esters or fatty acid triglyceride esters) that comprise such oils. In other embodiments, increases in viscosity observed upon curing some oils may occur as a result of the volatilization of one or more species (e.g., as saturated or monounsaturated fatty acid ethyl esters or as secondary oil oxidation by-products including aldehydes, ketones, alcohols and/or hydrocarbons) present in the oil. Continued curing of the oil may increase the number or the degree of fatty acid cross-linking and thereby increase the viscosity of such cured oil material such that a solid or a semi-solid coating, material or gel is produced. In certain embodiments, such solid or semi-solid cured oil materials are suitable for use as a coating on a device (e.g., medical device).
Oils (e.g., blended oil compositions prepared by enriching native fish oil triglycerides with fish oil ethyl esters and/or various plant oil triglycerides) may be partially cured (e.g., by exposure to heat). In certain embodiments, partially curing oils induces an initial amount of fatty acid oxidative cross-linking of such fatty acids and in certain embodiments may increase the viscosity of such oils. The process of partially curing an oil has the advantage of creating an initial platform of oxidized fatty acid cross-links that are capable of being hydrolyzed by tissue in vivo (e.g., by human tissue). Accordingly, in certain embodiments, the oils are cured to induce partial cross-linking of the constituent fatty acids that comprise such oils.
It has been determined that the ability of an oil (e.g., a plant or marine oil) to undergo cross-linking is dependent upon the constituent fatty acids comprising such oil and furthermore, that the ability of an oil to cross-link may be manipulated by altering its fatty acid composition. For example, contemplated herein are modifications made to native or non-enriched oils to increase the probability that the fatty acids comprising such oils will oxidize and/or cross-link (e.g., upon exposure to curing conditions). As used herein to qualify one or more oils, the term “non-enriched” refers to an unmodified oil, whether synthetically derived or in its native or natural state. Non-enriched or native oils may include, for example, marine oil triglycerides or alkyl esters, and plant triglycerides including, but not limited to, flaxseed oil, grapeseed oil, safflower oil, soybean oil, corn oil, echium oil, hempseed oil, walnut oil, olive oil and combinations thereof. The designation “non-enriched” is intended to distinguish such oils from their enriched counterparts (e.g., blended oil compositions comprising a plant oil enriched with one or more lower alkyl fatty acid esters) which are also the subject of the present invention and in certain instances is used synonymously with the term “native.”
The physical characteristics of the cured oils of the present invention are a function of the chemical characteristics of the oil from which they were prepared, and such chemical characteristics may be used to predict the physical characteristics of the cured oil composition (e.g., ability to be hydrolyzed). For example, upon exposure to curing conditions (e.g., by thermal or ultraviolet treatment), some non-enriched oils may remain in a liquid state that may be difficult to physically manipulate or that may not be physically suitable as a stable coating on a medical device, but may be suitable for other applications. As shown in Table 1 below and as further illustrated in the Examples, upon exposure of some native or non-enriched oils to thermal curing conditions for at least about 24 hours at about 200° F. the resulting cured oil materials demonstrated varying degrees of solidification and/or changes in viscosity. For example, native olive oil did not produce a solid coating and remained liquid throughout the curing process. Native corn oil and soybean oil, on the other hand, demonstrated an increase in viscosity, but did not demonstrate the physical handling characteristics seen for example with cured fish, grapeseed, safflower and flaxseed oils following exposure to the same curing conditions. Although not all oils are capable of forming cured coatings or materials, such oils or materials may be suitable for alternative uses.
To determine the relevant characteristics of oils that influence their ability to oxidize and/or form coatings or materials following exposure to curing conditions, the oils used to prepare such coatings or materials were evaluated to determine their constituent fatty acids and the relative concentrations of such fatty acids in such oils. The fatty acid compositions of native or non-enriched oils (e.g., marine oils and plant oils) are unique relative to each other. For example,
When correlated to the physical characteristics of the cured oils, as shown in Table 1, it was determined that curing of native or non-enriched oils and the ability (or inability) of such cured oils to form materials or coatings was directly dependent on the fatty acid composition of the oil from which such cured oils were prepared. In particular, it was discovered that the more polyunsaturated fatty acids present in the non-enriched oil, the more efficient that oil would be at undergoing oxidative cross-linking and forming a cured material, gel or coating. Specifically, the C22:6, C20:5, C18:3, and/or C18:2 polyunsaturated fatty acids present in fish and flaxseed oils are more efficient in forming a cured or cross-linked oil based material, gel or coating. Conversely, the oils which are deficient in the C22:6, C20:5 and C18:3 polyunsaturated fatty acids are more prone to forming less viscous (e.g., more liquid-like) compositions.
These findings are supported by contrasting the presence of polyunsaturated fatty acids in the non-enriched oils both pre- and post-exposure to curing conditions as shown in
Polyunsaturated oils with only two double bonds in their fatty acid chains (e.g., non-enriched grapeseed and safflower oils which have C18:2 fatty acids) are capable of forming a semi-solid or solid composition, but only in the presence of a higher concentration of C18:2 fatty acids (e.g., more than about 65-70% C18:2 polyunsaturated fatty acids). Oils containing less polyunsaturated fatty acids (e.g., soybean and corn oils which contain less than about 60% polyunsaturated fatty acids) demonstrate an increase in viscosity following exposure to curing conditions, but remain sticky and fluid. Finally, oils that contain predominantly monounsaturated fatty acids (e.g., non-enriched olive oil) are unable to form a cured material or coating on a selected substrate (e.g., a polypropylene mesh) and remain in a liquid state following exposure to curing conditions.
The comparison of the fatty acids, and in particular, the polyunsaturated fatty acids (PUFA), present in such native or non-enriched oils both pre- and post-exposure to curing conditions reveals that certain polyunsaturated fatty acids are being consumed following exposure of such oils to thermal curing conditions, thereby confirming that such fatty acids are participating in the cross-linking reaction that is catalyzed by exposure to such thermal curing conditions. The polyunsaturated fatty acids from native fish oil triglycerides that are participating in the cross-linking reactions include the C22:6, C20:5, C18:3 and C18:2 fatty acids, as evidenced by their absence in the cured coating. In comparison, the plant oils polyunsaturated fatty acids participating in the cross-linking reactions include the C18:3 and C18:2 fatty acids, as evidenced by their absence or reduced concentration in the cured materials. The concentrations of plant oil polyunsaturated fatty acids (e.g., relative to native fish oil triglycerides) capable of participating the cross-linking reactions correlate with a reduced ability of the fatty acids present in some the subject plant oils to participate in oxidative cross-linking reactions and thereby form a solid coating or coating. Consistent with the properties observed for some of the cured plant oils (e.g., little to no solidification following exposure to thermal curing conditions), the concentrations of monounsaturated fatty acids present in the plant oils (e.g., C18:1 monounsaturated fatty acids) generally remained consistent both before and after exposure of the subject plant oils to thermal curing conditions. The lack of consumption of the C18:1 monounsaturated fatty acids therefore confirms that such monounsaturated fatty acids that are present in the plant oil triglycerides (e.g., C18:1 fatty acids) are not participating in the oxidative cross-linking reactions. Similarly, the relatively low concentrations of polyunsaturated fatty acids in some of the plant oil triglycerides (e.g., corn oil and olive oil) correlates to the inability of such plant oils to form solidified cross-linked materials, gels or coatings following exposure to thermal curing conditions.
The identification of the constituent fatty acids comprising the oils that participate in the oxidative cross-linking reactions provides valuable information that can be used to further manipulate the behavior of other oils. For example, the ability of the polyunsaturated fatty acids EPA and DHA to participate in oxidative cross-linking and form solid coatings provides information that may be used to direct the modification of other oils that do not efficiently undergo oxidative cross-linking to form solid coatings. In particular, certain oils (e.g., plant oils that are partially deficient in polyunsaturated fatty acids) may be enriched with other secondary, tertiary and/or quaternary oils known to be high in polyunsaturated fatty acids to promote cross-linking of such oils and the production of a cured oil based material or coating. Enriching oils with, for example a secondary oil, therefore provides a means of imparting one or more desired characteristics to the oil and the cured oil coating or materials prepared therefrom. Generally, enrichment may be accomplished by combining one or more secondary oils (e.g., native or synthetic marine oils) to a primary oil (e.g., a native plant oil). For example, the enrichment of oils (e.g., native fish oil triglyceride esters) with fatty acid alkyl esters (e.g., lower alkyl esters of eicosapentaenoic acid and/or docosahexaenoic acid) has been found to modify and/or enhance the physical and chemical properties of the cured oil.
As the term is used herein to qualify one or more oils, “enriched” refers to oils to which have been added one or more secondary oils. Generally, enrichment imparts one or more benefits to the oil or the cured oil material or coating prepared from such oil. In certain embodiments, the secondary oil used to enrich, for example a plant oil, comprises one or more fatty acid alkyl esters (such as, for example, ethyl esters of fish oil with concentrated levels of EPA and/or DHA). Curing of enriched oils has lead to the development of biocompatible materials and coatings demonstrating modified hydrolysis characteristics relative to the cured non-enriched oil. By varying the degree of enrichment (i.e., the concentration of fatty acid alkyl esters in the native or non-enriched oil) the properties of the cured oil can be specifically modified (e.g., the rate at which the cured oil hydrolyzes can be increased). In some embodiments, an oil is enriched with a secondary, tertiary or quaternary oil of different origin(s). For example, a plant oil (e.g., flaxseed oil triglycerides) may be enriched with a marine oil (e.g., native fish oil triglycerides) and vice versa to form a homogeneous blended oil. Such blended oils may be exposed to curing conditions to catalyze cross-linking of the constituent fatty acids (e.g., polyunsaturated fatty acids) that comprise such blended oils and thereby form a hybrid cured coating or material
Enrichment of oils with fatty acid alkyl esters may be used as a means to alter the chemical and physical characteristics of oils. For example, cured oils that are resistant to in vivo hydrolysis may be considered for targeted delivery and extended or long-term release of a therapeutic agent to an intended site of action. Enrichment of such oil prior to curing may be used as a means of modifying the chemical and physical characteristics of the cured oil such that it may be easily hydrolyzed in vivo. The ability to manipulate coating hydrolysis behavior may be exploited depending on specific release requirements based on the properties of one or more therapeutic agents and the doses needed to effectuate a therapeutic response.
In certain embodiments the cured oil coating or material is hydrolyzable (e.g., in vivo). The ability of a cured coating or material to be hydrolyzable may be a function of both the types and the quantity of cross-links formed between the constituent fatty acids of the oil material following exposure to curing conditions. Accordingly, in some embodiments the cross-links or partial cross-links comprise bonds that render such coating or material hydrolyzable in vivo (e.g., ether and ester cross-links). In particular applications where the cured oil coating or material will be applied as a coating onto a device (e.g., a medical device) or used as a stand-alone film for in vivo applications, it may be preferable that the coating hydrolyzes in vivo into fatty acids, glycerols, and glycerides; hydrolyzes in vivo into non-inflammatory components; and/or contains an amount of polar hydroxyl or carboxylic acid groups sufficient to facilitate hydrolysis in vivo.
Alternatively, in one embodiment of the present invention, enrichment may also be used as a means to alter the characteristics of the cured oil such that the cured oil material is resistant to hydrolysis relative to the non-enriched oil (e.g., by blending oils). For example, an oil may be enriched or otherwise combined with a second oil such that upon exposure to curing conditions, the cured oil material, or coating is non-absorbable or is poorly absorbable in vivo, yet would still be biocompatible. In this particular embodiment, enrichment using an oil may provide a means of conferring altered chemical or physical properties to the cured oil. For example, if the intended use of the cured oil requires a less viscous cured oil composition, a second oil comprising one or more fatty acids which are less efficient in forming cross-links (e.g., C18:2 fatty acids) may be the oil used to enrich the first oil. Similarly, if the intended use of the cured oil requires that such cured oil demonstrate resistance to in vivo hydrolysis, enrichment using a second oil demonstrating such desired characteristics may be used as a means to modify the characteristics of the cured composition. Enriching a native or non-enriched oil with a second oil (i.e., blending the oils to form a homogeneous oil composition) may provide additional means of tailoring the physical and chemical characteristics of the cured material to better correlate with the intended use of such cured material.
Enrichment of oils (whether done using fatty acid alkyl esters or other triglyceride oils), and in particular the degree of enrichment, may also be used as a means of altering or manipulating the release characteristics of the cured oil as it relates to the elution of one or more therapeutic agents incorporated therein (e.g., as a coating on a drug eluting stent, hernia mesh or standalone film). For example, enrichment of an oil may be used a means of extending the release or elution of a therapeutic agent from a cured oil over extended periods of time in vivo (e.g., for delivering a therapeutic agent to its intended site of action over about 6 hours, 12 hours, 24 hours, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 12 months or more).
Fatty acids esterified with lower alkyls such as, for example, fish oil ethyl esters are distinguishable from native oils. For example, the chemical structure of each fatty acid comprising fish oil ethyl esters is altered relative to native fish oil triglycerides such that each fatty acid ethyl ester is approximately one-third of the size of that found in native fish oil (where the fatty acids are present in triglyceride form). To distinguish the lower alkyl ester forms of fatty acids from native triglyceride fatty acids, the lower alkyl ester forms of fatty acids are generally referred to herein as “fatty acid alkyl esters”. Ethyl esters of fish oil fatty acids may be referred to herein as “fish oil ethyl esters” to distinguish such ethyl esters from native fish oil triglycerides. Each fatty acid ester consists of one fatty acid linked to a lower alkyl compound (e.g., ethane) head group, while native triglyceride oils consist of three fatty acids bound to a glycerol backbone.
The fatty acid alkyl esters contemplated by the present invention include, for example, lower alkyl esters (e.g., such as methyl and ethyl esters of EPA and/or DHA). As the term is used to describe fatty acid esters, “lower alkyl” means a group having about one to about six carbon atoms in the chain, which for the purposes hereof may be straight or branched. The use of designations such as, for example, “C1-C6” is intended to refer to a lower alkyl (e.g., straight or branched chain and inclusive of alkenes and alkyls) having the recited range carbon atoms. Enriched oils may contain higher concentrations of esterified fatty acid species (e.g., ethyl esters of DHA and/or EPA) relative to the non-enriched oil. For example, enriched oils may contain about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, about 95%, about 99% or more fatty acid alkyl esters. The enrichment of fish oil (e.g., native fish oil triglycerides) with fatty acid alkyl esters can be exploited as a means to alter (e.g., increase) the hydrolysis rate of the cured oil coating. In certain embodiments, enrichment using fish oil ethyl esters (which are typically concentrated in EPA and DHA content) increase the probability (e.g., relative to the un-enriched or native oil) that the fatty acids comprising the enriched oil will cross-link and form a cured oil material or coating.
The increased rate of hydrolysis of the cured enriched oil occurs as a result of the length of the fatty acids and the availability of unsaturated sites in such fatty acids that comprise the enriched oil. Chemically, the rate of hydrolysis of the coating prepared using the enriched oil may be altered based on the selection of the esterified fatty acid. For example, factors such as the fatty acid chain length and the degree of unsaturation of the esterified fatty acid may alter the rate at which the cured enriched oil will hydrolyze.
The rate of hydrolysis of the cured oil is also dependent upon the nature of the fatty acids esters used to enrich the oil. For example, relative to triglyceride esters, ethyl esters of fatty acids demonstrate faster hydrolysis. Accordingly, by enriching oils with fatty acid alkyl esters (e.g., ethyl ester fatty acids) the resulting cured oil composition can be more easily hydrolyzed (i.e., the rate of hydrolysis is increased). As shown in
In certain embodiments, the cured coatings prepared using enriched oil compositions comprise polar functional groups (e.g., hydroxyl groups) that facilitate the hydrolysis of such coating or that render such coating more hydrophilic. The presence of more polar functional groups will encourage water hydration of the cured material or coating and thereby cause such cured material or coating to hydrolyze at a faster rate. In various embodiments, enrichment (e.g., using fish oil ethyl esters) can be utilized as a means to alter (e.g., increase) the polarity of cured oil surfaces. For example, enrichment of a native plant oil with fish oil ethyl esters may be used as means of rendering the cured coating formed from such enriched oil more polar (e.g., as determined by a contact angle less than about 90°).
In various embodiments, the polarity of the cured oil materials or coatings is determined with reference to the contact angle of such cured oil material coating. Cured materials or coatings characterized as having a high contact angles (e.g., greater that 90°) indicate that such cured materials or coating are more hydrophobic in nature. Conversely, cured materials or coatings characterized has having low contract angles (e.g., less than 90°) are indicative of cured materials or coatings that are more hydrophilic in nature. In certain embodiments, the cured materials and coatings described herein have a contact angle of less than about 90° (e.g., less than about 85°, 80°, 75°, 70°, 65°, 60°, 55°, 50°, 45°, 40°, 35° or 30°).
The presence of polar functional groups in the cured materials and coatings described herein may also be determined by FTIR spectral data analysis. The FTIR spectral data analysis provides a signal plot in which functional groups present in the cured coating's molecular structure absorb at specific wavelengths. Each cured oil coating has a unique spectral profile that may be used as a fingerprint to distinguish differences in chemistry. Functional group abundance can also be inferred by absorbance intensity comparison (e.g., spectral peak height). In certain embodiments, preparing the cured materials or coatings using enriched oils increases the presence of one or more polar functional groups (e.g., increasing the presence of polar hydroxyl functional groups as determined by the coating exhibit a broad peak absorbing between 3300-3600 cm−1).
In certain embodiments, the cured materials or coatings undergo complete hydrolysis in a basic media (e.g., 0.1M NaOH solution) in less than about 30-120 minutes (e.g., in about 30-90 minutes). In embodiments where such cured coatings or materials are used as coatings on medical devices, preferably such coatings completely hydrolyze in vivo into substantially non-inflammatory compounds (e.g., fatty acids and glycerides).
In addition to altering the rate of hydrolysis of the cured oil coating, enrichment can alter other physical properties of the cured oil. As shown in Table 2 below, the flexibility of the cured oil coating appears unaffected until an enrichment with at least 75% fish oil ethyl esters is achieved. Enrichment with a fish oil ethyl ester concentration of 75% resulted in a cured coating that became physically stiffer, which may be useful or desirous in the formation of stand alone articles, such as films, particles and stents for some alternative applications. Similarly, the cured oil formed using 100% fish oil ethyl ester oil is inelastic, which may also be useful in some alternative applications. Enrichment of native oils (e.g., using fish oil ethyl esters) therefore provides a means of modifying the physical properties of cured oil materials prepared from native oils.
In certain embodiments, the cured coatings and materials described herein comprise one or more therapeutic agents. As used herein, the phrase “therapeutic agent(s)” refers to a number of different drugs or agents presently available, as well as future agents that may be beneficial for use with methods and processes described herein. The therapeutic agent can take a number of different forms including anti-oxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, anti-microbial agents, anti-imaging agents, anesthetic agents, therapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, anti-septics, analgesics, prodrugs thereof, and any additional desired therapeutic agents such as those listed in Table 3 below.
Some specific examples of therapeutic agents useful in the anti-restenosis realm and that may be delivered by the cured coatings of the present invention in accordance with the methods and compositions disclosed herein include cerivastatin, cilostazol, fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydrate derivative (for example, as described in U.S. Pat. No. 7,160,867), a rapamycin derivative (for example, as described in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin, seco-everolimus, and simvastatin. With systemic administration of a therapeutic agent, the therapeutic agent is administered orally or intravenously and is systemically available. However, there are drawbacks to a systemic delivery of a therapeutic agent, one of which is that the therapeutic agent travels throughout the patient's body and can have undesired effects at areas not targeted for treatment by the therapeutic agent. Furthermore, large doses of the therapeutic agent only amplify the undesired effects at non-target areas. As a result, the amount of therapeutic agent that results in application to a specific targeted location in a patient may have to be reduced when administered systemically to reduce complications from toxicity resulting from a higher dosage of the therapeutic agent.
Calcineurin is a serine/threonine phospho-protein phosphatase and is composed of a catalytic (calcineurin A) and regulatory (calcineurin B) subunit (about 60 and about 18 kDa, respectively). In mammals, three distinct genes (A-alpha, A-beta, A-gamma) for the catalytic subunit have been characterized, each of which can undergo alternative splicing to yield additional variants. Although mRNA for all three genes appears to be expressed in most tissues, two isoforms (A-alpha and A-beta) are most predominant in brain.
The calcineurin signaling pathway is involved in immune response as well as apoptosis induction by glutamate excitotoxicity in neuronal cells. Low enzymatic levels of calcineurin have been associated with Alzheimers disease. In the heart or in the brain calcineurin also plays a key role in the stress response after hypoxia or ischemia.
Substances that are able to block the calcineurin signal pathway can be suitable therapeutic agents that may be administered in accordance with the methods and compositions of the present invention. Examples of such therapeutic agents include, but are not limited to, FK506, tacrolimus, cyclosporin and include derivatives, analogs, esters, prodrugs, pharmaceutically acceptably salts thereof, and conjugates thereof which have or whose metabolic products have the same mechanism of action. Further examples of cyclosporin derivatives include, but are not limited to, naturally occurring and non-natural cyclosporins prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprising cyclosporins includes, for example, the naturally occurring Cyclosporins A through Z, as well as various non-natural cyclosporin derivatives, artificial or synthetic cyclosporin derivatives. Artificial or synthetic cyclosporins can include dihydrocyclosporins, derivatized cyclosporins, and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence, for example, dihydro-cyclosporin D.
In various embodiments, the therapeutic agent comprises one or more of mTOR targeting compounds and a calcineurin inhibitor. The term “mTOR targeting compound” refers to any compound that modulates mTOR directly or indirectly. In various embodiments, mTOR targeting compounds inhibit mTOR. An example of an “mTOR targeting compound” is a compound that binds to FKBP 12 to form, e.g., a complex, which in turn inhibits phosphoinostide (PI)-3 kinase, that is, mTOR. Suitable mTOR targeting compounds that may be used in accordance with the methods and processes disclosed herein include, for example, rapamycin and its derivatives, analogs, prodrugs, esters and pharmaceutically acceptable salts.
In various embodiments, the mTOR targeting compound is a rapamycin or a derivative, analog, ester, prodrug, pharmaceutically acceptably salts thereof, or conjugate thereof which has or whose metabolic products have the same mechanism of action. In various embodiments, the calcineurin inhibitor is a compound of Tacrolimus, or a derivative, analog, ester, prodrug, pharmaceutically acceptably salts thereof, or conjugate thereof which has or whose metabolic products have the same mechanism of action or a compound of Cyclosporin or a derivative, analog, ester, prodrug, pharmaceutically acceptably salts thereof, or conjugate thereof which has or whose metabolic products have the same mechanism of action.
The therapeutic agents that may be administered in accordance with the methods and compositions disclosed herein also include antimicrobial agents, including antivirals antibiotics, antifungals and antiparasitics. Specific antimicrobial agents that can be used with the cured materials and coatings of the invention include Penicillin G, Ephalothin, Ampicillin, Amoxicillin, Augmentin, Aztreonam, Imipenem, Streptomycin, Vancomycin, Clindamycin, Erythromycin, Azithromycin, Polymyxin, Bacitracin, Amphotericin, Nystatin, Rifampicin, Tetracycline, Doxycycline, Chloramphenicol, Nalidixic acid, Ciprofloxacin, Sulfanilamide, Gantrisin, Trimethoprim Isoniazid (INH), para-aminosalicylic acid (PAS), and Gentamicin.
In certain embodiments, the ability of the cured materials and coatings disclosed herein to elute one or more therapeutic agents is a function of the rate at which such cured materials or coatings ability to hydrolyze upon exposure to predetermined conditions (e.g., in vivo). Such coatings may be prepared to elute or otherwise release such therapeutic agents from the coatings over a pre-determined period of time in vivo (e.g., least one, two, three, four, five, six, seven, fourteen, twenty-one, thirty, forty, fifty, sixty, ninety, one hundred twenty days, one hundred eighty days or more). As previously discussed, the rate at which such cured materials or coatings hydrolyze may be modulated (e.g., enhanced) by modifying or enriching the oil from which such cured materials or coatings are prepared. Accordingly, in certain embodiments, enrichment (e.g., using fish oil ethyl esters) can be utilized as a means to alter (e.g., increase) the rate at which one or more therapeutic agents elutes from a cured coating or material. For example, enrichment of a native plant oil with fish oil ethyl esters may be used as means of increasing the rate at which a cured coating formed from such enriched oil hydrolyzes and therefore elutes one or more therapeutic agents. Similarly, one or more oils (e.g., native fish oil) may be enriched with a secondary oil (e.g., flaxseed oil) to retard the rate at which a coating formed from such enriched oil hydrolyzes and one or more therapeutic agents elute.
While certain compounds and methods of the present invention have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds of the invention and are not intended to limit the same.
The articles “a” and “an” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to include the plural referents. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim (or, as relevant, any other claim) unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where elements are presented as lists, (e.g., in Markush group or similar format) it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not in every case been specifically set forth in so many words herein. It should also be understood that any embodiment or aspect of the invention can be explicitly excluded from the claims, regardless of whether the specific exclusion is recited in the specification. The publications, websites and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.
The following examples illustrate that the chemical properties of oils, and in particular of the constituent fatty acids that comprise both marine oils and plant oils, may be used to predict the ability of such oils to undergo oxidative cross-linking, for example upon exposure to thermal curing conditions. Additionally, the physical properties of the coatings or materials prepared upon exposure of such oils to, for example, thermal curing conditions may also be predicted based on the chemical properties of the oil. These teachings provide means of manipulating oils such that cured coatings or materials prepared therefrom have one or more properties capable of rendering such coatings or materials fit for a particular purpose (e.g., as a drug-eluting coating on a medical device).
The purpose of the present experiments was to investigate the ability of native or “un-enriched” plant oils to thermally cross-link and form a cured oil material or coating; to compare the properties of such plant oils to native fish oil triglycerides; and to investigate how the fatty acid composition of the plant oils evaluated influenced the properties and chemistry of the final cured oil coatings prepared therefrom. The plant oils investigated included corn oil, echium oil, flaxseed oil, grapeseed oil, hempseed oil, olive oil, peanut oil, safflower oil, soybean oil, sunflower oil and walnut oil.
The oils were each gravimetrically applied to a 6×6 cm polypropylene mesh by pipette and subsequently thermally cured by exposure to 93° C. for a minimum of 24 hours. After thermal exposure, the coated mesh samples were physically inspected for oil solidification, appearance and texture. As depicted in Table 1, following the exposure of specific plant oils to thermal curing conditions, varying degrees of solidification were observed. For example, some of the plant oils evaluated (e.g., olive oil) did not cure or cross-link and remained in a liquid state. Other oils appeared to exhibit an increase in viscosity and partially solidified around the polypropylene mesh, but subsequent heat exposure did not result in the formation of a solid, dry coating. Some of the plant oils investigated readily cross-linked and formed a continuous coating around the polypropylene mesh following exposure to thermal curing conditions. In particular, cured coatings physically similar to the coatings prepared using native fish oil triglycerides were achieved with flaxseed, safflower and grapeseed oils.
By evaluating the fatty acid compositions of native oils and comparing such fatty acid compositions to the fatty acid compositions of cured coatings prepared from such oils, it was determined that the fatty acid composition of the subject oils was the determining property responsible for the physical differences observed in the thermally-cured plant oils. The plant oils that were capable of cross-linking to form a cured material or coating upon exposure to thermal conditions contained higher concentrations of the polyunsaturated C18 fatty acids.
None of the plant oils evaluated contain EPA or DHA in their triglyceride structures. Rather, each of the plant oils evaluated comprised triglyceride molecules with unique fatty acid compositions that differed markedly from the fatty acids found in fish oil. For example, the alkyl tails of the fatty acids components of the plant oil triglycerides ranged from about C16-C18 in length with varying degrees of saturation (e.g., each unsaturated fatty acid in the evaluated plant oils contained one to a maximum of three double bonds). In contrast, the alkyl tails of the fatty acid components of the fish oil triglycerides ranged from about C14-C22 in length with varying degrees of saturation (e.g., each unsaturated fatty acid contained one to a maximum of six double bonds).
The native fish oil triglycerides and the selected non-enriched plant oils were also analyzed to determine the relative amounts of the constituent fatty acids that comprise such oils. The amount of constituent fatty acids present in the oils were then compared to the fatty acid composition of the thermally cured coatings that were prepared using the native fish oil triglycerides and plant oils. As illustrated in
Compared to native fish oil, the plant oils evaluated predominantly have C18:2 polyunsaturated fatty acids and C18:1 monounsaturated fatty acids.
As an alternative to native fish oil which comprises fatty acids largely in triglyceride form, fish oil fatty acids in ethyl ester form were evaluated for their ability to undergo oxidative cross-linking and form solid coatings upon exposure to thermal curing conditions. To distinguish the ethyl ester forms of such fish oil fatty acids from native fish oil in triglyceride form, the ethyl ester forms of fish oil fatty acids are referred to herein as the “fish oil ethyl esters”.
The fish oil ethyl esters evaluated were distinguishable from the native fish oil in several ways. For example, the chemical structure of each fatty acid comprising the fish oil ethyl esters was altered relative to native fish oil such that each fatty acid molecule was approximately one-third of the size of that found in native fish oil where the fatty acids are largely present in triglyceride form. Furthermore, each fatty acid comprising the fish oil ethyl esters consisted of one fatty acid linked to an ethanol head group, while native triglyceride oils consist of three fatty acids connected via a glycerol backbone.
The fatty acid composition of the fish oil ethyl esters also differed from that of native fish oil. For example, the fish oil ethyl esters contained the same polyunsaturated fatty acid species as the native fish oil, however such polyunsaturated fatty acids were present in different proportions. The higher concentrations of EPA and DHA present in the fish oil ethyl esters corresponds to approximately twice the amount of omega-3 polyunsaturated fatty acids EPA and DHA found in native fish oil, which typically contains about 16-18% EPA and 10-11% DHA.
To evaluate the ability of the fish oil ethyl esters to undergo oxidative cross-linking and form coatings, the fish oil ethyl esters were applied gravimetrically to 6×6 cm polypropylene mesh by pipette and subsequently cured for 24 hours at 200° F. For comparison purposes, native fish oil was also applied gravimetrically to 6×6 cm polypropylene mesh by pipette and subsequently cured for 24 hours at 200° F.
A dry, solid, coating was formed upon exposure of the fish oil ethyl esters to the thermal curing conditions. Small voids were also observed within the gaps of the polypropylene mesh substrate onto which the fish oil ethyl ester coating was formed, that were not observed on the coatings formed using the native fish oil triglycerides. The voids were evident despite having applied the same mass of starting oil per unit of polypropylene mesh surface area. The presence of such voids in the coatings were attributed to the higher volatility of the fish oil ethyl esters and the volatilization of fatty acids that were not directly participating in the oxidative cross-linking reactions during the exposure of such fish oil ethyl esters to thermal curing conditions (e.g., saturated and monounsaturated fatty acids).
The cured coatings made from the fish oil ethyl esters were observed to be physically stiffer (i.e., more rigid and less flexible) and more inelastic in texture when compared to the coatings prepared using native fish oil under the same conditions. The increased physical rigidity observed with the coating prepared using the fish oil ethyl esters was likely due to increased intermolecular linkages or cross-links resulting from the increased concentration of available cross-linking fatty acids (e.g., EPA and DHA).
Further evaluation of the coatings prepared using fish oil ethyl esters also revealed marked differences in the chemical and physical properties of such coatings compared to the coatings prepared using native fish oil triglycerides. In vitro bench hydrolysis testing was performed using an aqueous 0.1 molar sodium hydroxide (0.1M NaOH) solution and demonstrated that the coatings prepared from the fish oil ethyl esters dissolved at a much faster rate than the coatings prepared using native fish oil triglycerides. As illustrated in
Blends of native oils from different origins (e.g., plant oils and fish oils) and fatty acid compositions were investigated to determine means of manipulating the physical properties of the oils and of the cured coatings prepared using such oils. Native fish oil triglycerides were enriched with oils of plant origin at various ratios to form a blended oil composition and such blended oils were evaluated to determine their ability to cross-link and form solidified coatings or materials upon exposure the thermal curing conditions. Additionally, further studies were conducted using blended oils that were prepared by enriching native fish oil triglycerides with fish oil ethyl esters. In the foregoing studies, the blended oil formulations were prepared gravimetrically at different ratios (e.g., at 10%, 25%, 50%, 75%, and/or 90% w/w), were each applied as homogenous liquids onto 6×6 cm Prolite Ultra polypropylene mesh by pipette and subsequently exposed to thermal curing conditions for at least 24 hours at 200° F. Following their exposure to thermal curing conditions, the coated meshes were further evaluated.
Blends of Native Plant and Fish Oils
Blended oils were prepared by enriching native plant-oils with native fish oils to determine if the polyunsaturated fatty acids from native fish oil (e.g., EPA and DHA) would participate in the oxidative cross-linking reactions with the polyunsaturated fatty acids from plant oils (e.g., LA and ALA) to form cured hybrid coatings or materials. The plant oils assessed included flaxseed oil, which (as discussed in Example 1) was capable of forming a solid coating or material upon exposure to thermal curing conditions, and olive oil, which (as also discussed in Example 1) was incapable of forming a solid coating and remained liquid during exposure to thermal curing conditions.
Following exposure to thermal curing conditions, the blended combination of native fish oil and flaxseed oil readily formed homogenous coatings at all of the ratios evaluated. In particular, upon exposure to thermal curing conditions, polyunsaturated fatty acids from the native fish oil triglycerides (e.g., EPA and/or DHA) participated in an oxidative cross-linking reaction with polyunsaturated fatty acids from flaxseed oil triglycerides (e.g., LA and/or ALA) and thereby formed coatings on the polypropylene mesh. The observed solid coatings produced upon thermal curing of the blended fish oil and flaxseed oil combinations support the conclusion that fatty acids of different origins (e.g., plant- and marine-based polyunsaturated fatty acids) can readily cross-link with each other to form solid coatings and materials.
To determine whether enrichment of olive oil with native fish oil triglycerides could facilitate the cross linking of the fatty acids present in olive oil, additional studies were conducted using a blended oil formulation prepared by gravimetrically combining native fish oil and olive oil at different ratios. Following exposure to thermal curing conditions, the blended oil combinations of native fish oil and olive oil did not produce a solid homogeneous coating at any of the ratios evaluated. Accordingly, enrichment of olive oil with fish oil triglycerides could not induce cross-linking of the polyunsaturated fatty acids present in the olive oil with the polyunsaturated fatty acids present in the native fish oil triglycerides to form a homogeneous solid coating or material.
Blends of Native Fish Oil Triglycerides and Fish Oil Ethyl Esters
Additional studies were conducted to determine whether fatty acids from different triglyceride oils would react to form a cross-linked network with the fish oil ethyl ester fatty acids having an enriched EPA and DHA content. Blended oil formulations were prepared by enriching native fish oil or flaxseed oil with fish oil ethyl esters at various ratios.
Following exposure of the blended oils to thermal curing conditions, all of such blended oil combinations at all ratios evaluated produced solid homogeneous coatings on the polypropylene mesh substrates to which they were applied. Upon exposure to thermal curing conditions, the fish oil triglycerides enriched with the fish oil ethyl esters produced homogenous, coatings at all ratios evaluated. Similarly, the flaxseed oil enriched with fish oil ethyl esters produced homogenous, coatings at all ratios evaluated. The foregoing provides evidence that blended oil combinations can be used to produce coatings or materials and that triglyceride fatly acids can react with ethyl ester fatty acids to form oxidative cross-links.
Additional studies were conducted to evaluate and compare the ability of coatings prepared using plant oils, marine oils, fish oil ethyl esters and blended oil combinations of the foregoing, to hydrolyze in an alkaline hydrolysis solution. In the foregoing studies, the oil formulations were prepared and applied as homogenous liquids onto 6×6 cm polypropylene mesh by pipette and subsequently exposed to thermal curing conditions for at least 24 hours at 200° F. Samples were obtained by taking a 1×1″ laser-cut area of each cured oil coated mesh. Such samples were then placed in clear glass vials, submerged into a fixed volume of 0.1 molar sodium hydroxide solution and monitored for complete coating dissolution. During the coating hydration and hydrolysis reaction time, the vials were heated to 37° C. and stored on a shaker table rotating at approximately 75 rotations per minute. The temperature evaluated was equivalent to the typical body temperature to which the coating on a substrate (e.g., a medical device) would be exposed in vivo. The purpose of the present studies was to provide a metric with which to compare coating integrity and resilience under basic conditions. The data generated with this in vitro hydrolysis test method are useful to help predict coating breakdown and performance in vivo.
Under the test conditions evaluated, the coatings prepared using native fish oil triglycerides completely hydrolyzed into solution after about 20-30 minutes. All of the plant oil coatings evaluated, which included flaxseed, safflower and grapeseed oils, took significantly longer to hydrate, hydrolyze and dissolve. In comparison, the coatings prepared using the fish oil ethyl esters hydrolyzed at a significantly faster rate.
Coatings were also prepared using blends of either native fish or plant oil triglycerides enriched with fish oil ethyl esters and were also evaluated for ability to be hydrolyzed upon exposure to the basic media. The coatings prepared using the blended oils comprised either native fish oil or flaxseed oil enriched with fish oil ethyl esters provided unique, altered hydrolysis profiles. A graph depicting these in vitro hydrolysis times for these oil blends as a function of ethyl ester quantity in the blended oil material is illustrated in
As depicted in
The coatings prepared using the blended oil formulations (i.e., plant oil or fish oil enriched with fish oil ethyl esters) were also evaluated for coating polarity using FTIR spectral identity and surface contact angle analysis. The FTIR spectral identity provides a signal plot in which functional groups present in the coating's molecular structure absorb at specific wavelengths. Each cured oil coating prepared had a unique spectral profile that may be used as a fingerprint to distinguish differences in the chemical structure of such coating. For example, the presence of hydroxyl functional groups in the coating exhibited a broad peak absorbing between about 3300-3600 cm−1. As depicted in
The polarity and the hydrophilicity of the coatings prepared using blended oils were also evaluated and compared by determining the contact angles of such coatings. The contact angle analysis was conducted by placing a drop of water onto the coating and thereafter a snapshot image was immediately acquired. The image of the water droplet upon the surface of the coating was then analyzed to calculate the angle at which the water droplet contacted the surface of the coating. Angles of higher degree (e.g., greater than 90°) indicate that the surface is more hydrophobic in nature. Conversely, angles of a lower degree (e.g., less than 90°) indicate that the surface is more hydrophilic in nature. The presence of polar species on the surface chemistry of a solid material encourages wettability (i.e. hydrophilicity). As depicted in
The FTIR spectral data and contact angle measurements presented herein demonstrate that the addition of fish oil ethyl esters can be utilized to alter the polarity of cured oil coatings or materials. The ability to modify the surface chemistries of cured oil coatings and materials can be advantageous in that more polar functional groups will encourage water hydration and thereby facilitate the hydrolysis of the coating.
The instant studies were conducted to compare the release profiles of a model therapeutic compound from the coatings prepared using native plant oils or fish oils enriched with ethyl ester fatty acids. Three cross-linked oil coatings were prepared by applying native fish oil, flaxseed oil or fish oil ethyl esters to 6×6 cm polypropylene mesh by pipette and subsequently curing for 24 hours at 200° F. Triclosan, a lipophilic, hydrophobic, antimicrobial therapeutic agent, was incorporated into the three different oil formulations at the same target drug load. Samples of each cured coating prepared were then subjected to a drug dissolution testing. High performance liquid chromatography (HPLC) was performed to assay the dissolution aliquots of the quantity of drug eluted from the coatings in order to generate the release curves unique to each coating.
The triclosan dissolution curves are shown in
The present studies were conducted to evaluate the in vivo biocompatability and resorption kinetics of blended coatings on polypropylene mesh. The coated polypropylene meshes were implanted into the muscle tissue of rabbit models. The cross-linked oil coatings were prepared using either native fish oil triglycerides, fish oil ethyl esters, flaxseed oil, or various blends of marine oils enriched with fish oil ethyl esters. After 2 months implantation time, the coated polypropylene meshes were harvested from the muscle tissue and evaluated microscopically.
All animals evaluated survived until scheduled sacrifice. Histological evaluation of the harvested tissue did not indicate any adverse cellular responses or inflammation with respect to any of the implant coated meshes. Microscopic evaluation of the explanted coated meshes did indicate differences in amounts of remaining coating present on the mesh as well as cellular infiltration. Images of cross-sections of the devices inserted into tissue after 2 months are shown in
As illustrated in
Discussion
The foregoing studies illustrate that cured lipid or oil-based coatings or materials having desired properties may be formed by altering the oil composition used to prepare such cured coatings. In particular, manipulating the underlying chemical properties (e.g., fatty acid composition) of the oils (e.g., by blending with other oils) prior to exposure to, for example, thermal curing conditions, facilitates the tailoring of the cured coating's or material's physical characteristics, which include, for example polarity, flexibility and the ability to hydrolyze. Furthermore, the present inventions provide means of controlling the elution of therapeutic agents from a coating or material to thereby control the release of such therapeutic agents. The teachings provided herein also provide means of tailoring the properties of cured coatings or materials and thereby expand the potential application of oils and such cured coatings or materials prepared from such oils and thereby expand the purposes for which such oils or cured coatings may be used (e.g., as a drug-eluting coating on medical devices), and further provide that modifying the composition of starting oils provides a means of manipulating coating resorption kinetics in vivo. Accordingly, by manipulating chemical properties of oils, the compositions and methods disclosed herein effectively increase the population of available native or enriched oils that may be cured or cross-linked as well as the number of specific applications for which such oils may be used.
This application is a divisional application of U.S. patent application Ser. No. 13/184,512, filed Jul. 16, 2011 (now U.S. Pat. No. 10,322,213 B2), which claims priority to, and the benefit of, U.S. Application No. 61/365,125, filed on Jul. 16, 2010. The entire teachings of the above application(s) are incorporated herein by reference. The disclosures of U.S. Publication Nos. 2006/0078586 to Ferraro et al., published Apr. 13, 2006, entitled “Barrier layer”, 2006/0067983 to Swanick et al., published Mar. 30, 2006, entitled “Stand-alone film and methods for making the same”, 2006/0067974 to Labrecque et al., published Mar. 30, 2006, entitled “Drug delivery coating for use with a stent”, 2007/0202149 to Faucher et al., published Aug. 30, 2007, entitled “Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings”, 2009/0181937 to Faucher et al., published Jul. 16, 2009, entitled “Cross-linked Fatty Acid-Based Biomaterials” and 2009/0208552 to Faucher et al., published Aug. 20, 2009, entitled “Cross-linked Fatty Acid-Based Biomaterials” which relate to oil coatings and materials used as stand-alone films and as medical device coatings are incorporated herein by reference in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1948959 | Croce | Feb 1934 | A |
| 2368306 | Kefer et al. | Jan 1945 | A |
| 2403458 | Ransom | Jul 1946 | A |
| 2555976 | Keenan | Jun 1951 | A |
| 2735814 | Hodson et al. | Feb 1956 | A |
| 2986540 | Posnansky | May 1961 | A |
| 3328259 | Anderson | Jun 1967 | A |
| 3464413 | Goldfarb et al. | Sep 1969 | A |
| 3556294 | Walck et al. | Jan 1971 | A |
| 3567820 | Sperti | Mar 1971 | A |
| 3803109 | Nemoto et al. | Apr 1974 | A |
| 3967728 | Gordon et al. | Jul 1976 | A |
| 4308120 | Pennewiss et al. | Dec 1981 | A |
| 4323547 | Knust et al. | Apr 1982 | A |
| 4345414 | Bomat et al. | Aug 1982 | A |
| 4447418 | Maddoux | May 1984 | A |
| 4557925 | Lindahl et al. | Dec 1985 | A |
| 4655221 | Devereux | Apr 1987 | A |
| 4664114 | Ghodsian | May 1987 | A |
| 4702252 | Brooks et al. | Oct 1987 | A |
| 4711902 | Semo | Dec 1987 | A |
| 4733665 | Palmaz | Mar 1988 | A |
| 4769038 | Bendavid et al. | Sep 1988 | A |
| 4813210 | Masuda et al. | Mar 1989 | A |
| 4814329 | Harsanyi et al. | Mar 1989 | A |
| 4824436 | Wolinsky | Apr 1989 | A |
| 4846844 | De Leon et al. | Jul 1989 | A |
| 4847301 | Murray | Jul 1989 | A |
| 4880455 | Blank | Nov 1989 | A |
| 4883667 | Eckenhoff | Nov 1989 | A |
| 4886787 | De Belder et al. | Dec 1989 | A |
| 4894231 | Moreau et al. | Jan 1990 | A |
| 4895724 | Cardinal et al. | Jan 1990 | A |
| 4911707 | Heiber et al. | Mar 1990 | A |
| 4937254 | Sheffield et al. | Jun 1990 | A |
| 4938763 | Dunn et al. | Jul 1990 | A |
| 4941308 | Grabenkort et al. | Jul 1990 | A |
| 4941877 | Montano, Jr. | Jul 1990 | A |
| 4947840 | Yannas et al. | Aug 1990 | A |
| 4952419 | de Leon et al. | Aug 1990 | A |
| 4968302 | Schluter et al. | Nov 1990 | A |
| 4994033 | Shockey et al. | Feb 1991 | A |
| 5017229 | Burns et al. | May 1991 | A |
| 5041125 | Montano, Jr. | Aug 1991 | A |
| 5049132 | Shaffer et al. | Sep 1991 | A |
| 5061281 | Mares et al. | Oct 1991 | A |
| 5071609 | Tu et al. | Dec 1991 | A |
| 5087244 | Wolinsky et al. | Feb 1992 | A |
| 5087246 | Smith | Feb 1992 | A |
| 5102402 | Dror et al. | Apr 1992 | A |
| 5118493 | Kelley et al. | Jun 1992 | A |
| 5132115 | Wolter et al. | Jul 1992 | A |
| 5147374 | Fernandez | Sep 1992 | A |
| 5151272 | Engstrom et al. | Sep 1992 | A |
| 5171148 | Wasserman et al. | Dec 1992 | A |
| 5179174 | Elton | Jan 1993 | A |
| 5199951 | Spears | Apr 1993 | A |
| 5202310 | Levy et al. | Apr 1993 | A |
| 5206077 | Cowley et al. | Apr 1993 | A |
| 5176956 | Jevne et al. | May 1993 | A |
| 5224579 | Brown | Jul 1993 | A |
| 5254105 | Haaga | Oct 1993 | A |
| 5267985 | Shimada et al. | Dec 1993 | A |
| 5279565 | Klein et al. | Jan 1994 | A |
| 5282785 | Shapland et al. | Feb 1994 | A |
| 5283257 | Gregory et al. | Feb 1994 | A |
| 5286254 | Shapland et al. | Feb 1994 | A |
| 5295962 | Crocker et al. | Mar 1994 | A |
| 5304121 | Sahatjian | Apr 1994 | A |
| 5336178 | Kaplan et al. | Aug 1994 | A |
| 5356432 | Rutkow et al. | Oct 1994 | A |
| 5368602 | de la Torre | Nov 1994 | A |
| 5371109 | Engstrom et al. | Dec 1994 | A |
| 5380328 | Morgan | Jan 1995 | A |
| 5387658 | Schroder et al. | Feb 1995 | A |
| 5403283 | Luther | Apr 1995 | A |
| 5411951 | Mitchell | May 1995 | A |
| 5411988 | Bochow et al. | Jun 1995 | A |
| 5447940 | Harvey et al. | Sep 1995 | A |
| 5456666 | Campbell et al. | Oct 1995 | A |
| 5456720 | Schultz et al. | Oct 1995 | A |
| 5458568 | Racchini et al. | Oct 1995 | A |
| 5458572 | Campbell et al. | Oct 1995 | A |
| 5464650 | Berg et al. | Nov 1995 | A |
| 5468242 | Reisberg | Nov 1995 | A |
| 5480436 | Bakker et al. | Jan 1996 | A |
| 5480653 | Aguadish et al. | Jan 1996 | A |
| 5490839 | Wang et al. | Feb 1996 | A |
| 5498238 | Shapland et al. | Mar 1996 | A |
| 5499971 | Shapland et al. | Mar 1996 | A |
| 5502077 | Breivik | Mar 1996 | A |
| 5509899 | Fan et al. | Apr 1996 | A |
| 5514092 | Forman et al. | May 1996 | A |
| 5547677 | Wright | Aug 1996 | A |
| 5549901 | Wright | Aug 1996 | A |
| 5558071 | Ward et al. | Sep 1996 | A |
| 5569198 | Racchini | Oct 1996 | A |
| 5573781 | Brown | Nov 1996 | A |
| 5579149 | Moret et al. | Nov 1996 | A |
| 5580923 | Yeung et al. | Dec 1996 | A |
| 5589508 | Schlotzer et al. | Dec 1996 | A |
| 5591230 | Horn et al. | Jan 1997 | A |
| 5593441 | Lichtenstein et al. | Jan 1997 | A |
| 5603721 | Lau et al. | Feb 1997 | A |
| 5605696 | Eury et al. | Feb 1997 | A |
| 5612074 | Leach | Mar 1997 | A |
| 5614284 | Kranzler et al. | Mar 1997 | A |
| 5627077 | Dyllick-Brenzinger et al. | May 1997 | A |
| 5628730 | Shapland et al. | May 1997 | A |
| 5629021 | Wright | May 1997 | A |
| 5634899 | Shapland et al. | Jun 1997 | A |
| 5634931 | Kugel | Jun 1997 | A |
| 5637113 | Tartagalia et al. | Jun 1997 | A |
| 5637317 | Dietl | Jun 1997 | A |
| 5641767 | Wess et al. | Jun 1997 | A |
| 5665115 | Cragg | Sep 1997 | A |
| 5693014 | Abele et al. | Dec 1997 | A |
| 5695525 | Mulhauser et al. | Dec 1997 | A |
| 5700286 | Tartagalia et al. | Dec 1997 | A |
| 5700848 | Soon-Shiong et al. | Dec 1997 | A |
| 5705485 | Cini et al. | Jan 1998 | A |
| 5731346 | Egberg et al. | Mar 1998 | A |
| 5736152 | Dunn | Apr 1998 | A |
| 5738869 | Fischer et al. | Apr 1998 | A |
| 5747533 | Egberg et al. | May 1998 | A |
| 5749845 | Hildebrand et al. | May 1998 | A |
| 5753259 | Engstrom et al. | May 1998 | A |
| 5760081 | Leaf et al. | Jun 1998 | A |
| 5766246 | Mulhauser et al. | Jun 1998 | A |
| 5766710 | Turnlund et al. | Jun 1998 | A |
| 5789465 | Harvey et al. | Aug 1998 | A |
| 5800392 | Racchini | Sep 1998 | A |
| 5807306 | Shapland et al. | Sep 1998 | A |
| 5817343 | Burke | Oct 1998 | A |
| 5824082 | Brown | Oct 1998 | A |
| 5827325 | Landgrebe et al. | Oct 1998 | A |
| 5828785 | Kitsuki | Oct 1998 | A |
| 5837313 | Ding et al. | Nov 1998 | A |
| 5843172 | Yan | Dec 1998 | A |
| 5843919 | Burger | Dec 1998 | A |
| 5865787 | Shapland et al. | Feb 1999 | A |
| 5874470 | Nehne et al. | Feb 1999 | A |
| 5879359 | Dorigatti et al. | Mar 1999 | A |
| 5897911 | Loeffler | Apr 1999 | A |
| 5898040 | Shalaby et al. | Apr 1999 | A |
| 5902266 | Leone et al. | May 1999 | A |
| 5906831 | Larsson et al. | May 1999 | A |
| 5931165 | Reich et al. | Aug 1999 | A |
| 5947977 | Slepian et al. | Sep 1999 | A |
| 5954767 | Pajotin et al. | Sep 1999 | A |
| 5955502 | Hansen et al. | Sep 1999 | A |
| 5986043 | Hubbell et al. | Nov 1999 | A |
| 6004549 | Reichert et al. | Dec 1999 | A |
| 6005004 | Katz et al. | Dec 1999 | A |
| 6010480 | Abele et al. | Jan 2000 | A |
| 6010766 | Braun et al. | Jan 2000 | A |
| 6010776 | Exsted et al. | Jan 2000 | A |
| 6013055 | Bampos et al. | Jan 2000 | A |
| 6015844 | Harvey et al. | Jan 2000 | A |
| 6028164 | Loomis | Feb 2000 | A |
| 6033380 | Butaric et al. | Mar 2000 | A |
| 6033436 | Steinke et al. | Mar 2000 | A |
| 6040330 | Hausheer et al. | Mar 2000 | A |
| 6048332 | Duffy et al. | Apr 2000 | A |
| 6048725 | Shimada et al. | Apr 2000 | A |
| 6056970 | Greenawalt et al. | May 2000 | A |
| 6066777 | Benchetrit | May 2000 | A |
| 6075180 | Sharber et al. | Jun 2000 | A |
| 6077698 | Swan et al. | Jun 2000 | A |
| 6080442 | Yoshikawa et al. | Jun 2000 | A |
| 6083950 | Anand et al. | Jul 2000 | A |
| 6090809 | Anand et al. | Jul 2000 | A |
| 6093792 | Gross et al. | Jul 2000 | A |
| 6117911 | Grainger et al. | Sep 2000 | A |
| 6120477 | Campbell et al. | Sep 2000 | A |
| 6120539 | Eldridge et al. | Sep 2000 | A |
| 6120789 | Dunn | Sep 2000 | A |
| 6132765 | DiCosmo et al. | Oct 2000 | A |
| 6146358 | Rowe | Nov 2000 | A |
| 6152944 | Holman et al. | Nov 2000 | A |
| 6176863 | Kugel et al. | Jan 2001 | B1 |
| 6193746 | Strecker | Feb 2001 | B1 |
| 6197357 | Lawton et al. | Mar 2001 | B1 |
| 6200985 | Cottens et al. | Mar 2001 | B1 |
| 6203551 | Wu | Mar 2001 | B1 |
| 6206916 | Furst | Mar 2001 | B1 |
| 6211315 | Larock et al. | Apr 2001 | B1 |
| 6224909 | Opitz et al. | May 2001 | B1 |
| 6228383 | Hansen et al. | May 2001 | B1 |
| 6229032 | Jacobs et al. | May 2001 | B1 |
| 6231600 | Zhong | May 2001 | B1 |
| 6245366 | Popplewell et al. | Jun 2001 | B1 |
| 6245811 | Harrobin et al. | Jun 2001 | B1 |
| 6254634 | Anderson et al. | Jul 2001 | B1 |
| 6258124 | Darois et al. | Jul 2001 | B1 |
| 6262109 | Clark et al. | Jul 2001 | B1 |
| 6273913 | Wright et al. | Aug 2001 | B1 |
| 6284268 | Mishra et al. | Sep 2001 | B1 |
| 6287285 | Michal et al. | Sep 2001 | B1 |
| 6287316 | Agarwal et al. | Sep 2001 | B1 |
| 6299604 | Ragheb et al. | Oct 2001 | B1 |
| 6306438 | Oshlack et al. | Oct 2001 | B1 |
| 6326360 | Kanazawa et al. | Dec 2001 | B1 |
| 6331568 | Horrobin | Dec 2001 | B1 |
| 6342254 | Soudant et al. | Jan 2002 | B1 |
| 6346110 | Wu | Feb 2002 | B2 |
| 6355063 | Calcote | Mar 2002 | B1 |
| 6358556 | Ding et al. | Mar 2002 | B1 |
| 6364856 | Ding et al. | Apr 2002 | B1 |
| 6364893 | Sahatjian et al. | Apr 2002 | B1 |
| 6364903 | Tseng et al. | Apr 2002 | B2 |
| 6368541 | Pajotin et al. | Apr 2002 | B1 |
| 6368658 | Schwarz et al. | Apr 2002 | B1 |
| 6369039 | Palasis et al. | Apr 2002 | B1 |
| 6387301 | Nakajima et al. | May 2002 | B1 |
| 6387379 | Goldberg et al. | May 2002 | B1 |
| 6410587 | Grainger et al. | Jun 2002 | B1 |
| 6444318 | Guire et al. | Sep 2002 | B1 |
| 6451373 | Hossainy et al. | Sep 2002 | B1 |
| 6463323 | Conrad-Vlasak et al. | Oct 2002 | B1 |
| 6465525 | Guire et al. | Oct 2002 | B1 |
| 6471980 | Sirhan et al. | Oct 2002 | B2 |
| 6479683 | Abney et al. | Nov 2002 | B1 |
| 6485752 | Rein et al. | Nov 2002 | B1 |
| 6491938 | Kunz | Dec 2002 | B2 |
| 6500174 | Maguire et al. | Dec 2002 | B1 |
| 6500453 | Brey et al. | Dec 2002 | B2 |
| 6503556 | Harish et al. | Jan 2003 | B2 |
| 6506410 | Park et al. | Jan 2003 | B1 |
| 6525145 | Gavaert et al. | Feb 2003 | B2 |
| 6527801 | Dutta | Mar 2003 | B1 |
| 6534693 | Fischell et al. | Mar 2003 | B2 |
| 6541116 | Michal et al. | Apr 2003 | B2 |
| 6544223 | Kokish | Apr 2003 | B1 |
| 6544224 | Steese-Bradley | Apr 2003 | B1 |
| 6548081 | Sadozai et al. | Apr 2003 | B2 |
| 6565659 | Pacetti et al. | May 2003 | B1 |
| 6569441 | Kunz et al. | May 2003 | B2 |
| 6579851 | Gocke et al. | Jun 2003 | B2 |
| 6596002 | Therin et al. | Jul 2003 | B2 |
| 6599323 | Melican et al. | Jul 2003 | B2 |
| 6610006 | Amid et al. | Aug 2003 | B1 |
| 6610035 | Yang et al. | Aug 2003 | B2 |
| 6610068 | Yang et al. | Aug 2003 | B1 |
| 6616650 | Rowe | Sep 2003 | B1 |
| 6630151 | Tarletsky et al. | Oct 2003 | B1 |
| 6630167 | Zhang | Oct 2003 | B2 |
| 6632822 | Rickards et al. | Oct 2003 | B1 |
| 6641611 | Jayaraman | Nov 2003 | B2 |
| 6645547 | Shekalim | Nov 2003 | B1 |
| 6663880 | Roorda et al. | Dec 2003 | B1 |
| 6669735 | Pelissier | Dec 2003 | B1 |
| 6670355 | Azrolan et al. | Dec 2003 | B2 |
| 6677342 | Wolff et al. | Jan 2004 | B2 |
| 6677386 | Giezen et al. | Jan 2004 | B1 |
| 6685956 | Chu et al. | Feb 2004 | B2 |
| 6689388 | Kuhrts | Feb 2004 | B2 |
| 6696583 | Koncar et al. | Feb 2004 | B2 |
| 6723133 | Pajotin | Apr 2004 | B1 |
| 6730016 | Cox et al. | May 2004 | B1 |
| 6730064 | Ragheb et al. | May 2004 | B2 |
| 6740122 | Pajotin | May 2004 | B1 |
| 6753071 | Pacetti | Jun 2004 | B1 |
| 6758847 | Maguire | Jul 2004 | B2 |
| 6761903 | Chen et al. | Jul 2004 | B2 |
| 6764509 | Chinn et al. | Jul 2004 | B2 |
| 6776796 | Falotico et al. | Aug 2004 | B2 |
| 6794485 | Shalaby et al. | Sep 2004 | B2 |
| 6808536 | Wright et al. | Oct 2004 | B2 |
| 6833004 | Ishii | Dec 2004 | B2 |
| 6852330 | Bowman et al. | Feb 2005 | B2 |
| 6875230 | Morita et al. | Apr 2005 | B1 |
| 6884428 | Binette et al. | Apr 2005 | B2 |
| 6887270 | Miller et al. | May 2005 | B2 |
| 6899729 | Cox et al. | May 2005 | B1 |
| 6902522 | Walsh et al. | Jun 2005 | B1 |
| 6918927 | Bates et al. | Jul 2005 | B2 |
| 6996952 | Gupta et al. | Feb 2006 | B2 |
| 7070858 | Shalaby et al. | Jul 2006 | B2 |
| 7090655 | Barry | Aug 2006 | B2 |
| 7101381 | Ford et al. | Sep 2006 | B2 |
| 7112209 | Ramshaw et al. | Sep 2006 | B2 |
| 7135164 | Rojanapanthu et al. | Nov 2006 | B2 |
| 7152611 | Brown et al. | Dec 2006 | B2 |
| 7311980 | Hossainy et al. | Dec 2007 | B1 |
| 7323178 | Zhang et al. | Jan 2008 | B1 |
| 7323189 | Pathak | Jan 2008 | B2 |
| 7415811 | Gottlieb et al. | Aug 2008 | B2 |
| 7691946 | Liu et al. | Apr 2010 | B2 |
| 7854958 | Kramer | Dec 2010 | B2 |
| 7947015 | Herweck et al. | May 2011 | B2 |
| 8001922 | Labrecque et al. | Aug 2011 | B2 |
| 8021331 | Herweck et al. | Sep 2011 | B2 |
| 8124127 | Faucher et al. | Feb 2012 | B2 |
| 8263102 | Labrecque et al. | Sep 2012 | B2 |
| 8298290 | Pelissier et al. | Oct 2012 | B2 |
| 8308684 | Herweck et al. | Nov 2012 | B2 |
| 8312836 | Corbeil et al. | Nov 2012 | B2 |
| 8367099 | Herweck et al. | Feb 2013 | B2 |
| 8461129 | Boldue et al. | Jun 2013 | B2 |
| 8501229 | Faucher et al. | Aug 2013 | B2 |
| 8722077 | Labrecque et al. | May 2014 | B2 |
| 8888887 | Hargrove et al. | Nov 2014 | B2 |
| 9000040 | Faucher et al. | Apr 2015 | B2 |
| 9012506 | Faucher et al. | Apr 2015 | B2 |
| 9220820 | Faucher et al. | Dec 2015 | B2 |
| 9278161 | Swanick et al. | Mar 2016 | B2 |
| 9427423 | Swanick et al. | Aug 2016 | B2 |
| 9493636 | Ah et al. | Nov 2016 | B2 |
| 20010022988 | Schwarz et al. | Sep 2001 | A1 |
| 20010025034 | Arbiser | Sep 2001 | A1 |
| 20010025196 | Chinn et al. | Sep 2001 | A1 |
| 20010026803 | Tebbe et al. | Oct 2001 | A1 |
| 20010027299 | Yang et al. | Oct 2001 | A1 |
| 20010051595 | Lyons et al. | Dec 2001 | A1 |
| 20020002154 | Guivarc'h et al. | Jan 2002 | A1 |
| 20020007209 | Scheerder et al. | Jan 2002 | A1 |
| 20020012741 | Heinz et al. | Jan 2002 | A1 |
| 20020013590 | Therin | Jan 2002 | A1 |
| 20020015970 | Murray et al. | Feb 2002 | A1 |
| 20020022052 | Dransfield | Feb 2002 | A1 |
| 20020026899 | McLaughlin et al. | Mar 2002 | A1 |
| 20020026900 | Huang et al. | Mar 2002 | A1 |
| 20020032414 | Ragheb et al. | Mar 2002 | A1 |
| 20020055701 | Fischell et al. | May 2002 | A1 |
| 20020077652 | Kieturakis et al. | Jun 2002 | A1 |
| 20020082679 | Sirhan et al. | Jun 2002 | A1 |
| 20020098278 | Bates et al. | Jul 2002 | A1 |
| 20020103494 | Pacey | Aug 2002 | A1 |
| 20020116045 | Eidenschink | Aug 2002 | A1 |
| 20020120333 | Keogh et al. | Aug 2002 | A1 |
| 20020122877 | Harish et al. | Sep 2002 | A1 |
| 20020127327 | Schwarz et al. | Sep 2002 | A1 |
| 20020142089 | Koike et al. | Oct 2002 | A1 |
| 20020183716 | Herweck et al. | Dec 2002 | A1 |
| 20020192352 | Dar | Dec 2002 | A1 |
| 20020193829 | Kennedy et al. | Dec 2002 | A1 |
| 20030003125 | Nathan et al. | Jan 2003 | A1 |
| 20030003221 | Zhong | Jan 2003 | A1 |
| 20030004564 | Elkins et al. | Jan 2003 | A1 |
| 20030009213 | Yang | Jan 2003 | A1 |
| 20030033004 | Ishii et al. | Feb 2003 | A1 |
| 20030036803 | McGhan | Feb 2003 | A1 |
| 20030055403 | Nestenborg et al. | Mar 2003 | A1 |
| 20030065292 | Darouiche et al. | Apr 2003 | A1 |
| 20030065345 | Weadock | Apr 2003 | A1 |
| 20030069632 | De Scheerder et al. | Apr 2003 | A1 |
| 20030072784 | Williams | Apr 2003 | A1 |
| 20030077272 | Pathak | Apr 2003 | A1 |
| 20030077310 | Pathak et al. | Apr 2003 | A1 |
| 20030077452 | Guire et al. | Apr 2003 | A1 |
| 20030083740 | Pathak | May 2003 | A1 |
| 20030086958 | Arnold et al. | May 2003 | A1 |
| 20030094728 | Tayebi | May 2003 | A1 |
| 20030100955 | Greenawalt et al. | May 2003 | A1 |
| 20030108588 | Chen et al. | Jun 2003 | A1 |
| 20030130206 | Koziak et al. | Jun 2003 | A1 |
| 20030124087 | Kim et al. | Jul 2003 | A1 |
| 20030152609 | Fischell et al. | Aug 2003 | A1 |
| 20030175408 | Timm et al. | Sep 2003 | A1 |
| 20030176915 | Wright et al. | Sep 2003 | A1 |
| 20030181975 | Ishii et al. | Sep 2003 | A1 |
| 20030181988 | Rousseau | Sep 2003 | A1 |
| 20030187516 | Amid et al. | Oct 2003 | A1 |
| 20030191179 | Joshi-Hangal et al. | Oct 2003 | A1 |
| 20030204168 | Bosma et al. | Oct 2003 | A1 |
| 20030204618 | Foster et al. | Oct 2003 | A1 |
| 20030207019 | Shekalim et al. | Nov 2003 | A1 |
| 20030211230 | Pacetti et al. | Nov 2003 | A1 |
| 20030212462 | Gryska et al. | Nov 2003 | A1 |
| 20030220297 | Berstein et al. | Nov 2003 | A1 |
| 20040006296 | Fischell et al. | Jan 2004 | A1 |
| 20040013704 | Kabra et al. | Jan 2004 | A1 |
| 20040014810 | Horrobin | Jan 2004 | A1 |
| 20040018228 | Fischell et al. | Jan 2004 | A1 |
| 20040039441 | Rowland et al. | Feb 2004 | A1 |
| 20040058008 | Tarcha et al. | Mar 2004 | A1 |
| 20040060260 | Gottlieb et al. | Apr 2004 | A1 |
| 20040071756 | Fischell et al. | Apr 2004 | A1 |
| 20040072849 | Schreiber et al. | Apr 2004 | A1 |
| 20040073284 | Bates et al. | Apr 2004 | A1 |
| 20040092969 | Kumar | May 2004 | A1 |
| 20040102758 | Davila et al. | May 2004 | A1 |
| 20040117007 | Whitbourne et al. | Jun 2004 | A1 |
| 20040123877 | Brown et al. | Jul 2004 | A1 |
| 20040131755 | Zhong et al. | Jul 2004 | A1 |
| 20040133275 | Mansmann | Jul 2004 | A1 |
| 20040137066 | Jayaraman | Jul 2004 | A1 |
| 20040137179 | Matsuda et al. | Jul 2004 | A1 |
| 20040142094 | Narayanan | Jul 2004 | A1 |
| 20040146546 | Gravett et al. | Jul 2004 | A1 |
| 20040156879 | Muratoglu et al. | Aug 2004 | A1 |
| 20040161464 | Domb | Aug 2004 | A1 |
| 20040167572 | Roth et al. | Aug 2004 | A1 |
| 20040170685 | Carpenter et al. | Sep 2004 | A1 |
| 20040192643 | Pressato et al. | Sep 2004 | A1 |
| 20040215219 | Eldridge et al. | Oct 2004 | A1 |
| 20040224003 | Schultz | Nov 2004 | A1 |
| 20040230176 | Shanahan et al. | Nov 2004 | A1 |
| 20040234574 | Sawhney et al. | Nov 2004 | A9 |
| 20040236278 | Herweek et al. | Nov 2004 | A1 |
| 20040241211 | Fischell | Dec 2004 | A9 |
| 20040256264 | Israelsson et al. | Dec 2004 | A1 |
| 20050010078 | Jamiolkowski et al. | Jan 2005 | A1 |
| 20050025804 | Heller | Feb 2005 | A1 |
| 20050084514 | Shebuski et al. | Apr 2005 | A1 |
| 20050095267 | Campbell et al. | May 2005 | A1 |
| 20050100655 | Zhong et al. | May 2005 | A1 |
| 20050101522 | Speck et al. | May 2005 | A1 |
| 20050106206 | Herweek et al. | May 2005 | A1 |
| 20050106209 | Ameri et al. | May 2005 | A1 |
| 20050112170 | Hossainy et al. | May 2005 | A1 |
| 20050113687 | Herweek et al. | May 2005 | A1 |
| 20050113849 | Popadiuk et al. | May 2005 | A1 |
| 20050124062 | Subirade | Jun 2005 | A1 |
| 20050129787 | Murad | Jun 2005 | A1 |
| 20050154416 | Herweek et al. | Jul 2005 | A1 |
| 20050159809 | Hezi-Yamit et al. | Jul 2005 | A1 |
| 20050165476 | Furst et al. | Jul 2005 | A1 |
| 20050165477 | Anduiza et al. | Jul 2005 | A1 |
| 20050158361 | Hunter et al. | Aug 2005 | A1 |
| 20050181061 | Ray et al. | Aug 2005 | A1 |
| 20050182485 | Falotico et al. | Aug 2005 | A1 |
| 20050186244 | Hunter et al. | Aug 2005 | A1 |
| 20050187376 | Pacetti | Aug 2005 | A1 |
| 20050203635 | Hunter et al. | Sep 2005 | A1 |
| 20050203636 | McFetridge | Sep 2005 | A1 |
| 20050223679 | Gottlieb et al. | Oct 2005 | A1 |
| 20050232971 | Hossainy et al. | Oct 2005 | A1 |
| 20050249775 | Falotico et al. | Nov 2005 | A1 |
| 20050283229 | Dugan et al. | Dec 2005 | A1 |
| 20060008501 | Dhont et al. | Jan 2006 | A1 |
| 20060020031 | Berlin | Jan 2006 | A1 |
| 20060030669 | Taton | Feb 2006 | A1 |
| 20060036311 | Nakayama et al. | Feb 2006 | A1 |
| 20060051544 | Goldmann | Mar 2006 | A1 |
| 20060058737 | Herweek et al. | Mar 2006 | A1 |
| 20060058881 | Trieu | Mar 2006 | A1 |
| 20060064175 | Pelissier et al. | Mar 2006 | A1 |
| 20060067974 | Labrecque et al. | Mar 2006 | A1 |
| 20060067975 | Labrecque et al. | Mar 2006 | A1 |
| 20060067976 | Ferraro et al. | Mar 2006 | A1 |
| 20060067977 | Labrecque et al. | Mar 2006 | A1 |
| 20060067983 | Swanick et al. | Mar 2006 | A1 |
| 20060068674 | Dixit et al. | Mar 2006 | A1 |
| 20060078586 | Ferraro et al. | Apr 2006 | A1 |
| 20060083768 | Labrecque et al. | Apr 2006 | A1 |
| 20060088596 | Labrecque et al. | Apr 2006 | A1 |
| 20060093643 | Stenzel | May 2006 | A1 |
| 20060110457 | Labrecque et al. | May 2006 | A1 |
| 20060112536 | Herweek et al. | Jun 2006 | A1 |
| 20060121081 | Labrecque et al. | Jun 2006 | A1 |
| 20060124056 | Behnisch et al. | Jun 2006 | A1 |
| 20060134209 | Labhasetwar et al. | Jun 2006 | A1 |
| 20060158361 | Chou | Jul 2006 | A1 |
| 20060188607 | Schramm et al. | Aug 2006 | A1 |
| 20060204738 | Dubrow et al. | Sep 2006 | A1 |
| 20060210701 | Chappa et al. | Sep 2006 | A1 |
| 20060240069 | Utas et al. | Oct 2006 | A1 |
| 20060263330 | Emeta et al. | Nov 2006 | A1 |
| 20060269485 | Friedman et al. | Nov 2006 | A1 |
| 20060246105 | Molz et al. | Dec 2006 | A1 |
| 20070003603 | Karandikar et al. | Jan 2007 | A1 |
| 20070015893 | Hakuta et al. | Jan 2007 | A1 |
| 20070071798 | Herweek et al. | Mar 2007 | A1 |
| 20070084144 | Labrecque et al. | Apr 2007 | A1 |
| 20070093894 | Darouiche | Apr 2007 | A1 |
| 20070141112 | Falotico et al. | Jun 2007 | A1 |
| 20070198040 | Buevich et al. | Aug 2007 | A1 |
| 20070202149 | Faucher et al. | Aug 2007 | A1 |
| 20070212411 | Fawzy et al. | Sep 2007 | A1 |
| 20070218182 | Schneider et al. | Sep 2007 | A1 |
| 20070238697 | Jackson et al. | Oct 2007 | A1 |
| 20070264460 | Del Tredici | Nov 2007 | A1 |
| 20070275074 | Holm et al. | Nov 2007 | A1 |
| 20070276487 | Carleton et al. | Nov 2007 | A1 |
| 20070280986 | Gil et al. | Dec 2007 | A1 |
| 20070286891 | Kettlewell et al. | Dec 2007 | A1 |
| 20070299538 | Roeber | Dec 2007 | A1 |
| 20080016037 | Enomoto et al. | Jan 2008 | A1 |
| 20080038307 | Hoffmann | Feb 2008 | A1 |
| 20080044481 | Harel | Feb 2008 | A1 |
| 20080045557 | Grainger et al. | Feb 2008 | A1 |
| 20080071385 | Binette et al. | Mar 2008 | A1 |
| 20080086216 | Wilson et al. | Apr 2008 | A1 |
| 20080109017 | Herweck et al. | May 2008 | A1 |
| 20080113001 | Herweck et al. | May 2008 | A1 |
| 20080118550 | Martakos et al. | May 2008 | A1 |
| 20080160307 | Bauchet | Jul 2008 | A1 |
| 20080206305 | Herweck et al. | Aug 2008 | A1 |
| 20080207756 | Herweek et al. | Aug 2008 | A1 |
| 20080279929 | Devane et al. | Nov 2008 | A1 |
| 20080286440 | Scheer | Nov 2008 | A1 |
| 20080289300 | Gottlieb et al. | Nov 2008 | A1 |
| 20090011116 | Herweck et al. | Jan 2009 | A1 |
| 20090036996 | Roeber | Feb 2009 | A1 |
| 20090047414 | Corbeil et al. | Feb 2009 | A1 |
| 20090082864 | Chen et al. | Mar 2009 | A1 |
| 20090092665 | Mitra et al. | Apr 2009 | A1 |
| 20090099651 | Hakimi-Mehr et al. | Apr 2009 | A1 |
| 20090181074 | Makower et al. | Jul 2009 | A1 |
| 20090181937 | Faucher | Jul 2009 | A1 |
| 20090186081 | Holm et al. | Jul 2009 | A1 |
| 20090208552 | Faucher et al. | Aug 2009 | A1 |
| 20090226601 | Zhong et al. | Sep 2009 | A1 |
| 20090240288 | Guetty | Sep 2009 | A1 |
| 20090259235 | Doucet et al. | Oct 2009 | A1 |
| 20090270999 | Brown | Oct 2009 | A1 |
| 20100183697 | Swanick et al. | Jul 2010 | A1 |
| 20100209473 | Dhont et al. | Aug 2010 | A1 |
| 20100233232 | Swanick et al. | Sep 2010 | A1 |
| 20100318108 | Datta et al. | Dec 2010 | A1 |
| 20110028412 | Cappello et al. | Feb 2011 | A1 |
| 20110045050 | Elbayoumi et al. | Feb 2011 | A1 |
| 20110144667 | Horton et al. | Jun 2011 | A1 |
| 20110213302 | Herweek et al. | Sep 2011 | A1 |
| 20110274823 | Labrecque et al. | Nov 2011 | A1 |
| 20120016038 | Faucher et al. | Jan 2012 | A1 |
| 20120213839 | Faucher et al. | Aug 2012 | A1 |
| 20120259348 | Paul | Oct 2012 | A1 |
| 20120315219 | Labrecque et al. | Dec 2012 | A1 |
| 20130041004 | Drager et al. | Feb 2013 | A1 |
| 20130084243 | Goetsch et al. | Apr 2013 | A1 |
| 20130096073 | Sidelman | Apr 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 1360951 | Jul 2002 | CN |
| 1429559 | Jul 2003 | CN |
| 101448474 | Jun 2009 | CN |
| 102256565 | Nov 2011 | CN |
| 19916086 | Oct 1999 | DE |
| 10115740 | Oct 2002 | DE |
| 0471566 | Feb 1992 | EP |
| 0610731 | Aug 1994 | EP |
| 0623354 | Nov 1994 | EP |
| 0655222 | Nov 1994 | EP |
| 0730864 | Sep 1996 | EP |
| 0790822 | Aug 1997 | EP |
| 0873133 | Oct 1998 | EP |
| 0950386 | Apr 1999 | EP |
| 0917561 | May 1999 | EP |
| 1132058 | Sep 2001 | EP |
| 1140243 | Oct 2001 | EP |
| 1181943 | Feb 2002 | EP |
| 1219265 | Jul 2002 | EP |
| 1270024 | Jan 2003 | EP |
| 1273314 | Jan 2003 | EP |
| 1364628 | Nov 2003 | EP |
| 1520795 | Apr 2005 | EP |
| 1557183 | Jul 2005 | EP |
| 1576970 | Sep 2005 | EP |
| 1718347 | Sep 2005 | EP |
| 1952807 | Aug 2008 | EP |
| 07867319 | Aug 2009 | EP |
| 2201965 | Jun 2010 | EP |
| 1402906 | Jun 2011 | EP |
| 2083875 | Mar 2013 | EP |
| 2363572 | Jan 2002 | GB |
| 49050124 | May 1974 | JP |
| S61291520 | Dec 1986 | JP |
| H01175864 | Jul 1989 | JP |
| H01503296 | Nov 1989 | JP |
| H08224297 | Sep 1996 | JP |
| 200110958 | Jan 2001 | JP |
| 2006512140 | Apr 2006 | JP |
| 2012505025 | Mar 2012 | JP |
| 2012505030 | Mar 2012 | JP |
| 2013508033 | Mar 2013 | JP |
| 20080025986 | Mar 2008 | KR |
| 2125887 | Feb 1999 | RU |
| 1297865 | Mar 1987 | SU |
| WO 1986000912 | Jul 1984 | WO |
| 198706463 | Nov 1987 | WO |
| WO 1990001969 | Mar 1990 | WO |
| 90008544 | Aug 1990 | WO |
| 199321912 | Nov 1993 | WO |
| 199517901 | Jul 1995 | WO |
| WO 1995026715 | Oct 1995 | WO |
| 199618417 | Jun 1996 | WO |
| 199641588 | Dec 1996 | WO |
| WO 1997002042 | Jan 1997 | WO |
| WO 1997009367 | Mar 1997 | WO |
| WO 1997013528 | Apr 1997 | WO |
| 199823228 | Jun 1998 | WO |
| WO 1998030206 | Jul 1998 | WO |
| 9846287 | Oct 1998 | WO |
| WO 1998054275 | Dec 1998 | WO |
| 199908544 | Feb 1999 | WO |
| WO 1999025336 | May 1999 | WO |
| 199927989 | Jun 1999 | WO |
| 199940874 | Aug 1999 | WO |
| 199956664 | Nov 1999 | WO |
| 200012147 | Mar 2000 | WO |
| 200040236 | Jul 2000 | WO |
| WO 200040278 | Jul 2000 | WO |
| 200053212 | Sep 2000 | WO |
| WO 200062830 | Oct 2000 | WO |
| 200115764 | Mar 2001 | WO |
| WO 2001024866 | Apr 2001 | WO |
| WO 2001026585 | Apr 2001 | WO |
| WO 2001037808 | May 2001 | WO |
| 200145763 | Jun 2001 | WO |
| WO 2001060586 | Aug 2001 | WO |
| WO 2001066036 | Sep 2001 | WO |
| WO 2001076649 | Oct 2001 | WO |
| 200185060 | Nov 2001 | WO |
| 200222047 | Mar 2002 | WO |
| 200222199 | Mar 2002 | WO |
| WO 2002049535 | Jun 2002 | WO |
| 2002076509 | Oct 2002 | WO |
| WO 2002100455 | Dec 2002 | WO |
| WO 2003000308 | Jan 2003 | WO |
| WO 2003015748 | Feb 2003 | WO |
| WO 2003028622 | Apr 2003 | WO |
| 2003039612 | May 2003 | WO |
| WO 2003037397 | May 2003 | WO |
| WO 2003037398 | May 2003 | WO |
| WO 2003039612 | May 2003 | WO |
| WO 2003041756 | May 2003 | WO |
| WO 2003070125 | Aug 2003 | WO |
| 2003073960 | Sep 2003 | WO |
| 2003094787 | Nov 2003 | WO |
| WO 2003092741 | Nov 2003 | WO |
| WO 2003092779 | Nov 2003 | WO |
| 2003105727 | Dec 2003 | WO |
| WO 2004004598 | Jan 2004 | WO |
| WO 2004006976 | Jan 2004 | WO |
| WO 2004006978 | Jan 2004 | WO |
| 2004028582 | Apr 2004 | WO |
| 2004028610 | Apr 2004 | WO |
| WO 2004028583 | Apr 2004 | WO |
| WO 2004091684 | Oct 2004 | WO |
| 20040101010 | Nov 2004 | WO |
| WO 2005000165 | Jan 2005 | WO |
| WO 2005016400 | Feb 2005 | WO |
| WO 2005053767 | Jun 2005 | WO |
| WO 2005073091 | Aug 2005 | WO |
| 2005082434 | Sep 2005 | WO |
| WO 2005116118 | Dec 2005 | WO |
| 2006032812 | Mar 2006 | WO |
| WO 2006024488 | Mar 2006 | WO |
| WO 2006036967 | Apr 2006 | WO |
| WO 2006102374 | Sep 2006 | WO |
| 2007047781 | Apr 2007 | WO |
| WO 2007047028 | Apr 2007 | WO |
| 2008010788 | Jan 2008 | WO |
| 2008016664 | Feb 2008 | WO |
| 2008039308 | Apr 2008 | WO |
| WO 2008057328 | May 2008 | WO |
| 2009091900 | Jul 2009 | WO |
| 2010042134 | Apr 2010 | WO |
| 2010042241 | Apr 2010 | WO |
| 2010042134 | Apr 2010 | WO |
| 2010042241 | Apr 2010 | WO |
| WO 2012009707 | Jan 2012 | WO |
| Entry |
|---|
| Saghir et al (American Journal of Physiology, Gastrointestinal and Liver Physiology, 1997, vol. 273, p. G184-G190) (Year: 1997). |
| Van den Berg (ICOM Committee for Conservation, 1999, pp. 248-253) (Year: 1999). |
| Oliveira, Fernanda L.C., et al., Triglyceride Hydrolysis of Soy Oil vs Fish Oil Emulsions, Journal of Parenteral and Enteral Nutrition, Jul./Aug. 1997, 224-229, vol. 21, No. 4. |
| Wagner, Karl-Heinz, et al., Effects of tocopherols and their mixtures on the oxidative stability of olive oil and inseed oil under heating, Eur. J. Lipid Sci. Technol., 2000, 624-629, 102. |
| U.S. Office Action dated Sep. 19, 2018 for related U.S. Appl. No. 15/817,018, 47 pages. |
| Saghir et al (American Journal of Physiology, Gastrointestinal and Liver Physiology, 1997, vol. 273, pp. G184-G190) (Year: 1997). |
| H. Fineberg et al., Industrial Use of Fish Oils, pp. 222-238, http://spo.nmfs.noaa.gov/Circulars/CIRC278.pdf, downloaded Aug. 3, 2015. |
| Lewis, Richard J., Sr., Hawley's Condensed Chemical Dictionary, 2001, pp. 308, 309 and 896-898, 14th edision, John Wiley & Sons, Inc., New York. |
| Webster's II New College Dictionary (1995), 1075, Houghton Mifflin Company, New York, US. |
| Polymers made from multiple monomers, A Natural Approach to Chemistry, Chapter 8, 241, http://lab-aids. com/assets/uploads/NAC/NAC_student_book/Texas%20Student%20Edition%20253.pdf (downloaded Dec. 3, 2015). |
| Polymer, Encyclopedia Britannica. Encyclopedia Britannica Online, Encyclopedia Britannica Inc., 105, Web. Dec. 2, 2015, http://www.britannica.com/print/article/468696 (downloaded Dec. 2, 2015). |
| SepraFilm Adhesion Barrier package insert (Genzyme Biosurgery 2008). |
| Sannino, Alessandro, et al., Biodegradeable Cellulose-based Hydrogels: Design and Applications, 2 Materials, pp. 353-373, 2009. |
| Heinz, Thomas, Carboxymethyl Ethers of Cellulose and Starch—A Review, Center of Excellence for Polysaccharide Research, Friedrich Schiller University of Jena (Germany), pp. 13-29, 2005. |
| Omidian, H. et al., Swelling Agents and Devices in Oral Drug Delivery, J. Drug. Del. Sci. Tech., No. 18, vol. 2, 2008, pp. 83-93. |
| Kamel, S. et al., Pharmaceutical Significance of Cellulose: A Review, Express Polymer Letters vol. 2, No. 11, 2008, pp. 758-778. |
| Adel, A. M. et al., Carboxymethylated Cellulose Hydrogel: Sorption Behavior and Characterization, Nature and Science, No. 8, vol. 8, 2010, pp. 244-256. |
| Bacteria in Water, The USGS Water Science School, http://water.usgs.gov/edu/bacteria.html (downloaded Nov. 9, 2015). |
| Novotny, L. et al., Fish: a potential source of bacterial pathogens for human beings, Vet. Med.—Czech, 49, 2004, vol. 9, pp. 343-358. |
| Allergies, Asthma and Allergy Foundation of America (2011), http://www.aafa.org/page/types-of-allergies,aspx (downloaded Oct. 5, 2015). |
| Sicherer, Scott H., Food Allergies: A Complete Guide for Eating When Your Life Depends on it, 2013, 15, Johns Hopkins University Press, Baltimore, MD, USA. |
| Omega-3 DHA—The Problem May be the Quality of Your Fish Oil, Not Your Allergy to Fish, Fatty Acids Hub, http://www.fattyacidshub.com/fatty-acids/omega-3-dha/ (downloaded Nov. 10, 2015). |
| Soy Allergy, Asthma and Allergy Foundation of America (2005), http://www.aafa.org/display.cfm?id=9&sub=20&cont=522 (downloaded Nov. 10, 2015). |
| Refined soybean oil not an allergen, say food scientists, FOOD navigator-usa.com (2005), http://www.foodnavigator-usa.com/content/view/print/127438 (downloaded Nov. 10, 2015). |
| Yahyaee, R. et al., Waste fish oil biodiesel as a source of renewable fuel in Iran, Renewable and Sustainable Energy Reviews, 2013, pp. 312-319, 17, Elsevier Ltd. |
| Biological evaluation of medical devices—Part 1: Evaluation and testing, International Standard ISO 109931-1, Aug. 1, 2003, Third Edition, Switzerland. |
| Mayo Clinic (http://www.mayoclinic.org/drugs-supplements/omega-3-fatty-acids-fish-oil-alpha-linolenic-acids/safety/hrb-20059372?p=1 (downloaded Sep. 28, 2015). |
| Milk allergy, at http://www.mayoclinic.org/diseases-conditions/milk-allergy/basics/definition/con-20032147?p=1 (downloaded Jul. 29, 2015). |
| Soy allergy, at http://www.mayoclinic.org/diseases-conditions/soy-allergy/basics/definition/con-20031370?p=1(downloaded Jul. 29, 2015). |
| F.D. Gunstone, Fatty Acid and Lipid Chemistry 72 (1999). |
| Hawley's Condensed Chemical Dictionary 315, 316, 332, 333, 334, 825 and 826 (2001). |
| Hultin, Herbert O. et al., Chemical Composition and Stability of Fish Oil (International Association of Fish Meal Manufacturers Apr. 10, 1991). |
| F.V.K Young, The Chemical & Physical Properties of Crude Fish Oils for Refiners and Hydrogenators, 18 Fish Oil Bulletin 1-18 (1986). |
| Karrick, Neva L., Nutritional Value of Fish Oils as Animal Feed, Circular 281 (Fish and Wildlife Service Bureau of Commercial Fisheries 1967), reprinted from M.E. Stansby (ed.), Fish Oils 362-382 (Avi Publishing Company 1967). |
| Luley et al., Fatty acid composition and degree of peroxidation in fish oil and cod liver oil preparations, Arzneimittelforschung. Dec. 1998, vol. 38, No. 12, pp. 1783-1786. |
| Drying Oil, http://en.wikipedia.org/wiki/drying_oil (downloaded Jun. 28, 2013). |
| Szebeni et al., “Complement Activation by Cremophor EL as a Possible Contributor to Hypersensitivity to Paclitaxel: an In Vitro Study”, Journal of the National Cancer Institute, 1998, vol. 90, No. 4, pp. 300-306. |
| Birsan, et al., “The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro”, Transpl. Int., 2005, vol. 17, pp. 767-771. |
| About.com, “Orthopedics, Synvisc injections,” retrieved online at http://orthopedics.about.com/cs/treatment/a/synvisc_2.htm (2005). |
| Cath Lab Digest, “Olive Oil Emulsion Helps With Problem Heart Arteries”, retrieved online at http://www.cathlabdigest.com/displaynews.cfm?newsid=0103073 (2007). |
| Doctor's Guide to Medical and Other News, “AAOS Meeting: Synvisc Delays Total Knee Replacement in Osteoarthritis Patients”, retrieved online at http://www.docguide.com/dg.nsf/PrintPrint/4585EC355198EEF08525670E006B10FF (1999). |
| Methodist, “Evaluation of Biocompatibility and Antirestenotic Potential of Drug Eluting Stents Employing Polymer-free Highly-Hydrogenated Lipid-Based Stent Coatings in Porcine Coronary Arteries”, Transcatheter Cardiovascular Therapeutics (TCT), sponsored by the Cardiovascular Research Foundation®, Oct. 22-27, 2006, Washington Convention Center, Washington, D.C. |
| Novavax, retrieved online at http://www.novavax.com/go.cfm?do=Page.View&pid=3 (2006). |
| Orthovisc, “New Treatment Option is Potential Alternative to OTC Pain Medications for Osteoarthritis of the Knee” retrieved online at http://www.jnj.com/innovations/new_features/ORTHOVISC.htm: essionid=33N2RBQDVODZKCQPCCEGU3AKB2IIWTT1 (2006). |
| Orthovisc, “What is ORTHOVISC®?” retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.jhtml?itemname=about_orthovisc (2005). |
| Orthovisc, “Your Knees and Osteoarthritis”, retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.jhtml?itemname=understanding_knee_oa (2003). |
| Orthovisc, “What to expect from your treatment,” retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.jhtml?itemname=what_to_expect (2007). |
| Orthovisc, “Tools and Resources for Managing Your Osteoarthritis”, retrieved online at http://www.orthovisc.com/khtmlbgdisplay.jhtml?itemname=patient_resources (2007). |
| Pohibinska, A., et al., “Time to reconsider saline as the ideal rinsing solution during abdominal surgery”, The American Journal of Surgery, vol. 192, pp. 281-222 (2007). |
| Singh, Alok, et al., “Facilitated Stent Delivery Using Applied Topical Lubrication”, Catherization and Cardiovascular Interventions, vol. 69, pp. 218-222 (2007). |
| Urakaze, Masaharu et al., “Infusion of fish oil emulsion: effects on platelet aggregation and fatty acid composition in phospholipids of plasma, platelets and red blood cell membranes in rabbits”, Am. J. Clin. Nutr., vol. 46, pp. 936-940 (!987). |
| Hortolam, Juliane G., et al., “Connective tissue diseases following silicone breast implantation: where do we stand?”, Clinics, 2013, vol. 3, p. 281. |
| Lidar, M. et al., “Silicone and sclerodema revisited”, Lupus, 2012, vol. 21, pp. 121-127. |
| “Lead”, Article by Centers for Disease Control and Prevention (CDC), Nov. 2009, 2 pages. |
| “Cure” in Academic Press Dictionary of Science and Technology, 1992. |
| Triglycerides, at https://www.lipid.org/sites/default/files/triglycerides.pdf (downloaded Sep. 24, 2015). |
| Fish Oil Triglycerides vs. Ethyl Esters: A Comparative Review of Absorption, Stability and Safety Concerns (Ascenta Health Ltd. 2010 at http://www.ascentaprofessional.com/science/articles/fish-oil-triglycerides-vs-ethyl-esters (downloaded Sep. 24, 2015)). |
| Swanson, Danielle, et al., Omega-3 Fatty Acids EPA and DHA: Health Benefits Throughout Life, 3 Advances in Nutrition 1-7 (American Society for Nutrition 2012). |
| Fats & Oils (2008) at http://scifun.chem.wisc.edu/chemweek/pdf/fats&oils.pdf (downloaded Sep. 24, 2015). |
| Wicks et al. Organic Coatings:Science and Technology 1999 New York:Wiley Interscience, pp. 258-267. |
| Mills et al. Oils and Fats. “The Organic Chemistry of Museum Objects” London:Buttersworth and Co. 1987, pp. 26-40. |
| Erhardt Paints Based on Drying Oil Media. Painted Wood: History & Conservation. Ed. Berland Singapore: The J. Paul Getty Trust 1998. pp. 17-32. |
| Wexler et al. Chemical Reviews 1964, vol. 64, No. 6, pp. 591-611. |
| Polymers—The Chambers 21st Century Dictionary M. Robinson and G. Davidson (Eds.), London, United Kingdom: Chambers Harrap. Retrieved from http://search.credoreference.com/content/entry/chambdict!polymer/O. |
| Polymer—Academic Press Dictionary of Science and TechnologyC. Morris (Ed.), Academic Press Dictionary of Science and Technology. Oxford, United Kingdom: Elsevier Science & Technology. Retrieved from http://search.credoreference.com/content/entry/apdst!polymer/O. |
| Falagas et al. European Society of Clinical Microbiology and Infection Diseases, 2005, vol. 11, pp. 3-8. |
| Bimbo, INFORM 1998, vol. 9, No. 5, pp. 473-483. |
| Final Office Action for U.S. Appl. No. 13/843,068, dated Apr. 23, 2015. |
| Final Office Action for U.S. Appl. No. 11/701,799, dated Mar. 12, 2015. |
| Final Office Action for U.S. Appl. No. 12/581,582, dated Jan. 8, 2015. |
| Final Office Action for U.S. Appl. No. 12/401,243, dated Jan. 16, 2015. |
| Non-Final Office Action for U.S. Appl. No. 11/237,420, dated Jan. 21, 2015. |
| Notice of Allowance for U.S. Appl. No. 13/943,489, dated Jan. 29, 2015. |
| Non-Final Office Action for U.S. Appl. No. 11/980,155, dated Nov. 7, 2014. |
| Notice of Allowance for U.S. Appl. No. 12/364,763 (listed on SB-08 as U.S. Publication No. US-2009-0208552), dated Dec. 5, 2014. |
| Notice of Allowance for U.S. Appl. No. 12/325,546 (listed on SB-08 as U.S. Publication No. US-2009-0181937), dated Dec. 8, 2014. |
| Non-Final Office Action for U.S. Appl. No. 13/843,068, dated Sep. 29, 2014. |
| Notice of Allowance for U.S. Appl. No. 11/236,943 (listed on SB-08 as U.S. Publication No. US-2006-0067975), dated Oct. 6, 2014. |
| Non-Final Office Action for U.S. Appl. No. 12/075,223, dated Oct. 29, 2014. |
| Uchida, et al., “Swelling Process and Order-Disorder Transition of Hydrogel Containing Hydrophobic Ionizable Groups”, Macromolecules, 28, 4583-4586 (1995). |
| Gutfinger, et al., “Polyphenols in Olive Oils”, Journal of the American Oil Chemists Society, 58(11): 966-968 (1981). |
| Portilla, et al., “Prevention of Peritoneal Adhesions by Intraperitoneal Administration of Vitamin E: An Experimental Study in Rats”, Diseases of the Colon and Rectum, 47; 2157-2161 (2005). |
| Sano, et al., “A controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease”, The New England Journal of Medicine, 336; 1216-1299 (1997). |
| Non Final Office Action for U.S. Appl. No. 12/581,582 (listed on SB-08 as U.S. Publication 2010-0183697), dated May 29, 2014. |
| Non-Final Office Action for U.S. Appl. No. 13/943,489, dated Jul. 1, 2014. |
| Final Office Action for U.S. Appl. No. 11/980,155, dated Jul. 21, 2014. |
| Final Office Action for U.S. Appl. No. 11/237,420, dated Jul. 22, 2014. |
| Non-Final Office Action for U.S. Appl. No. 11/701,799, dated Jul. 22, 2014. |
| Supplementary European Search Report for Application No. EP 10825447, dated Mar. 31, 2014. |
| Non Final Office Action for U.S. Appl. No. 12/325,546 (listed on SB-08 as U.S. Publication No. US-2009-0181937), dated Apr. 22, 2014. |
| Non Final Office Action for U.S. Appl. No. 12/364,763 (listed on SB-08 as U.S. Publication No. US-2009-0208552), dated Apr. 23, 2014. |
| Non Final Office Action for U.S. Appl. No. 12/401,243 (listed on SB/08 as US 2010-0233232), dated May 8, 2014. |
| Notice of Allowance for U.S. Appl. No. 11/237,264 (listed on SB-08 as U.S. Publication No. US-2006-0067983), dated Mar. 27, 2014. |
| Notice of Allowance for U.S. Appl. No. 11/237,263 (listed on SB-08 as U.S. Publication No. US-2006-0110457), dated Mar. 27, 2014. |
| Final Office Action for U.S. Appl. No. 11/236,943 (listed on SB-08 as U.S. Publication No. US-2006-0067975), dated Dec. 4, 2013. |
| Final Office Action for U.S. Appl. No. 11/237,264 (listed on SB-08 as U.S. Publication No. US-2006-0067983), dated Dec. 17, 2013. |
| Notice of Allowance for U.S. Appl. No. 13/593,656 (listed on SB-08 as U.S. Publication 2012-03115219), dated Jan. 24, 2014. |
| Mallegol, “Long-Term Behavior of Oil-Based Varnishes and Paints Photo-and Thermooxidation of Cured Linseed Oil”, Journal of the American Oil Chemists' Society, 77:257-263 (2000). |
| Non-Final Office Action for U.S. Appl. No. 11/237,420 (listed on SB-08 as U.S. Publication No. US-2006-0078586), dated Nov. 12, 2013. |
| Non-Final Office Action for U.S. Appl. No. 12/075,223 (listed on SB-08 as U.S. Publication No. US-2008-0206305), dated Nov. 12, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/980,155 (listed on SB-08 as U.S. Publication No. US-2008-0113001), dated Nov. 12, 2013. |
| Lipids, Chapter 19, pp. 1-12 (2002). |
| Jorge, N., “Grasas y Aceites”, 48(1): 17-24, (1997). |
| Supplementary European Search Report for EP12004057, dated Apr. 10, 2013. |
| International Search Report for International Application PCT/US2013/044653, dated Sep. 4, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/236,943 (listed on SB-08 as U.S. Publication No. US-2006-0067975), dated Apr. 22, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/237,264 (listed on SB-08 as U.S. Publication No. US-2006-0067983), dated Jul. 3, 2013. |
| Non-Final Office Action for U.S. Appl. No. 13/593,656 (listed on SB-08 as U.S. Publication No. US-2012-03115219), dated Jul. 15, 2013. |
| Notice of Allowance for U.S. Appl. No. 13/682,991 (listed on SB-08 as U.S. Publication No. US 2013-0074452), dated Aug. 1, 2013. |
| Notice of Allowance for U.S. Appl. No. 11/978,840 (listed on SB-08 as U.S. Publication No. US-2008-0118550), dated Aug. 6, 2013. |
| Lipids, Chapter 19, (Mar. 16, 2002), pp. 1-12. |
| Jorge, N., Grasas y Aceites, Vo. 48, Fasc. 1, (1997), pp. 17-24. |
| Ackman, R.G., “Fish Oils”, Bailey's Industrial Oil and Fat Products, 6th Edition, 279-317 (2005). |
| Andes, et al. “Antiproliferative Strategies for the Treatment of Vascular Proliferative Disease”, Current Vascular Pharmacology, 1)1): 85-98 (2003). |
| Winter, et al., “Physical and Chemical Gelation” Encyclopedia of Materials—Science and Technology, vols. 1-11: 6691-6999 (2001). |
| Non-Final Office Action for U.S. Appl. No. 11/978,840 (listed on SB-08 as U.S. Publication No. US-2008-0118550), dated Feb. 19, 2013. |
| Non-Final Office Action for U.S. Appl. No. 13/682,991 (listed on SB-08 as U.S. Publication No. US-2013-0074452), dated Mar. 18, 2013. |
| Notice of Allowance for U.S. Appl. No. 13/404,487 (listed on SB-08 as U.S. Publication No. US-2012-0213839), dated Apr. 2, 2013. |
| Autosuture, “ParietexTM Composite OS Series Mesh,” retrieved online at http://www.autosuture.com/AutoSuture/pagebuilder.aspx?topicID=135734&breadcrumbs=135 601:0 (2007). |
| Binder et al., “Chromatographic Analysis of Seed Oils. Fatty Acid Composition of Castor Oil,” The Journal of the American Oil Chemists' Society, vol. 39:513-517 (1962). |
| Camurus, “In our endeavors to create the unique, we start with the best. Your product.” |
| Redman, L.V. et al., “The drying rate of raw paint oils—a comparison,” The Journal of Industrial and Engineering Chemistry, vol. 5: 630-636 (1913). |
| De Scheerder, Ivan K., et al. “Biocompatibility of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries,” Atherosclerosis, vol. 114:105-114. |
| Drummond, Calum J., et al., “Surfactant self-assembly objects as novel drug delivery vehicles,” Current Opinion in Colliod & Interface Science, vol. 4:449-456 (2000). |
| Engstrom, Sven, “Drug Delivery from Cubic and Other Lipid-water Phases,” Lipid Technology, vol. 2(2):42-45 (1990). |
| Guler, et al. “Some empirical equations for oxopolymerization of linseed oil,” Progress in Organic Coatings, vol. 51:365-371 (2004). |
| Hwang, Chao-Wei, et al, “Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery,” Circulation, vol. 104:600-605 (2001). |
| Mallegol, et al., “Drier Influence on the Curing of Linseed Oil,” Progress in Organic Coatings 39:107-113 (2000). |
| Morse, Richard “Molecular Distillation of Polymerized Drying Oils,” Industrial and Engineering Chemisry 33:1039-1043 (1941). |
| Oberhoff, Martin, et al, “Local and Systemic Delivery of Low Molecular Weight Heparin Following PTCA: Acute Results and 6-Month Follow-Up of the Initial Clinical Experience With the Porous Balloon (PILOT-Study),” Catheterization and Cardiovascular Diagnosis, vol. 44:267-274 (1998). |
| Salu, Koen J., et al, “Addition of cytochalasin D to a biocompatible oil stent coating inhibits intimal hyperplasia in a porcine coronary model,” Coronary Artery Disease, vol. 14(8):545-555 (2003). |
| Scheller, Bruno, et al, “Addition of Paclitaxel to Contrast Media Prevents Restenosis After Coronary Stent Implantation,” Journal of the American College of Cardiology, vol. 42(8):1415-1420 (2003). |
| Van der Giessen, Willem J., et al, “Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries,” Circulation, vol. 94:1690-1697 (1996). |
| Ogunniyi, D.S., “Castor oil: A vital industrial raw material,” Biosource Technology, vol. 97: 1086-1091 (2006). |
| Crivello et al., “Epoxidized triglycerides as renewable monomers in photoinitiated cationic polymerization,” Chem. Mater, 1992:692-699. |
| Encylopedia Britannica Online, “Surface Coating,” available online at http://www.britannica.com/EBchecked/topic/575029/surface-coating>, date accessed Jun. 17, 2011. |
| Timir-Balizsy et al., “Chemical Principals of Textile Conservation,” Oxford: Elsevier Science Ltd., 1998:117-119. |
| A paper entitled “Evaluation of the Biocompatibility and Drug Delivery Capabilities of Biological Oil Based Stent Coatings” by Shengqio Li of the Katholieke Universiteit Leuven. |
| “Polymerization” Merriam-Webster Online Dictionary, retrieved from <www.merriam-webster.com> on Dec. 13, 2009; Merriam-Webster's Inc. 2009; pp. 1. |
| Shahidi, Fereidoon ed.; “Bailey's Industrial Oil and Fats Products” 2005; John Wiley and Sons; vol. 5, Edible Oil and Fat Products: Processing Technologies, pp. 1-15. |
| Ahuja et al. Journal of Indian Pediatric Surgery 2002 7:15-20. |
| Jonasson, Lena et al., “Cyclosporon A inhibits smooth muscle proliferation in the vascular response to injury,” Proc. Natl. Acad. Sci. USA, vol. 85: 2303-2306 (1988). |
| Wikipedia, “Sirolimus,” pp. 1-13, available online at http://en.wikipedia.org/wiki/Sirolimus, date accessed May 11, 2011. |
| CECW-EE, “Ch. 4: Coating Types and Characteristics,” Engineering and Design—Painting: New Construction and Maintenance, pp. 4-1 to 4-24 (1995). |
| Rutkow, Ira M. et al., “Tension-free' inguinal herniorrhaphy: A preliminary report on the ‘mesh plug’ technique,” Surgery, vol. 114:3-8 (1993). |
| Websters Dictionary Online, Accessed on Feb. 13, 2009, entry for “polymer” p. 1 of 1. |
| International Search Report for International Application PCT/US05/034601, dated Apr. 10, 2006. |
| International Search Report for International Application PCT/US05/034610, dated Mar. 16, 2006. |
| International Search Report for International Application PCT/US05/034614, dated Aug. 29, 2006. |
| International Search Report for International Application PCT/US05/034615, dated May 16, 2006. |
| International Search Report for International Application PCT/US05/034678, dated Aug. 28, 2006. |
| International Search Report for International Application PCT/US05/034681, dated Jul. 26, 2006. |
| International Search Report for International Application PCT/US05/034682, dated Jul. 20, 2006. |
| International Search Report for International Application PCT/US05/034836, dated Jul. 6, 2006. |
| International Search Report for International Application PCT/US06/037184, dated Feb. 22, 2007. |
| International Preliminary Report on Patentability for International Application PCT/US06/040753, dated Oct. 3, 2008. |
| International Search Report for International Application PCT/US06/040753, dated Sep. 24, 2007. |
| International Search Report for International Application PCT/US07/019978, dated May 7, 2009. |
| International Search Report for International Application PCT/US07/022860, dated Apr. 22, 2009. |
| International Search Report for International Application PCT/US07/022944, dated Apr. 8, 2009. |
| International Search Report for International Application PCT/US08/000565, dated May 4, 2009. |
| International Preliminary Examination Report for International Application PCT/US08/071547, dated Aug. 26, 2010. |
| International Search Report for International Application PCT/US08/071547, dated Oct. 22, 2008. |
| International Preliminary Report on Patentability for International Application PCT/US08/071565, dated Aug. 27, 2009. |
| International Search Report for International Application PCT/US08/071565, dated Nov. 10, 2008. |
| International Search Report for International Application PCT/US08/085386, dated Feb. 4, 2009. |
| International Search Report for International Application PCT/US09/037364, dated Aug. 27, 2009. |
| International Search Report for International Application PCT/US10/026521, dated Jun. 23, 2010. |
| International Search Report for International Application PCT/US10/052899, dated Jan. 10, 2011. |
| Supplementary European Search Report for Application No. EP 05 80 2894, dated Jul. 27, 2011. |
| Supplementary European Search Report in Application No. 05 800 844, dated Aug. 19, 2011. |
| Supplementary European Search Report in Application No. EP 05 80 4291, dated Jul. 26, 2011. |
| Supplementary European Search Report in Application No. EP 05 85 8430, dated Aug. 18, 2011. |
| International Search Report for International Application No. PCT/US05/34941, dated May 4, 2006. |
| Supplementary European Search Report for Application No. EP 08877338.7, dated Aug. 16, 2012. |
| Supplementary European Search Report for Application No. EP09819594.4, dated Aug. 14, 2012. |
| International Search Report for PCT/US2011/44292, dated Dec. 6, 2011. |
| Non-final Office Action for U.S. Appl. No. 11/236,908 (listed on SB/08 as US 2006/0067974), dated Mar. 25, 2006. |
| Final Office Action for U.S. Appl. No. 11/236,908 (listed on SB/08 as US 2006/0067974), dated May 17, 2011. |
| Non-final Office Action for U.S. Appl. No. 11/236,908 (listed on SB/08 as US 2006/0067974), dated Aug. 24, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/236,977 (listed on SB/08 as US 2006/0088596), dated Aug. 3, 2009. |
| Final Office Action for U.S. Appl. No. 11/237,263 (listed on SB/08 as US 2006/0110457), dated Jul. 7, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/237,263 (listed on SB/08 as US 2006/0110457), dated Oct. 7, 2009. |
| Final Office Action for U.S. Appl. No. 11/237,264 (listed on SB/08 as US 2006/0067983), dated Jun. 2, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/237,264 (listed on SB/08 as US 2006/0067983), dated Oct. 5, 2009. |
| Final Office Action for U.S. Appl. No. 11/701,799 (listed on SB/08 as US 2008/0109017), dated Nov. 23, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/237,420 (listed on SB/08 as US 2006/0078586), dated Mar. 5, 2009. |
| Final Office Action for U.S. Appl. No. 11/237,420 (listed on SB/08 as US 2006/0078586), dated Nov. 4, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/237,420 (listed on SB/08 as US 2006/0078586), dated Dec. 6, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/238,532 (listed on SB/08 as US 2006/0067976), dated Mar. 30, 2009. |
| Final Office Action for U.S. Appl. No. 11/238,532 (listed on SB/08 as US 2006/0067976), dated Sep. 9, 2009. |
| Final Office Action for U.S. Appl. No. 11/238,554 (listed on SB/08 as US 2006/0121081), dated May 12, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/238,554 (listed on SB/08 as US 2006/0121081), dated Oct. 9, 2009. |
| Final Office Action for U.S. Appl. No. 11/238,554 (listed on SB/08 as US 2006/0121081), dated May 1, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/238,554 (listed on SB/08 as US 2006/0121081), dated Jul. 25, 2008. |
| Non-final Office Action for U.S. Appl. No. 11/238,564 (listed on SB/08 as US 2006/0083768), dated Apr. 16, 2008. |
| Final Office Action for U.S. Appl. No. 11/238,564 (listed on SB/08 as US 2006/0083768), dated Aug. 6, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/239,555 (listed on SB/08 as US 2006/0067977), dated Mar. 30, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/525,328 (listed on SB/08 as US 2007/0084144), dated Apr. 30, 2007. |
| Non-final Office Action for U.S. Appl. No. 11/525,390 (listed on SB/08 as US 2007/0071798), dated Jul. 14, 2010. |
| Final Office Action for U.S. Appl. No. 11/525,390 (listed on SB/08 as US 2007/0071798), dated Feb. 21, 2011. |
| Final Office Action for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007/0202149), dated May 12, 2011. |
| Non-final Office Action for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007/0202149), dated Nov. 9, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007/0202149), dated Jan. 6, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007/0202149), dated May 12, 2009. |
| Non-final Office Action for U.S. Appl. No. 11/701,799 (listed on SB/08 as US 2008/0109017), dated Apr. 12, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/978,840 (listed on SB/08 as US 2008/0118550), dated Dec. 3, 2010. |
| Non-final Office Action for U.S. Appl. No. 11/980,155 (listed on SB/08 as US 2008/0113001.), dated Mar. 24, 2011. |
| Non-final Office Action for U.S. Appl. No. 12/075,223 (listed on SB/08 as US 2008/0206305.), dated Dec. 8, 2010. |
| Non-final Office Action for U.S. Appl. No. 12/325,546 (listed on SB/08 as US 2009/0181937.), dated Feb. 25, 2010. |
| Final Office Action for U.S. Appl. No. 12/325,546 (listed on SB/08 as US 2009/0181937), dated Aug. 31, 2010. |
| Non-final Office Action for U.S. Appl. No. 12/364,763 (listed on SB/08 as US 2009/0208552), dated Dec. 11, 2009. |
| Final Office Action for U.S. Appl. No. 12/364,763 (listed on SB/08 as US 2009/0208552), dated Sep. 21, 2010. |
| Interview summary for U.S. Appl. No. 11/236,908 (listed on SB/08 as US 2006/0067974) dated May 5, 2009. |
| Interview summary for U.S. Appl. No. 11/236,908 (listed on SB/08 as US 2006/0067974) dated Dec. 2, 2010. |
| Interview summary for U.S. Appl. No. 11/237,420 (listed on SB/08 as US 2006/0078586) dated May 5, 2009. |
| Interview summary for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007/0202149) dated Dec. 7, 2010. |
| Interview summary for U.S. Appl. No. 12/325,546 (listed on SB/08 as US 2009/0181937) dated Dec. 2, 2010. |
| Interview summary for U.S. Appl. No. 12/364,763 (listed on SB/08 as US 2009/0208552) dated Dec. 2, 2010. |
| Final Office Action for U.S. Appl. No. 11/237,420 (listed on SB/08 as US 2006/0078586), dated Jul. 13, 2011. |
| Final Office Action for U.S. Appl. No. 11/978,840 (listed on SB/08 as US 2008/0118550), dated Jun. 22, 2011. |
| Final Office Action for U.S. Appl. No. 12/075,223 (listed on SB/08 as US 2008/0206305.), dated Aug. 11, 2011. |
| Non-final Office Action for U.S. Appl. No. 11/525,390 (listed on SB/08 as US 2007/0071798), dated Jul. 11, 2011. |
| Non-Final Office Action for U.S. Appl. No. 11/701,799 (listed on SB/08 as US 2008/0109017), dated Aug. 17, 2011. |
| Non-Final Office Action for U.S. Appl. No. 11/582,135 (listed on SB/08 as US-2007-0202149), dated Oct. 14, 2011. |
| Final Office Action for U.S. Appl. No. 11/980,155 (listed on SB/08 as US-2008-0113001), dated Oct. 21, 2011. |
| Non-Final Office Action for U.S. Appl. No. 11/236,908 (listed on SB/08 as US-2006-0067974), dated Dec. 2, 2011. |
| Non-Final Office Action for U.S. Appl. No. 12/182,261 (listed on SB/08 as US 2009-0047414), dated Dec. 21, 2011. |
| Non-Final Office Action for U.S. Appl. No. 12/401,243 (listed on SB/08 as US 2010-0233232), dated Jan. 5, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/582,135 (listed on SB/08 as US 2007-0202149), dated Jan. 9, 2012. |
| Non-Final Office Action for U.S. Appl. No. 12/182,165 (listed on SB/08 as US 2009-0011116), dated Jan. 5, 2012. |
| Final Office Action for U.S. Appl. No. 11/701,799 (listed on SB/08 as US 2008/0109017), dated Feb. 13, 2012. |
| Non-Final Office Action for U.S. Appl. No. 12/581,582 (listed on SB/08 as US 20100183697), dated Mar. 14, 2012. |
| Final Office Action for U.S. Appl. No. 12/182,165 (listed on SB/08 as US 2009-0011116), dated Apr. 6, 2012. |
| Final Office Action for U.S. Appl. No. 12/182,261 (listed on SB-08 as US 2009/0047414) dated Apr. 30, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/236,908 (listed on SB/08 as US-2006-0067974), dated May 11, 2012. |
| Final Office Action for U.S. Appl. No. 12/401,243 (listed on SB/08 as US- 20100233232), dated Jun. 11, 2012. |
| Notice of Allowance for U.S. Appl. 12/182,261 (listed on SB/08 as US US-20090047414), dated Jul. 23, 2012. |
| Advisory Action for U.S. Appl. No. 12/401,243 (listed on SB/08 as US 2010-0233232), dated Aug. 27, 2012. |
| Final Office Action for U.S. Appl. No. 12/581,582 (listed on SB-08 as US 2010/0183697) dated Aug. 29, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 (listed on SB/08 as US-2007/0071798), dated Oct. 4, 2012. |
| Final Office Action for U.S. Appl. No. 11/236,943 (listed on SB/08 as US 2006/0067975), dated Dec. 23, 2009. |
| Non-Final Office Action for U.S. Appl. No. 11/236,943 (listed on SB/08 as US 2006/0067975), dated Mar. 5, 2009. |
| Advisory Action for U.S. Appl. No. 12/581,582 (listed on SB/08 as US 2010-0183697), dated Nov. 14, 2012. |
| Non-Final Office Action for U.S. Appl. No. 13/404,487 (listed on SB/08 as 2012-0213839), dated Dec. 20, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 (listed on SB/08 as US-2007/0071798), dated Nov. 20, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 (listed on SB/08 as US-2007/0071798), dated Nov. 30, 2012. |
| Non-Final Office Action issued in U.S. Appl. No. 16/165,628, dated Oct. 28, 2019. |
| Notice of Allowance issued in U.S. Appl. No. 15/841,993, dated Oct. 30, 2019. |
| Hogg, Ronald J., et al., Clinical Trial to Evaluate Omega-3 Fatty Acids and Alternate Day Prednisone in Patients with IgA Nephropathy: Report from the Southwest Pediatric Nephrology Study Group, Clin J Am Soc Nephrol 1, Apr. 12, 2006, 467-474. |
| Bruno, Gene, Omega-3 Fatty Acids, Literature Education Series on Dietary Supplements, 2009, 1-4, Huntington College of Health Sciences, Knoxville, TN, US. |
| Mateo, R. D., et al., Effect of dietary supplementation of n-3 fatty acids and elevated concentrations of dietary protein on the performance of sows, J. Anim. Sci., 2009, 948-959, 87. |
| Senzyme Corporation, 510(k) Notification, Section 10: 510(k) Summary, Dec. 21, 1999, 11 pages. |
| Deeken, Corey R., et al., A review of the composition, characteristics, and effectiveness of barrier mesh prostheses utilized for laparoscopic ventral hernia repair, Surg Endosc, 2011, 10 pages. |
| Extended European Search Report dated Dec. 10, 2015 issued for EP Patent Application No. 13804477. |
| Petrovic, Z. S., Polymers from biological oils, Contemporary Materials, I-1, 2010, 39-50. |
| Sahni, Vasav, et al., A Review on Spider Silk Adhesion, The Journal of Adhesion, 2011, 595-614, 87. |
| “What are Omega-9 Fats?”, Paleo Leap, LLC, printed from http://paleoleap.com/omega-9-fats on Sep. 14, 2016, 5 pages. |
| Kumar, Ashavani, et al., “Silver-nanoparticle-embedded antimicrobial paints based on vegetable oil”, Nature Materials, vol. 7, Mar. 2008, pp. 236-241. |
| Ralph L. Shriner et al., “The Systematic Identification of Organic Compounds—a laboratory manual”, pp. 284 and 285, 6th ed. (John Wiley & Sons—1980). |
| Olive Oil Reference Book (PerkinElmer, Inc. 2012), pp. 1-48. |
| Standard for Olive Oils and Olive Pomace Oils, CODEX STAN 33/1981 (World Health Organization 2013), pp. 1-9. |
| Wei Wang et al., “Directing Oleate Stabilized Nanosized Silver Colloids into Organic Phases”, Langmuir, vol. 14, No. 3, (1998), pp. 602-610. |
| Bechert et al., “A New Method for Screening Anti-Infective Biomaterials”, Nature Medicine. 6(8):1053-1056(2000). |
| Cheong et al., “Peritoneal healing and adhesion formation/reformation”, Human Reproduction Update. 7(6):556-566 (2001). |
| Carbonell et al., “The susceptibility of prosthetic biomaterials to infection”, Surgical Endoscopy. 19:430-435(2005) (abstract). |
| Kuijer et al., “Assessing infection risk in implanted tissue-engineered devices”, Biomaterials. 28:5148-5154(2007). |
| Arciola et al., “Strong biofilm production, antibiotic multi-resistance and high geIE expression in epidemic clones of Enterococcus faecalis from orthopaedic implant infections”, Biomaterials. 29:580-586(2008) (abstract). |
| Zheng et al., “Fatty acid synthesis is a target for antibacterial activity of unsaturated fatty acids”, FEBS Letters, Elsevier, Amsterdam, NL, vol. 579, No. 23, Sep. 26, 2005, pp. 5157-5162. |
| Lee, Ji-Young et al., “Antimicrobial Synergistic Effect of Linolenic Acid and Monoglyceride against Bacillus cereus and Staphylococcus aureus”, Journal of Agricultural and Food Chemistry, vol. 50, No. 7, Mar. 1, 2002, pp. 2193-2199. |
| Larsen, D. et al.., “Effect of cooking method on the fatty acid profile of New Zealand King Salmon (Oncorhynchus tshawytscha)” Food Chemistry 119 (2010) 785-790 (Year: 2010). |
| Steiner, M. et al. “Effect of Local Processing Methods (Cooking, Frying and Smoking) on Three Fish Species from Ghana: Part I. Proximate Composition, Fatty Acids, Minerals, Trace Elements and Vitamins” Food Chemistry 40 (1991) 309-321 (Year: 1991). |
| Gruger, Jr. E.H. Fatty Acid Composition. NMFS Scientific Publications by BOFC Fisheries. (http://spo.nmfs.noaa.gov/Circulars/CIRC276.pdf) 1967, pp. 1-30 (Year: 1967). |
| “Scientific Opinion on Fish Oil for Human consumption. Food Hygiene, including Rancidity”, EFSA Journal—pp. 1-48, vol. 8, (2010). |
| “Gas Chromatography Theory” —updated Apr. 1, 2016—http://www.chem.ucia.edu/%7Ebacher/General/30BL/gc/theory.html. |
| Steven J. Lehotay et al., “Application of Gas Chromatography in Food Analysis”, Trends in Analytical Chemistry—pp. 686-697, vol. 21, (2002). |
| Edible Oils. (http://www.chempro.in/fattyacid.htm) accessed Apr. 14, 2014. |
| Malayoglu et al. “Dietary vitamin E (α-tocopheryl acetate) and organic selenium supplementation: performance and antioxidant status of broilers fed n-3 PUFA-enriched feeds” South African Journal of Animal Science 2009, 39 (4), pp. 274-285 (Year: 2009). |
| Therapeutic definition (http://www.thefreedictionary.com/therapeutic) accessed Apr. 29, 2016. |
| Viscosity (http://www.vp-scientific.com/pdfs/www.liquidcontrol.com_eToolbox_viscosity.pdf) accessed Jan. 6, 2017, p. 1-4. |
| Babaev, Vladimir R., et al., Macrophage Lipoprotein Lipase Promotes Foam Cell Formation and Atherosclerosis in Vivo, 103 The Journal of Clinical Investigation, 1999, 1697-1705. |
| Final Office Action for U.S. Appl. No. 12/401,243 dated Jun. 11, 2012. |
| Henderson, R. James et al., “Hydrolysis of Fish Oils Containing Polymers of Triacylglycerols by Pancreatic Lipase in vitro”, Lipids, vol. 28, No. 4, 1993, pp. 313-319. |
| Non-Final Office Action issued in U.S. Appl. No. 13/184,512, dated May 1, 2018. |
| Final Office Action issued in U.S. Appl. No. 13/184,512, dated Mar. 22, 2017. |
| Multanen, M., et al., Bacterial adherence to silver nitrate coated poly-L-lactic acid urological stents in vitro, Urol Res., Oct. 2000, 327-31, 5. (Abstract). |
| Douglas, Kyle, et al., Zero-Order Controlled-Release Kinetics Through Polymer Matrices, available at http://www.drew.edu/wp-content/uploads/sites/99/Team5.pdf (downloaded Dec. 21, 2016). |
| Kaczynski, Jason, “Natural Omega3 Fish Oil Supplements—How to Avoid Synthetic Fish Oils,” accessed online at http://ezinearticles.com/?Natural-Omega3-Fish-Oil-Supplements-How-to-Avoid-Synthetic-Fish-Oils&id=2460278, Jun. 10, 2009. |
| Luostarinen et al., “Vitamin E supplementation counteracts the fish oil induced increase of blood glucose in humans,” Nutrition Research, vol. 15, No. 7, pp. 953-968, 1995. |
| The Lipid Handbook, 2nd edition, 1994, Tocopherols, pp. 129-131. |
| Non-Final OA for U.S. Appl. No. 12/767,289 dated Mar. 15, 2012. |
| ISR for PCT/BE02/00166, dated Apr. 3, 2003. |
| ESR for EP Application 05012112, dated Jul. 5, 2005. |
| ESR for EP Application 10157210, dated May 20, 2010. |
| Non-Final OA for U.S. Appl. No. 11/140,811 dated Sep. 15, 2008. |
| Final OA for U.S. Appl. No. 11/140,811 dated Nov. 25, 2009. |
| Non-Final OA for U.S. Appl. No. 12/767,289 dated Aug. 19, 2011. |
| De Scheerder et al., “Local Angiopeptin Delivery Using Coated Stents Reduces Neointimal Proliferation in Overstretched Porcine Coronary Arteries,” J. Invasive Cardiol., 1995, vol. 8, pp. 215-222. |
| De Scheerder et al., “Experimental Study of Thrombogenicity and Foreign Body Reaction Induced by Heparin-Coated Coronary Stents,” Circulation, 1997, vol. 95, pp. 1549-1553. |
| Schwartz et al., “Restenosis and the Proportional Neointimal Response to Coronary Artery Injury: Results in a Porcine Model,” J. Am. Coll. Cardiol., 1992, vol. 19, pp. 267-274. |
| Pilz and Marz, Free fatty acids as a cardiovascular risk factor. Clin Chem Lab Med, Feb. 2008, vol. 46, No. 4, pp. 429-434. |
| Sigma-Aldrich, Polyhydroxy compounds webpage, captured May 28, 2009. |
| Wanasundara et al., “Effect of processing on constituents and oxidative stability of marine oils,” Journal of Food Lipids, 1998, vol. 5, pp. 29-41. |
| Supplementary European Search Report for Application No. 05 80 2894 dated Jul. 27, 2011. |
| Supplementary European Search Report for Application No. 05 800 844 dated Aug. 19, 2011. |
| International Preliminary Report on Patentability for Application No. PCT/US08/71565, dated Apr. 5, 2010. |
| Supplementary European Search Report for EP Application No. 08782511 dated Apr. 23, 2013. |
| Notice of Allowance of U.S. Appl. No. 11/238,554, dated Apr. 28, 2011. |
| Non-Final Office Action of U.S. Appl. No. 13/185,135, dated Jan. 25, 2011. |
| Non-Final Office Action of U.S. Appl. No. 12/182,165, dated Jun. 24, 2013. |
| Sweetman, Sean C., “Martindale: The complete drug reference,” 33rd ed., 2002, Pharmaceutical Press, pp. 1-90. |
| Drugs.com “Drug Index A to Z,” retrieved on Apr. 1, 2013, pp. 1-4. |
| Garner, Brian A., “A Dictionary of Modern Legal Usage,” 2nd ed., 1987, pp. 389-390 and 713-717. |
| Pearlman, Daniel D. & Paul R., “Guide to Rapid Revision,” 3rd ed., 1982, Bobbs-Merrill Educational Publishing, pp. 25-27. |
| Canter, Sheryl, “Chemistry of Cast Iron Seasoning: A Science-Based Flow-To,” retrieved from sherylcanter.com on Apr. 5, 2013, pp. 1-5. |
| O'Neil, Maryadelle J. et al., The Merck Index—An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th ed., 2006, entries for “Calcium Carbonate”, “Cyclosporins”, “Prussian Blue”, and “Rapamycin”, pp. 1-12. |
| EP Office Action for EP Application No. 07838216.5, dated Feb. 11, 2010. |
| Kugel, et al., “Minimally invasive, Nonlaparoscopic, Preperitoneal, and Sutureless, Inguinal Herniorraphy,” The American Journal of Surgery, 1999, vol. 178, pp. 298-302. |
| Lichtenstein, et al., “Repair of Recurrent Ventral Hernias by an Internal Binder,” The American Journal of Surgery, 1976, vol. 132, pp. 121-125. |
| Moreno-Egea, “Laparoscopic repair of Ventral and Incisional Hernias Using a new Composite Mesh (Parletex),” Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 2001, vol. 11, No. 2, pp. 103-106. |
| “Sharper Curve, Stronger Egg”, Inside Science, printed Jan. 21, 2016, http://www.insidescience.org/content/sharper-curve-stronger-egg/779, 6 pages. |
| Moreno et al., J. Agric. Food Chem., 2003, vol. 51, pp. 2216-2221. |
| CRC Handbook of Chemistry and Physics, 89th Edition, 2008-2009, Composition and Properties of Common Oils and Fats, pp. 7-9 to 7-13. |
| Ali, Handbook of Industrial Chemistry: Organic Chemicals, Chapter 4, Edible Fats, Oils and Waxes, 1994, pp. 85-121. |
| Rietjens et al., “The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids, and flavonids,” Environmental Toxicology and Pharmacology, 2002, vol. 11, pp. 321-333. |
| European Communication for Application No. 07112611.4-2107, dated Nov. 30, 2007. |
| Clauss, Wolfram et al., “No Difference Among Modern Contrast Media's Effect on Neointimal Proliferation and Restenosis After Coronary Stenting in Pigs,” Investigative Reporting, 2004. |
| Nagao et al., “Conjugated Fatty Acids in Food and Their Health Benefits,” 2005, The Society for Biotechnology, Japan, Journal of Bioscience and Bioengineering, vol. 100, No. 2, pp. 152-157. |
| Goodnight et al., “Polyunsaturated Fatty Acids, Hyperlipidemia, and Thrombosis,” 1982, American Heart Association, Journal of the American Heart Association, vol. 2, No. 2, pp. 87-113. |
| Bard FDA 510K Approval (Jan. 2001). |
| Bard Internet Publication (Apr. 2001). |
| Bard FDA 510K Approval (Jul. 2002). |
| Bellon et al., “Evaluation of a New Composite Prosthesis (PL-PU99) for the Repair of Abdominal Wall Defects in Terms of Behavior at the Peritoneal Interface,” World Journal of Surgery, 26: 661-666 (2002). |
| Bendavid et al., “A Femoral ‘Umbrella’ for Femoral Hernial Repair Surgery,” Gynecology and Obstetrics, 165: 153-156 (1987). |
| Bendavid et al., “New Techniques in Hernia Repair,” World Journal of Surgery, 13: 522-531 (1989). |
| Greenawalt et al., “Evaluation of Sepramesh Biosurgical Composite in a Rabbit Hernia Repair Model,” Journal of Surgical Research, 94: 92-98 (2000). |
| Helfrich et al., “Abdominal Wall Hernia Repair: Use of the Gianturco-Helfrich-Eberhach Hernia Mesh,” Journal of Laparoendoscopic Surgery, 5(2): 91-96 (1995). |
| Hydrogenated Castor Oil, at http://www.acme-hardesty.com/product/hydrogenated-castor-oil/ (downloaded Jun. 2, 2017), which corresponds to “Exhibit B1.” |
| Hawley's Condensed Chemical Dictionary—pp. 425 and 426 (2001), which corresponds to “Exhibit A1”. |
| Hoefler, Andrew C., “Sodium Carboxymethyl Cellulose: Chemistry, Functionality, and Applications”, Hercules Incorporated, http://www.herc.com/foodgums/index.htm, 15 pages. |
| Hercules Inc./Aqualon Div. CMC Quality Specification, Oct. 19, 2001 (Revised Sep. 2, 2008), 1 page. |
| Aqualon: Sodium Carboxymethylcellulose: Physical and Chemical Properties, Hercules Incorporated, 1999, 30 pages. |
| Fei, Bin, et al., “Hydrogel of Biodegradable Cellulose Derivatives. I. Radiation-Induced Crosslinking of CMC”, Journal of Applied Polymer Science, 2000, vol. 78, pp. 278-283. |
| Shakhashiri, Chemical of the week Fats and Oils, at www.scifun.org (last revised Jan. 30, 2008) 2 pages. |
| “What are hydrogenated fats?” at http://www.whfoods.com/genpage.php?tname=george&dbid=10 (downloaded Dec. 19, 2017), 3 pages. |
| Sigma reference 2007. |
| Savolainen et al. “Evaluation of controlled-release polar lipid microparticles” International Journal of Pharmaceutics 2002 244:151-161. |
| Nair et al. “Antibacterial Effect of Caprylic Acid and Monocaprylin on Major Bacterial Mastitis Pathogens” Journal of Dairy Science 2005 88:3488-3495. |
| Nakatsuji et al. “Antimicrobial Property of Lauric Acid Against Propionibacterium acnes: Its Thereapeutic Potential for Inflammatory Acne Vulgarisu” Journal of Investigative Dermatology 2009 129(10): 2480-2488. |
| Gervajio “Fatty Acids and Derivatives from Coconut Oil.” Baileys Industrial Oil and Fat Products, Sixth Edition. Ed. Sahandi. Hoboken: John Wiley & Sons, Inc. 2005 1-3. |
| Pandey et al. “Solid lipid particle-based inhalable sustained drug delivery system against experiemental tuberculosis” Tuberculosis 2005 85:227-234. |
| Web article from http://www.buchi.com, “Slip Melting Point Determination of Palm Stearin”, 1 page. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 dated Nov. 20, 2012. |
| Interview summary for U.S. Appl. No. 11/237,420 dated May 5, 2009. |
| American heritage desk dictionary, 1981. p. 799, 2 pages. |
| John McMurray, Organic Chemistry, third edition, 1992, pp. 45-48. |
| 9.1 Terminology for Vegetable Oils and Animal Fats, at http://www.e-education.psu.edu/egee439/node/683 (downloaded Sep. 13, 2017), pp. 1-8. |
| Sunflower Oil, at https//en.wikipedia.org/wiki/Sunflower_oil (downloaded Sep. 19, 2017, pp. 1-8. |
| Fatty Acid Composition of Marine Oils by GLC, AOCS Official Method Ce 1b-89 (2009), pp. 1-7. |
| Preparation of Methyl Esters of Fatty Acids, AOCS Official Method Ce 2-66 (2009), pp. 1-2. |
| European Extended Search Report dated Jan. 18, 2016, issued for corresponding EP Patent Application No. 11807612.4, 7 pages. |
| Non-Final Office Action for U.S. Appl. No. 11/582,135, dated Oct. 14, 2011. |
| International Preliminary Report on Patentability for Application No. PCT/US08/85386, dated Apr. 12, 2011. |
| International Search Report for Application No. PCT/US10/048167, dated Oct. 20, 2010. |
| Non-Final Office Action for U.S. Appl. No. 12/401,228, dated Nov. 12, 2010. |
| Non-Final Office Action for U.S. Appl. No. 11/711,389, dated Dec. 17, 2010. |
| Final Office Action for U.S. Appl. No. 11/250,768, dated Nov. 9, 2010. |
| Advisory Action of U.S. Appl. 11/238,554, dated Jul. 10, 2009. |
| Wikipedia, Sunflower oil, accessed Jul. 23, 2015, pp. 1-7. |
| Esoteric Oils, Peppermint essential oil information, accessed Jul. 23, 2015, pp. 1-7. |
| Orthomolecular, Fish Oil, Jun. 29, 2004, http://orthomolecular.org/nutrients/fishoil.html, accessed Jul. 22, 2015, p. 1. |
| Non-Final Office Action issued in U.S. Appl. No. 13/184,512, dated Sep. 12, 2016. |
| Final Office Action issued in U.S. Appl. No. 13/184,512, dated Apr. 28, 2015. |
| Non-Final Office Action issued in U.S. Appl. No. 13/184,512, dated Oct. 10, 2014. |
| Final Office Action issued in U.S. Appl. No. 13/184,512, dated Jun. 25, 2013. |
| Non-Final Office Action issued in U.S. Appl. No. 13/184,512, dated Jan. 31, 2013. |
| Evans, D.F., et al., Measurement of gastrointestinal pH profiles in normal ambulant human subjects, Gut, 1988, 1035-1041. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 dated Oct. 4, 2012. |
| Final Office Action for U.S. Appl. No. 12/075,223 dated Aug. 11, 2011. |
| Extended European Search Report issued in EP Application No. 18000936.7 dated Jan. 7, 2020, 9 pages. |
| Office Action issued in EP Application No. 10825447.5 dated Feb. 20, 2020, 4 pages. |
| Non-Final Office Action issued in U.S. Appl. No. 15/817,018, dated Feb. 6, 2020, 28 pages. |
| Benchabane et al., Rheological properties of carboxymethyl cellulose (CMC) solutions, Colloid Polym Sci, 2008, 1173-1180, 286. |
| Office Action issued in Chinese Application No. 201610998395.8 dated Apr. 28, 2020, 14 pages. |
| Office Action issued in Chinese Application No. 201610997993.3 dated May 11, 2020, 7 pages. |
| Final Office Action issued in U.S. Appl. No. 16/165,628 dated Apr. 13, 2020, 9 pages. |
| Hoshino, Tamotsu et al., Selective Hydrolysis of Fish Oil by Lipase to Concentrate n-3 Polyunsaturated Fatty Acids, Agric. Biol. Chem, 1990, 1459-1467, 54,(6). |
| Office Action issued in CN Application No. 201610998395.8 dated Oct. 22, 2020, 13 pages. |
| Office Action issued in U.S. Appl. No. 16/165,628 dated Dec. 1, 2020, 15 pages. |
| Office Action and Search Report issued in CN Application No. 201610998395.8 dated Mar. 22, 2021, 25 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20190105430 A1 | Apr 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61365125 | Jul 2010 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13184512 | Jul 2011 | US |
| Child | 16213823 | US |
