Patent Grant
10016465
The present invention relates to coatings for medical devices, or films, which are cured, and more particularly to a method of curing a coating or stand alone film formed at least in part of a non-polymeric cross-linked gel cured a desired amount, and the resulting structure provided by the curing process.
Coatings and drugs, agents, or compounds are utilized in combination with a number of medical devices, and in particular with implantable medical devices such as stents, stent-grafts, surgical meshes, vascular grafts, and the like. Other devices such as vena cava filters and anastomosis devices may also be used with coatings having drugs, agents, or compounds therein. In addition, surgical medical film is often used in surgical settings, such as in patients undergoing abdominal or pelvic laparotomy as an adjunct intended to reduce the incidence, extent, and severity of postoperative adhesions between different tissues and organs and implantable medical devices such as soft tissue support membranes and mesh.
In general, such coatings and films are manufactured utilizing polymeric based materials. The coatings and films are formed using a number of different manufacturing techniques. However, there has been little progress in the manufacture of coatings or films utilizing non-polymeric based materials in a manner that can form the desired coating or film, with desired degradation properties, while maintaining some of the anti-inflammatory, non-inflammatory, and wound healing properties of some of the non-polymeric substances available.
More specifically, oils are occasionally briefly mentioned as being a potential carrier component for the delivery of a therapeutic from a medical device. However, there has been little development with regard to the determination of how to accomplish the provision of a non-polymeric coating containing a therapeutic, or even a non-polymeric coating maintaining its original anti-inflammatory, non-inflammatory, or wound healing properties. Some of these anti-inflammatory, non-inflammatory, and wound healing characteristics can be found in oils containing fatty acids, especially omega-3 fatty acids, such as fish oil. However, there is little known relating to methods for configuring non-polymeric coatings to carry therapeutic agents in a manner that results in a predefined, desired, rate of degradation to provide for the controlled release of the therapeutic agent or the controlled degradation of the coating.
What is desired is a method of making a non-polymeric biological oil based coating on a medical device or in the form of a stand alone film, which exhibits properties such as anti-adhesion, anti-inflammation, non-inflammation, and enhanced wound healing, to the local tissue that can also be further enhanced with the application of one or more therapeutic agents or medications for absorption into the tissue that is in contact with the coating or film. The method of making directly influences the resulting coating or film and corresponding rate of degradation of the coating or film following implantation, and thus the controlled release of any therapeutic agents contained within. The method of curing also influences the level of inherent anti-inflammation, non-inflammation, and wound healing properties of certain biological oils that is able to be maintained after curing. The present invention is directed toward further solutions to address this need.
Curing with respect to the present invention generally refers to thickening, hardening, or drying of a material brought about by heat, UV, or chemical means.
In accordance with one embodiment of the present invention, a method of curing to form a gel includes providing a non-polymeric substance to be cured. An amount of cross-linking desired within the substance as a result of curing is determined. Heat is applied at a selected temperature for a selected time period based on the determination of amount of cross-linking desired to achieve the desired amount of cross-linking within the substance to form the gel.
In accordance with aspects of the present invention, the substance to be cured can be an oil or oil composition. The substance to be cured can contain fatty acids. The substance to be cured can include at least one therapeutic agent. The agent can be any one or more of antioxidants, 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, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.
In accordance with further aspects of the present invention, the step of determining includes selecting the amount of cross-linking based on a desired rate of degradation of the gel following implantation. The application of heat occurs at a relatively higher temperature if more cross-linking is desired and at a relatively lower temperature if a lesser amount of cross-linking is desired. The application of heat occurs for a relatively greater duration of time if more cross-linking is desired and at a relatively lesser duration of time if a lesser amount of cross-linking is desired. A relatively faster rate of degradation provides for a relatively faster release of therapeutic agent contained within the gel, while a relatively slower rate of degradation provides for a relatively slower and more controlled release of therapeutic agent contained within the gel.
In accordance with aspects of the present invention, a relatively lesser amount of cross-links provides a relatively faster rate of degradation which provides for a relatively faster release of therapeutic agent contained within the gel, while a relatively greater amount of cross-links provides a relatively slower rate of degradation which provides for a relatively slower and more controlled release of therapeutic agent contained within the gel.
In accordance with one embodiment of the present invention, curing at a relatively greater temperature for a relatively lesser amount of time results in a greater amount of cross-linking within the substance than curing at a relatively lesser temperature for a relatively greater amount of time.
In accordance with further aspects of the present invention, the non-polymeric substance to be cured at least partially includes at least partially cured oil to reduce the amount of time required to achieve the desired amount of cross-linking. The substance can further include other oils, such as linseed oil or tung oil, as well as free fatty acids to reduce the amount of time required to achieve the desired amount of cross-linking.
In accordance with further aspects of the present invention, the cross-linked gel is configured to provide controlled release of a therapeutic agent component. The cross-linked gel is bio-absorbable. The cross-linked gel maintains at least one property, such as anti-inflammatory properties, non-inflammatory properties, and wound healing properties.
It should be noted that the term cross-linked gel, as utilized herein with reference to the present invention, refers to a gel that is non-polymeric and is derived from an oil composition comprising molecules covalently cross-linked into a three-dimensional network by one or more of ester, ether, peroxide, and carbon-carbon bonds in a substantially random configuration. In various preferred embodiments, the oil composition comprises a fatty acid molecule, a glyceride, and combinations thereof.
In accordance with further aspects of the present invention, the method can include sterilizing the cross-linked gel with a method of sterilization, such as ethylene oxide, gamma radiation, e-beam, steam, gas plasma, or vaporized hydrogen peroxide (VHP).
In accordance with one embodiment of the present invention, a heat cured non-polymeric gel includes a collection of non-polymeric cross-links resulting from application of heat for a selected temperature for a selected duration to achieve a desired amount of cross-linking to form the non-polymeric gel.
In accordance with aspects of the present invention, the gel can be derived from an oil or oil composition. The gel can be derived from a substance comprising fatty acids. The gel can include at least one therapeutic agent. The agent can be any one or more of antioxidants, 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, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.
In accordance with further aspects of the present invention, the gel is configured to maintain a desired rate of degradation of the gel following implantation. The gel is formed with application of heat at a relatively higher temperature if more cross-linking is desired and at a relatively lower temperature if a lesser amount of cross-linking is desired. The gel is formed with application of heat for a relatively greater duration of time if more cross-linking is desired and at a relatively lesser duration of time if a lesser amount of cross-linking is desired.
In accordance with further aspects of the present invention, the gel is formed from at least partially pre-cured oil to reduce the amount of time required to achieve the desired amount of cross-linking. The cross-linked gel is configured to provide controlled release of a therapeutic agent component. The cross-linked gel is bio-absorbable. The cross-linked gel maintains at least one property, such as anti-inflammatory properties, non-inflammatory properties, or wound healing properties.
In accordance with further aspects of the present invention, the gel has been sterilized with a method of sterilization including ethylene oxide, gamma radiation, e-beam, steam, gas plasma, or vaporized hydrogen peroxide (VHP).
In accordance with further aspects of the present invention, the gel is configured as a coating on a medical device or as a stand-alone film.
The aforementioned features and advantages, and other features and aspects of the present invention, will become better understood with regard to the following description and accompanying drawings, wherein:
An illustrative embodiment of the present invention relates to the provision of a coating or film that is a cured cross-linked gel and can exhibit anti-inflammatory properties, non-inflammatory properties, anti-adhesion properties, and/or wound healing properties, and corresponding method of making. The cross-linked gel can be its own medical device (i.e., a stand alone film), or the cross-linked gel can be combined with another medical device to provide the desired characteristics, in addition to potentially delivering therapeutic agents. The cross-linked gel is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil having fatty acids. In addition, the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent. The cross-linked gel is implantable in a patient, or applied on the skin surface of the patient, for short term or long term applications, and can include controlled release of the therapeutic agent. As implemented herein, the cross-linked gel is a non-polymeric cross-linked gel derived at least in part from a fatty acid compound.
As utilized herein, the term “bio-absorbable” generally refers to having the property or characteristic of being able to penetrate the tissue of a patient's body. In certain embodiments of the present invention bio-absorption occurs through a lipophilic mechanism. The bio-absorbable substance is soluble in the phospholipid bi-layer of cells of body tissue, and therefore impacts how the bio-absorbable substance penetrates into the cells.
It should be noted that a bio-absorbable substance is different from a biodegradable substance. Biodegradable is generally defined as capable of being decomposed by biological agents, or capable of being broken down by microorganisms or biological processes, in a manner that does not result in cellular uptake of the biodegradable substance. Biodegradation thus relates to the breaking down and distributing of a substance through the patient's body, verses the penetration of the cells of the patient's body tissue. Biodegradable substances, such as polymers, can cause inflammatory response due to either the parent substance or those substances formed during breakdown, and they may or may not be absorbed by tissues. Bio-absorbable substances break down into substances or components that do not cause an inflammatory response and can be consumed by the cells forming the body tissues.
The phrase “controlled release” generally refers to the release of a biologically active agent in a predictable manner over the time period of weeks or months, as desired and predetermined upon formation of the biologically active agent on the medical device from which it is being released. Controlled release includes the provision of an initial burst of release upon implantation, followed by the predictable release over the aforementioned time period.
With regard to the aforementioned oils, it is generally known that the greater the degree of unsaturation in the fatty acids the lower the melting point of a fat, and the longer the hydrocarbon chain the higher the melting point of the fat. A polyunsaturated fat, thus, has a lower melting point, and a saturated fat has a higher melting point. Those fats having a lower melting point are more often oils at room temperature. Those fats having a higher melting point are more often waxes or solids at room temperature. Therefore, a fat having the physical state of a liquid at room temperature is an oil. In general, polyunsaturated fats are liquid oils at room temperature, and saturated fats are waxes or solids at room temperature.
Polyunsaturated fats are one of four basic types of fat derived by the body from food. The other fats include saturated fat, as well as monounsaturated fat and cholesterol, Polyunsaturated fats can be further composed of omega-3 fatty acids and omega-6 fatty acids. Under the convention of naming the unsaturated fatty acid according to the position of its first double bond of carbons, those fatty acids having their first double bond at the third carbon atom from the methyl end of the molecule are referred to as omega-3 fatty acids. Likewise, a first double bond at the sixth carbon atom is called an omega-6 fatty acid. There can be both monounsaturated and polyunsaturated omega fatty acids.
Omega-3 and omega-6 fatty acids are also known as essential fatty acids because they are important for maintaining good health, despite the fact that the human body cannot make them on its own. As such, omega-3 and omega-6 fatty acids must be obtained from external sources, such as food. Omega-3 fatty acids can be further characterized as containing eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA and DHA are known to have anti-inflammatory effects and wound healing effects within the human body.
Oil that is hydrogenated becomes a waxy solid. Attempts have been made to convert the polyunsaturated oils into a wax or solid to allow the oil to adhere to a device for a longer period of time. One such approach is known as hydrogenation, which is a chemical reaction that adds hydrogen atoms to an unsaturated fat (oil) thus saturating it and making it solid at room temperature. This reaction requires a catalyst, such as a heavy metal, and high pressure. The resultant material forms a non-cross-linked semi-solid. Hydrogenation can reduce or eliminate omega-3 fatty acids, and any therapeutic effects (both anti-inflammatory and wound healing) they offer.
For long term controlled release applications, polymers, as previously mentioned, have been utilized in combination with a therapeutic agent. Such a combination provides a platform for the controlled long term release of the therapeutic agent from a medical device. However, polymers have been determined to themselves cause inflammation in body tissue. Therefore, the polymers often must include at least one therapeutic agent that has an anti-inflammatory effect to counter the inflammation caused by the polymer delivery agent. In addition, patients that received a polymer-based implant must also follow a course of long term systemic anti-platelet therapy, on a permanent basis, to offset the thrombogenic properties of the non-absorbable polymer. A significant percentage of patients that receive such implants are required to undergo additional medical procedures, such as surgeries (whether related follow-up surgery or non-related surgery) and are required to stop their anti-platelet therapy. This can lead to a thrombotic event, such as stroke, which can lead to death. Use of the inventive coating described herein can negate the necessity of anti-platelet therapy, and the corresponding related risks described, because there is no thrombogenic polymer reaction to the coating. Other polymer implant patients must follow a course of systemic anti-inflammatory therapy, to offset the inflammatory properties of the non-absorbable polymer. Typical anti-inflammatory agents are immunosupressants and systemic delivery of anti-inflammatory agents can sometimes lead to additional medical complications, such as infection or sepsis, which can lead to long term hospitalization or death. Use of the non-polymeric cross-linked gel of the inventive coating described herein may also negate the necessity of anti-inflammatory therapy, and the corresponding related risks described, because there is no inflammatory reaction to an oil-based coating or film formed in accordance with the present invention.
In addition, some curing methods have been indicated to have detrimental effects on the therapeutic agent combined with the omega-3 fatty acid, making them partially or completely ineffective. As such, oils, and more specifically oils containing omega-3 fatty acids, have been utilized as a delivery agent for the short term uncontrolled release of a therapeutic agent, so that minimal or no curing is required. However, there are no known uses of oils containing omega-3 fatty acids for combination with a therapeutic agent in a controlled release application that makes use of the therapeutic benefits of the omega-3 fatty acids. Further, some heating of the omega-3 fatty acids to cure the oil can lessen the total therapeutic effectiveness of the omega-3 fatty acids, but not eliminate the therapeutic effectiveness. One characteristic that can remain after certain curing by heating methods is the non-inflammatory response of the tissue when exposed to the cured omega-3 fatty acid material. As such, an oil containing omega-3 fatty acids can be heated for curing purposes, and still maintain some or even a majority of the therapeutic effectiveness of the omega-3 fatty acids. In addition, although the therapeutic agent combined with the omega-3 fatty acid and cured with the omega-3 fatty acid can be rendered partially ineffective, the portion remaining of the therapeutic agent can, in accordance with the present invention, maintain pharmacological activity and in some cases be more effective than an equivalent quantity of agent delivered with other barrier or coating materials.
It should be noted that as utilized herein to describe the present invention, the terms vitamin E, vitamin E compound, and alpha-tocopherol, are intended to refer to the same or substantially similar substance, such that they are interchangeable and the use of one includes an implicit reference to both. Further included in association with the term vitamin E are such variations including but not limited to one or more of alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate, delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocopherol succinate, gamma-tocopherol succinate, delta-tocopherol succinate, alpha-tocotrienol succinate, beta-tocotrienol succinate, delta-tocotrienol succinate, gamma-tocotrienol succinate, mixed tocopherols, vitamin E TPGS, derivatives, analogs and pharmaceutically acceptable salts thereof.
The cross-linked gel 10 is formed of an oil component. The oil component can be either an oil, or an oil composition. The oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics. One example embodiment of the present invention makes use of a fish oil in part because of the high content of omega-3 fatty acids, which provide healing support for damaged tissue, as discussed below. The fish oil also serves as an anti-adhesion agent. In addition, the fish oil maintains anti-inflammatory or non-inflammatory properties as well. The present invention is not limited to formation of the gel with fish oil as the naturally occurring oil. However, the following description makes reference to the use of fish oil as one example embodiment. Other naturally occurring oils can be utilized in accordance with the present invention as described herein.
It should be noted that as utilized herein, the term fish oil fatty acid includes but is not limited to omega-3 fatty acid, fish oil fatty acid, free fatty acid, esters of fish oil, triglycerides, or a combination thereof. The fish oil fatty acid includes one or more of arachidic acid, gadoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs and pharmaceutically acceptable salts thereof. Furthermore, as utilized herein, the term free fatty acid includes but is not limited to one or more of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, analogs and pharmaceutically acceptable salts thereof. The naturally occurring oils, including fish oil, are cured as described herein to form a hydrophobic cross-linked gel, creating the cross-linked gel 10.
It should further be noted that
One aspect of the cross-linked gel 10 mentioned above is that it has anti-adhesion characteristics or properties. By anti-adhesion, what is meant is a characteristic whereby the incidence, extent, and severity of postoperative adhesions, or lacerations or other tissue injuries, between different tissues and organs is reduced. The anti-adhesion characteristic results from the materials used to form the cross-linked gel 10.
More specifically, the cross-linked gel 10 provides a lubricious or anti-adhesive surface against tissue. The cross-linked gel 10 itself, in its substantially cured configuration, can provide a physical anti-adhesion barrier between two sections of tissue, or the cross-linked gel 10 can form an anti-adhesion surface on a medical device, such as the mesh 40. The use of the naturally occurring oil, such as fish oil, provides extra lubrication to the surface of the medical device, which helps to reduce injury. With less injury, there is less of an inflammatory response, and less healing required. The biological oil barrier created by the fatty acid oil derived cross-linked gel likewise provides anti-inflammatory properties and non-inflammatory properties, thus reducing the occurrence of inflammatory response and also adhesions due to inflammation. The oily surface of the cross-linked gel 10 provides the anti-adhesion characteristics. One of ordinary skill in the art will appreciate that different oils will have different anti-adhesive properties, and the oils can be modified to be more liquefied or more solid or waxy, as desired. Accordingly, the degree of anti-adhesive properties offered by the cross-linked gel 10 can vary. The modification of the oils from a more liquid physical state to a more solid, but still flexible, physical state is implemented through the curing process. As the oils are cured, especially in the case of fatty acid-based oils such as fish oil, cross-links form creating a gel. As the curing process is performed over increasing time durations and/or increasing temperature conditions, more cross-links form transitioning the gel from a relatively liquid gel to a relatively solid-like, but still flexible, gel structure.
Another aspect of the present invention is that the cross-linked gel 10 is formed of the bio-absorbable material, such as naturally occurring fish oil, in accordance with the example embodiment described herein. The bio-absorbable properties of the naturally occurring oil enable the cross-linked gel 10 to be absorbed by the cells of the body tissue (i.e., bio-absorbable). In example embodiments of the present invention, the bio-absorbable cross-linked gel contains lipids, many of which originate as triglycerides. It has previously been demonstrated that triglyceride byproducts, such as partially hydrolyzed triglycerides and fatty acid molecules can integrate into cellular membranes and enhance the solubility of drugs into the cell. Whole triglycerides are known not to enhance cellular uptake as well as partially hydrolyzed triglyceride, because it is difficult for whole triglycerides to cross cell membranes due to their relatively larger molecular size. Vitamin E compounds can also integrate into cellular membranes resulting in decreased membrane fluidity and cellular uptake.
Compounds that move too rapidly through a tissue may not be effective in providing a sufficiently concentrated dose in a region of interest. Conversely, compounds that do not migrate in a tissue may never reach the region of interest. Cellular uptake enhancers such as fatty acids and cellular uptake inhibitors such as alpha-tocopherol can be used alone or in combination to provide an effective transport of a given compound to a given region or location. Both fatty acids and alpha-tocopherol are accommodated by the cross-linked gel of the present invention described herein. Accordingly, fatty acids and alpha-tocopherol can be combined in differing amounts and ratios to contribute to a cross-linked gel in a manner that provides control over the cellular uptake characteristics of the cross-linked gel and any therapeutic agents mixed therein.
For example, the amount of alpha-tocopherol can be varied in the cross-linked gel. Alpha-tocopherol (vitamin E compound) is known to slow autoxidation in fish oil by reducing hydroperoxide formation, which results in a decrease in the amount of cross-linking in cured fish oil. It has been shown that even with fewer cross-links, the addition of varying amounts of alpha-tocopherol can be used to increase the time in which the cross-linked gel degrades compared to a cross-linked gel of fish oil alone. The addition of alpha-tocopherol to the oil or oil composition prior to forming the cross-linked gel can result in fewer cross-links when compared with the oil without alpha-tocopherol. Although there are fewer cross-links, the degradation period is extended with the alpha-tocopherol added. In addition alpha-tocopherol can be used to increase solubility of drugs in the fish oil forming the cross-linked gel. Thus, varying the amount of alpha-tocopherol present in the cross-linked gel can impact the resulting formation. Alpha-tocopherol can actually protect the therapeutic drug during curing, which increases the resulting drug load in the cross-linked gel after curing. Furthermore, with certain therapeutic drugs, the increase of alpha-tocopherol in the cross-linked gel serves to slow and extend drug release due to the increased solubility of the drug in the alpha-tocopherol component of the cross-linked gel. This reflects the cellular uptake inhibitor functionality of alpha-tocopherol, in that the uptake of the drug is slowed and extended over time.
It should further be emphasized that the bio-absorbable nature of the cross-linked gel results in the cross-linked gel 10 being completely absorbed over time by the cells of the body tissue. There are no substances in the cross-linked gel, or break down products of the cross-linked gel, that induce an inflammatory response. The cross-linked gel 10 is generally composed of, or derived from, omega-3 fatty acids bound to triglycerides, potentially also including a mixture of free fatty acids and vitamin E compounds (alpha-tocopherol). The triglycerides are broken down by lipases (enzymes) which result in free fatty acids that can than be transported across cell membranes. Subsequently, fatty acid metabolism by the cell occurs to metabolize any substances originating with the cross-linked gel. The bio-absorbable nature of the cross-linked gel of the present invention results in the cross-linked gel being absorbed over time, leaving only an underlying delivery or other medical device structure that is biocompatible. There is no foreign body inflammatory response to the bio-absorbable cross-linked gel.
Although the present invention is bio-absorbable to the extent that the cross-linked gel 10 experiences the uptake into or through body tissues, in the specific embodiment described herein formed using naturally occurring oils, the exemplar oils are also lipid based oils. The lipid content of the oils provides a highly bio-absorbable cross-linked gel 10. More specifically, there is a phospholipids layer in each cell of the body tissue. The fish oil, and equivalent oils, contain lipids as well. There is a lipophilic action that results where the lipids are attracted by each other in an effort to escape the aqueous environment surrounding the lipids.
A further aspect of the cross-linked gel 10 is that the specific type of oil can be varied, and can contain elements beneficial to healing. The cross-linked gel also provides a natural scaffold for cellular growth and remodeling with clinical applications in general surgery, spinal repair, orthopedic surgeries, tendon and ligament repairs, gynecological and pelvic surgeries, and nerve repair applications. The addition of therapeutic agents to the cross-linked gels used in these applications can be utilized for additional beneficial effects, such as pain relief or infection minimization. In addition, non-surgical applications include external wound care, such as a treatment for burns or skin ulcers, without therapeutics as a clean, non-permeable, non-adhesive, anti-inflammatory, non-inflammatory dressing, or with added therapeutics for additional beneficial effects. The cross-linked gel may also be used as a transdermal drug delivery patch.
The process of wound healing involves tissue repair in response to injury and it encompasses many different biologic processes, including epithelial growth and differentiation, fibrous tissue production and function, angiogenesis, and inflammation. The inventive cross-linked gel has been shown in an animal model not to produce an inflammatory response, but still provide excellent cellular overgrowth with little to no fibrous capsule formation. Accordingly, the cross-linked gel provides an excellent material suitable for wound healing applications.
Another aspect of the cross-linked gel 10 mentioned above is that the cross-linked gel 10 can contain therapeutic agents for delivery to the body tissue. Therapeutic agents have been delivered to a targeted location in a human utilizing a number of different methods in the past. For example, agents may be delivered nasally, transdermally, intravenously, orally, or via other conventional methods. Delivery may vary by release rate (i.e., quick release or slow release). Delivery may also vary as to how the drug is administered. Specifically, a drug may be administered locally to a targeted area, or administered systemically.
As utilized herein, the phrase “therapeutic agent(s)” refers to a number of different drugs or agents available, as well as future agents that may be beneficial for use with the cross-linked gel of the present invention. Therapeutic agents can be added to the cross-linked gel 10, and/or the medical device in combination with the cross-linked gel 10 as discussed herein. The therapeutic agent component 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-imaging agents, anesthetic agents, therapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, anti-septics, analgesics, prodrugs, and any additional desired therapeutic agents such as those listed in Table 1 below.
Some specific examples of therapeutic agents useful in the anti-restenosis realm include cerivastatin, cilostazol, fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydrate derivative (for example, as described in US Patent Application Publication 2004/0235762), 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, the therapeutic agent is administered orally or intravenously to be systemically processed by the patient. However, there are drawbacks to a systemic delivery of a therapeutic agent, one of which is that the therapeutic agent travels to all portions of 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.
Accordingly, an alternative to the systemic administration of a therapeutic agent is the use of a targeted local therapeutic agent delivery approach. With local delivery of a therapeutic agent, the therapeutic agent is administered using a medical device or apparatus, directly by hand, or sprayed on the tissue, at a selected targeted tissue location of the patient that requires treatment. The therapeutic agent emits, or is otherwise delivered, from the medical device apparatus, and/or carrier, and is applied to the targeted tissue location. The local delivery of a therapeutic agent enables a more concentrated and higher quantity of therapeutic agent to be delivered directly at the targeted tissue location, without having broader systemic side effects. With local delivery, the therapeutic agent that escapes the targeted tissue location dilutes as it travels to the remainder of the patient's body, substantially reducing or eliminating systemic side effects.
Targeted local therapeutic agent delivery using a medical device can be further broken into two categories, namely, short term and long term ranging generally within a matter of seconds or minutes to a few days or weeks to a number of months. Typically, to achieve the long term delivery of a therapeutic agent, the therapeutic agent must be combined with a delivery agent, or otherwise formed with a physical impediment as a part of the medical device, to slow the release of the therapeutic agent.
Prior attempts to create films and drug delivery platforms, such as in the field of stents, primarily make use of high molecular weight synthetic polymer based materials to provide the ability to better control the release of the therapeutic agent. Essentially, the polymer in the platform releases the drug or agent at a predetermined rate once implanted at a location within the patient. Regardless of how much of the therapeutic agent would be most beneficial to the damaged tissue, the polymer releases the therapeutic agent based on properties of the polymer. Accordingly, the effect of the therapeutic agent is substantially local at the surface of the tissue making contact with the medical device having the coating. In some instances the effect of the therapeutic agent is further localized to the specific locations of, for example, stent struts or mesh struts pressed against the tissue location being treated. These prior approaches can create the potential for a localized toxic effect.
The cross-linked gel 10 of the present invention, however, makes use of the natural oils to form a non-polymeric natural oil based therapeutic agent delivery platform, if desired. Furthermore, the cross-linked gel 10 can be formed in a manner that creates the potential for controlled long term release of a therapeutic agent, while still maintaining the benefits of the natural oil component of the cross-linked gel 10.
More specifically, it is known that oil that is oxygenated becomes a waxy solid. Attempts have been made to convert the polyunsaturated oils into a wax or solid to allow the oil to adhere to a device for a longer period of time. One such approach applies the oil to the medical device and allows the oil to dry.
With the present invention, and in the field of soft tissue applications, and in part because of the lipophilic mechanism enabled by the bio-absorbable lipid based cross-linked gel 10 of the present invention, the uptake of the therapeutic agent is facilitated by the delivery of the therapeutic agent to the cell membrane by the bio-absorbable cross-linked gel 10. Further, the therapeutic agent is not freely released into the body fluids, but rather, is delivered directly to the cells and tissue. In prior configurations using polymer based coatings, the drugs were released at a rate regardless of the reaction or need for the drug on the part of the cells receiving the drug.
In addition, when the oil provided to form the cross-linked gel 10 is a naturally occurring oil containing the omega-3 fatty acids (including DHA and EPA), the process for forming the cross-linked gel 10 can be tailored to avoid causing detrimental effects to the beneficial properties of the omega-3 fatty acids, or at least effects too detrimental to have any lasting effect. As described herein, certain properties of the fatty acids may lose their effectiveness, however other desired properties are maintained. If there is no concern for maintaining the beneficial effects, the curing and other steps leading to the formation of the cross-linked gel 10 can include steps that may reduce some of the beneficial properties of the omega-3 fatty acids, as understood by one of ordinary skill in the art. Example embodiments illustrating the formation and different configurations of the cross-linked gel 10 are provided herein.
The cross-linked gel 10 of the present invention serves as a non-polymeric biological oil based cross-linked gel and can also serve as a physical cross-linked gel if sufficiently cured. In accordance with the example embodiments described herein, the cross-linked gel is formed of a non-polymeric cross-linked gel derived from fatty acid compounds. The fatty acid compounds include omega-3 fatty acids when the oil utilized to form the cross-linked gel is fish oil or an analog or derivative thereof. As liquid fish oil is heated, autoxidation occurs with the absorption of oxygen into the fish oil to create hydroperoxides in an amount dependent upon the amount of unsaturated (C═C) sites in the fish oil. However, the (C═C) bonds are not consumed in the initial reaction. Concurrent with the formation of hydroperoxides is the isomerization of (C═C) double bonds from cis to trans in addition to double bond conjugation. It has been demonstrated that hydroperoxide formation increases with temperature. Heating of the fish oil allows for cross-linking between the fish oil unsaturated chains using a combination of peroxide (C—O—O—C), ether (C—O—C), and hydrocarbon (C—C) bridges. The formation of the cross-links results in gelation of the cross-linked gel after the (C═C) bonds have substantially isomerized into the trans configuration. The (C═C) bonds can also form C—C cross-linking bridges in the glyceride hydrocarbon chains using a Diels-Alder Reaction. In addition to solidifying the cross-linked gel through cross-linking, both the hydroperoxide and (C═C) bonds can undergo secondary reactions converting them into lower molecular weight secondary oxidation byproducts including aldehydes, ketones, alcohols, fatty acids, esters, lactones, ethers, and hydrocarbons.
Accordingly, the non-polymeric cross-linked gel derived from fatty acid compounds, such as those of fish oil, includes a cross-linked structure of triglyceride and fatty acid molecules in addition to free and bound glycerol, monoglyceride, diglyceride, and triglyceride, fatty acid, anhydride, lactone, aliphatic peroxide, aldehyde, and ketone molecules. There are a substantial amount of ester bonds remaining after curing in addition to peroxide linkages forming the majority of the cross-links in the gel. The cross-linked gel degrades into fatty acid, short and long chain alcohol, and glyceride molecules, which are all non-inflammatory and likewise consumable by cells in the soft tissue to which the cross-linked gel is applied. Thus, the cross-linked gel is bio-absorbable.
An oil component is applied to the surface on top of the release agent (step 102). As noted previously, the oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics. In addition, the oil component can be an oil composition, meaning a composition containing oil in addition to other substances. For example, the oil composition can be formed of the oil component in addition to a solvent and/or a preservative. Solvents can include a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). The preservative can also include a number of different alternatives, including vitamin E compounds. One of ordinary skill in the art will appreciate that there are a number of different solvents and preservatives available for use with the oil component to form the oil composition, and as such the present invention is not limited to only those listed in the examples herein. The solvent can be useful to alter the physical properties of the oil, as well as prepare the oil for combination with a therapeutic agent as described below. The preservative can also be useful in altering the physical properties of the oil component, as well as protecting some of the beneficial properties of the oil component during certain curing processes. Such beneficial properties include the healing and anti-inflammatory characteristics previously mentioned.
The oil component can be combined with one or more therapeutic agents to form an oil composition. Thus, if the added therapeutic benefit of a particular therapeutic agent or agents is desired, the therapeutic agent(s) can be added to the oil component prior to application to the surface, along with the oil component during application to the surface (including mixing with the oil component prior to application), or after the oil component has been applied (step 104). The different alternatives for adding the therapeutic agent(s) are determined in part based on the desired effect and in part on the particular therapeutic agent(s) being added. Some therapeutic agents may have reduced effect if present during a subsequent curing step. Some therapeutic agents may be more useful intermixed with the oil component to extend the release period, or applied to the surface of the oil component, resulting in a faster release because of increased exposure. One of ordinary skill in the art will appreciate that a number of different factors, such as those listed above in addition to others, can influence when in the process the therapeutic agent is added to the oil component, or the cross-linked gel 10. Accordingly, the present invention is not limited to the specific combinations described, but is intended to anticipate all such possible variations for adding the therapeutic agent(s).
For example, if 80% of a therapeutic agent is rendered ineffective during curing, the remaining 20% of therapeutic agent, combined with and delivered by the barrier can be efficacious in treating a medical disorder, and in some cases have a relatively greater therapeutic effect than the same quantity of agent delivered with a polymeric or other type of coating or barrier. This result can be modified with the variance of alpha-tocopherol to protect the therapeutic agent during the curing process, and then slow and extend the delivery of the therapeutic agent during absorption of the barrier layer into the tissue.
The oil component (or composition if mixed with other substances) is then hardened into the cross-linked gel 10 (step 106). The step of hardening can include hardening, or curing, such as by introduction of UV light, heat, oxygen or other reactive gases, chemical curing, or other curing or hardening method. The purpose of the hardening or curing is to transform the more liquid consistency of the oil component or oil composition into a more solid film or gel, while still maintaining sufficient flexibility to allow bending and wrapping of the film or gel as desired. However, the hardening process as described herein does not refer to or include the process of hydrogenation.
After the cross-linked gel 10 has formed, another determination is made as to whether therapeutic agents should be applied to the gel. If desired, the therapeutic agent(s) is added to the cross-linked gel 10 (step 108). Subsequently, the cross-linked gel 10 is removed from the surface (step 110). Once again, there is opportunity to apply a therapeutic agent(s) to the cross-linked gel 10 on one or both sides of the cross-linked gel 10. If such therapeutic agent(s) is desired, the therapeutic agent(s) is applied (step 112). The additional therapeutic agent can also be applied in the form of a non-cured or minimally cured oil, such as fish oil. The oil can likewise include other therapeutic agents mixed therewith. The resulting structure of such an application forms the underlying cross-linked gel 10 that is cured to form the film or gel, with a top coating of oil and potentially additional therapeutic agent layered on top. This structure enables the provision of a short term release of therapeutic from the oil top layer combined with a longer term release from the cured gel, which takes more time to degrade.
After application of the therapeutic agent(s), or after the cross-linked gel 10 is removed from the surface, the cross-linked gel 10 is sterilized. The sterilization process can be implemented in a number of different ways. For example, sterilization can be implemented utilizing ethylene oxide, gamma radiation, E beam, gas plasma, or vaporized hydrogen peroxide (VHF). One of ordinary skill in the art will appreciate that other sterilization processes can also be applied, and that those listed herein are merely examples of sterilization processes that result in a sterilization of the cross-linked gel 10, preferably without having a detrimental effect on the cross-linked gel.
It should be noted that the oil component or oil composition can be added multiple times to create multiple tiers in forming the cross-linked gel 10. For example, if a thicker cross-linked gel 10 is desired, additional tiers of the oil component or oil composition can be added after steps 100, 104, 106, 108, 110, or 112. Different variations relating to when the oil is hardened and when other substances are added to the oil are possible in a number of different process configurations. Accordingly, the present invention is not limited to the specific sequence illustrated. Rather, different combinations of the basic steps illustrated are anticipated by the present invention.
As understood by one of ordinary skill in the art, the properties of the mesh 40 and the cross-linked gel 10 can vary. There may be a requirement for the mesh 40 to have one side, or a portion of a side, that has anti-adhesion properties for a period of several days. Alternatively, multiple sides of the mesh 40 may be required to have anti-adhesion properties. As such, the cross-linked gel 10 can be applied to all sides, or portions of sides, or portions of one side of the mesh 40.
In addition, the requirement may be for the anti-adhesion properties to last several weeks, or even longer. Accordingly, the rate of degradation can also be varied by changing such properties as amount of cross-linking, thickness, and existence of additives, such as vitamin E compounds to achieve longer or shorter term anti-adhesion properties. In addition, there may be a desire to include a therapeutic agent to reduce inflammation, provide antibiotic therapy, or other therapeutic measures, in combination with the use of the mesh 40. Accordingly, the therapeutic agent(s) can be added to the cross-linked gel 10 to achieve the desired controlled release of the therapeutic agent after implantation. As previously described, combinations of cured oils top coated with lesser cured or non-cured oils and therapeutic agents can form the cross-linked gel 10.
The particular properties or characteristics of the mesh 40 are determined based on the desired use of the mesh 40. A common implementation is for the mesh 40 to be formed of a bio-compatible material, such as polypropylene, however other bio-compatible materials can be utilized, such as a mesh formed of the same or similar substance as the cross-linked gel 10 (i.e., oil based).
A determination is made as to whether a release agent should be added to the medical device to aid in removing the device from its location (e.g., on a surface) after combination with the cross-linked gel 10. If a release agent is required, the release agent is applied to the medical device (step 152). An example release agent for such an application is polyvinyl alcohol.
The medical device is then combined with the cross-linked gel 10 (step 154). Depending on the particular medical device, the combination with the cross-linked gel 10 can be implemented more efficiently by either applying the cross-linked gel 10 to the medical device, or placing the medical device on the cross-linked gel 10. For example, in the case of the mesh 40, the mesh 40 can be placed on top of the cross-linked gel 10, or the cross-linked gel 10 can be placed on top of the mesh 40.
The medical device and the cross-linked gel are then cured to create a bond (step 156). The curing process can be one of several known processes, including but not limited to applying heat, or UV light, or chemical curing, to cure the cross-linked gel. After curing, if there is any release agent present, the release agent is washed away using water, or some other washing agent (step 158).
As with the method of
Furthermore, the formation of the oil composition can be done in accordance with different alternatives to the methods described. For example, prior to forming the cross-linked gel 10, a preservative, such as a Vitamin E compounds can be mixed with the naturally occurring oil component to form the oil composition. A solvent can be mixed with a therapeutic agent, and then added to the naturally occurring oil to form the oil composition. The solvent can be chosen from a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). The solvent can later be removed with vacuum or heat. Other solvent alternatives can include, but are not limited to, a solvent or mixture of solvents including solvents that are generally acceptable for pharmaceutical use. Suitable solvents include, for example: alcohols and polyols, such as C2-C6 alkanols, 2-ethoxyethanol, ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, and polypropylene glycol; amides, such as 2-pyrrolidone, 2-piperidone, 2-caprolactam, N-alkylpyrrolidone, N-methyl-2-pyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide; esters, such as ethyl acetate, methyl acetate, butyl acetate, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, propylene glycol dimethyl ether, ethyl proprionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate, tracetin, ϵ-caprolactone and isomers thereof, δ-valerolactorne and isomers thereof, β-butyrolactone and isomers thereof; and other solvents, such as water, dimethylsulfoxide, benzyl benzoate, ethyl lactate, acetone, methylethyl ketone, dimethylsolfone, tetrahydrofuran, decylmethylsufoxide, N,N-diethyl-m-toulamide or 1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane.
In addition, it should again be noted that the oil component or oil composition can be added multiple times to create multiple tiers in forming the cross-linked gel 10. If a thicker cross-linked gel 10 is desired, additional tiers of the oil component or oil composition can be added after steps 174 and 176. Different variations relating to when the oil is hardened and when other substances are added to the oil are possible in a number of different process configurations. Accordingly, the present invention is not limited to the specific sequence illustrated. Rather, different combinations of the basic steps illustrated are anticipated by the present invention.
Depending on the type of therapeutic agent component, the resulting cross-linked gel 10 can maintain its bio-absorbable characteristics if the therapeutic agent component is also bio-absorbable.
The therapeutic agent component, as described herein, has some form of therapeutic or biological effect. The oil component or oil composition component can also have a therapeutic or biological effect. Specifically, the cross-linked gel 10 (and its oil constituents) enable the cells of body tissue of a patient to absorb the cross-linked gel 10 itself, rather than breaking down the gel and disbursing by-products of the gel for ultimate elimination by the patient's body.
As previously stated, and in accordance with embodiments of the present invention, the cross-linked gel 10 is formed of a naturally occurring oil, or composition including a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, and the like. A characteristic of the naturally occurring oil is that the oil includes lipids, which contributes to the lipophilic action described later herein, that is helpful in the delivery of therapeutic agents to the cells of the body tissue. In addition, the naturally occurring oil can include the essential omega-3 fatty acids in accordance with several embodiments of the present invention.
It should also be noted that the present description makes use of the mesh 40 as an example of a medical device that can be combined with the cross-linked gel 10 of the present invention. However, the present invention is not limited to use with the mesh 40. Instead, any number of other implantable medical devices can be combined with the cross-linked gel 10 in accordance with the teachings of the present invention. Such medical devices include catheters, grafts, balloons, prostheses, stents, other medical device implants, and the like. Furthermore, implantation refers to both temporarily implantable medical devices, as well as permanently implantable medical devices.
An embodiment of the present invention was implemented in a rat model to demonstrate the performance of the cross-linked gel of the present invention relative to other known surgical mesh devices. The devices were implanted in a rat to repair abdominal wall defects. Healing characteristics, adhesion formation and tenacity, and inflammatory response associated with these materials were compared.
A polypropylene mesh material (ProLite™) provided by Atrium Medical Corporation of Hudson, N.H., coated with one embodiment of the cross-linked gel described herein. The polypropylene mesh with cross-linked gel was compared with a bare polypropylene control mesh, and DualMesh® biomaterial provided by W. L. Gore & Associates, Inc.
Five samples of each mesh type were implanted according to a random schedule. On the day of surgery, the animals were anesthetized with an injection of 50 mg/kg Nembutal IP. The animal was prepped for surgery, and a midline abdominal incision was made. A portion of rectus muscle and fascia was removed leaving an approximately 20 mm×30 mm full thickness defect in the abdominal wall. Using 4-0 Prolene, the appropriate patch was sutured into place repairing the existing defect. An overlap of mesh was placed over the defect to ensure proper repair, with the mesh samples being 2.5 cm×3.5 cm in size. The mesh was placed such that the smoother side was toward the viscera in the case of the polypropylene mesh with cross-linked gel, and the appropriate side of the Gore DualMesh was also placed towards the viscera. Suture knots were made on the abdominal wall side of the implant rather than the visceral side as to not interfere with tissue attachment. The mesh was sutured around the entire perimeter to ensure adequate placement. The subdermal and subcutical layers were closed with Vicryl. The skin was closed using surgical staples. The animals received Buprenorphine for pain. The mesh was explanted at approximately 30 days.
Sample Explantation:
Approximately 30 days after implantation, the animals were again anesthetized for explant of the mesh samples. The skin staples were removed, and a vertical incision through the skin and subcutaneous tissue was made lateral to both the implantation site and patch. Through this incision, the implant was inspected and photos were taken to document adhesion formation. Upon gross examination, the same investigator evaluated each sample for adherent intraperitoneal tissues and assigned an adhesion grade to each sample (Jenkins S D, Klamer T W, Parteka J J, and Condon R E. A comparison of prosthetic materials used to repair abdominal wall defects. Surgery 1983; 94:392-8). In general, the adhesions were scored as: 0—no adhesions; 1—minimal adhesions that could be freed by gentle blunt dissection; 2—moderate adhesions that could be freed by aggressive blunt dissection; 3—dense adhesion that require sharp dissection.
Once the gross evaluation was complete, the mid-portion of the abdominal cavity was excised including the implant, and adhesive tissue not completely separated from the implant, and the overlying subcutaneous and skin. Sections were then fixed and processed for histological evaluation. The histology samples were stained with Hematoxylin and Eosin, Trichrome, GS1, and Vimentin.
Polypropylene Mesh Control:
These patches had a mean adhesion score of 2.1. Adhesions consisted of omentum, epididymal fat, and one had intestinal adhesions. Many of the adhesions were at the edges of the patch/tissue interface. The adhesions required aggressive blunt dissection to remove them. There was a moderate inflammatory response associated around the fibers of the mesh. There was a tight association of fat to the implant surface on the peritoneal cavity side, meaning the adhesions were not fully removed.
Gore DualMesh® Control:
Patches were entirely covered with adhesions. The adhesions consisted of epidiymal fat, omentum and bowel. The mean adhesion score was 2.9. There was a capsule covering the entire patch that needed sharp dissection to free from material. Adhesions pulled free from capsule with blunt dissection. A moderate to severe inflammatory response was observed in association with the skin side of the implant. The thin fibrous capsule on the peritoneal side of the implant was avascular and in some implants was loosely adherent to associated tissue.
Polypropylene Mesh with Cross-Linked Gel (Embodiment of Present Invention):
These patches had a mean adhesion score of 1.6. Adhesions included epididymal fat and some omentum. The adhesions dissociated from the patches relatively easily. There was a mild to minimal inflammatory response associated with the exposed polypropylene fibers of this material. Vimentin staining showed a layer of mesothelial cells formed on the tissue on the peritoneal cavity side of the implant.
The polypropylene mesh with cross-linked gel in accordance with one embodiment of the present invention showed good results in terms of adhesion minimization, tenacity of adhesions formed, and a low inflammatory response. The coated mesh product was also easy to handle, place, and suture for repair of an abdominal wall defect in this model.
Returning to the step of curing as described herein, the step can have a number of different variations and permutations that ultimately influence the properties of the resulting cured cross-linked gel, and any therapeutic agents if include therein. In this instance making use of a naturally occurring oil, such as fish oil, such oils or oil compositions as described herein can be heated to increase viscosity. The temperature, time duration, and volume of airflow over the oil or oil composition will affect how viscous the oil or oil composition becomes.
In addition, combining pre-cured, highly viscous oil with untreated oil results in a faster cure time of the resulting combination when forming the cross-linked gel. Also, taking a pre-cured oil and decreasing its viscosity slightly with solvent will result in a faster cure time as well. To demonstrate some of the possible variations of time and temperature, the following Examples #2 through #4 are provided.
Two samples of pre-cured fish oil were prepared. Epax 3000TG fish oil (with a starting viscosity of 40 Cps) was weighed out in two 57 mm weigh pans at 5 grams (Sample C) and 3 grams (Sample D). Both pans were heated at 150° F. for 70 hours. The resulting viscosities were: 1,500 Cps for Sample C and 14,000 Cps for Sample D (3 grams), respectively. Both of the thickened oils were mixed with non-cured oil at 25% ratio. These mixtures were used to coat polypropylene mesh against a control of non-cured oil. Once mesh was coated, it was placed on a curing substrate, Teflon®. The mesh samples were heated at 200° F. for 17 hours and checked. Both thickened samples were cured in 17 hours, displaying less “tackiness” than the control sample (which usually cures in 24 hours).
Sample D, at a viscosity of 14,000 Cps was mixed with 99% Isopropyl Alcohol, to decrease its viscosity in a ratio of 66% oil to 33% solvent. This mixture was then used to coat polypropylene mesh. A control of non-cured oil was used as a comparison. Once the mesh samples were coated, they were placed on a Teflon® curing substrate and heated at 200° F. An initial check was done at 15 hours. Sample D was cured (dry) better than the control at the same amount of time. In fact, this sample was more cured than the control at 24 hours in 200° F. oven.
Thickened oil (Sample C having a viscosity of about 1,500 Cps) was used to coat polypropylene mesh. This oil was not cut with a solvent. A control of non-cured fish oil coated mesh was used as a comparison. Both coated mesh samples were placed on a Teflon® curing substrate and heated at 200° F. After 15 hours, the samples were checked. The thickened oil Sample C had a slight inconsistent coating due to its start viscosity; however, the sample was more cured (displaying much less tackiness) than the control sample at the same time. In fact, Sample C was more cured than the control at 24 hours in 200° F. oven.
Modifying the starting pre-cured viscosity or pre-cured oil concentration in the mixture will enhance the curing speed. In addition, alternate methods of curing can be used in a similar manner (i.e. heat, UV, IR, and the like) and the sample will cure sooner than without pre-curing the oil. One of ordinary skill in the art will appreciate that the scope of the present invention is not limited to only coating on the mesh, but rather has application to other medical devices, or as a stand-alone film.
The curing conditions utilized, such as the duration of time and the degree of temperature, directly influence the amount of cross-linking that occurs in the cross-linked gel (i.e., the cross-link density). Cured fish oil coatings enable regulation of the release profile of drug-loaded oil-based coatings from implantable devices. The release profile can be controlled through changes in oil coating chemistry by varying coating composition, temperature, and cure times. The position of the drug-containing layer on the coated device provides an additional mechanism to alter the release profile of the drug-loaded fish oil coating. This can be achieved by either loading the drug into the encapsulating base layer of the device, or by coating a topcoat overlayer coating onto the previously cured encapsulating base layer.
More specifically, curing conditions utilized to form the cross-links, such as time and temperature, directly influence the amount of coating cross-linking density and byproduct formation, which in turn effects the coating degradation. Thus, by altering the curing conditions employed, the dissolution rate of the therapeutic compound of interest is also altered. The effects of curing conditions on fish oil curing chemistry and drug release properties are demonstrated in the following examples,
Two different curing profiles were provided to demonstrate the effects of curing temperature and time on the chemistry of the cured fish oil coatings. Atrium® ProLite Ultra™ polypropylene mesh was coated with Epax 3000TG fish oil and oven cured. The conditions were 200° F. for 24 hrs and 150° F. for 3 days.
FTIR analysis showed that curing at 150° F. for 3 days resulted in a 36% reduction in the anhydride/aliphatic peroxide/lactone cross-linking, 25% increase in the trans C═C bonds, and a 10% decrease in the amount of fatty acid/ketone byproducts formed compared to samples that were cured at 200° F. for 24 hours.
DSC analysis was performed on 150° F. and 200° F. cured fish oil coatings that were extracted in THF for 3 hrs at 37° C. to isolate the soluble (soluble oxidized byproducts, i.e. fatty acid, ketone, alcohols, etc.) and insoluble (cross-linked fatty acid and glyceride molecules) components of the mesh coating. Gravimetric analysis showed that the 200° F. coating consisted of a 50:50 mix of soluble:insoluble coating components, where as the 150° F. sample had a ratio of 62:38 soluble:insoluble coating components. DSC analysis of the insoluble components of the coatings showed that the 200° F. and 150° F. insoluble coating components were 93% and 70% cured, respectively. DSC analysis of the soluble components of the coatings showed that the 200° F. coating possessed less long chained oxidized byproducts than the 150° F. coating.
These above described examples are illustrative of the fact that coatings cured at 200° F. are relatively more cross-linked and further cured than 150° F. coatings.
The cross-link density and chemistry of the coating affects its degradation properties. FTIR analysis of the cured fish oil coating shows that the cured coating is formed of primarily ester bonds in addition to lesser amounts of anhydride, lactone, and aliphatic peroxide bonds that will undergo hydrolysis and degrade into smaller components over time. To demonstrate the differences in the 150° F. and 200° F. cured fish oil coating degradation behavior, both cured fish oil encapsulated mesh samples were placed in 0.1 M sodium phosphate buffer containing 0.1 M sodium chloride solution at pH=7.4 at either 37° C. or 55° C. The 200° F. cured fish oil coating dissolved during an 18-day period at 55° C., where it took 12 weeks to dissolve at 37° C. The 150° F. cured fish oil coating dissolved during an 18-21 day period at 55° C., where ongoing degradation at 37° C. demonstrates the coating to be partially dissolved after 21 days.
These results show that both the 200° F. and 150° F. cured fish oil coatings dissolve into solution using a hydrolysis mechanism.
Model drug delivery demonstrations were performed using coatings cured at 200° F. for 24 hours or 150° F. for 3 days. All samples were 1×1″ and dissolution was performed in 0.01 M PBS solution. All drug samples were loaded as an encapsulated mesh coating created by mixing the liquid fish oil and drug together, with or without solvent, followed by coating a piece of bare mesh and curing using either the 150° F. or 200° F. curing conditions described herein.
Demonstrating the delivery of an anti-inflammatory drug, a comparison of pure fish oil encapsulated mesh coatings was performed, using the 150° F. curing method and the 200° F. curing method. An amount of about 2.4% of anti-inflammatory drug remained in the fish oil after the nMP solvent was removed. The anti-inflammatory drug and the fish oil were cured at either 200° F. for 24 hours or 150° F. for 3 days. Based on an HPLC analysis, the initial drug loading after curing was about 442 ug (14.84% recovery) for the sample cured at 200° F. and about 238 ug (10.97% recovery) for the sample cured at 150° F. The amount of drug released over time measured in days is shown in
These results show that the 150° F. cured coating, which has less cross-linking, results in a faster drug release than the 200° F. cured coating, which possess more cross-linking. This example demonstrates the ability to load an anti-inflammatory into cured fish oil encapsulated coatings, and alter the drug dissolution release profile by using temperature to control the cross-linking properties of that coating.
Demonstrating the delivery of an anti-proliferative drug, cyclosporine, a comparison of pure fish oil encapsulated mesh coatings was performed, using the 150° F. curing method and the 200° F. curing method. An amount of about 2.84% of anti-proliferative drug (cyclosporine) was in the fish oil; no solvent was used because the cyclosporine was soluble in the fish oil with slight heat at 37° C. The anti-proliferative drug and the fish oil were cured at either 200° F. for 24 hours or 150° F. for 3 days. Based on an HPLC analysis, the initial drug loading after curing was about 478 ug (14.22% recovery) for the sample cured at 200° F. and about 1158 ug (26.00% recovery) for the sample cured at 150° F. The amount of drug released over time measured in days is shown in
These results confirm that the 150° F. cured coating, which has less cross-linking, results in a faster drug release than the 200° F. cured coating, which possess more cross-linking. This example demonstrates the ability to load an anti-proliferative, Cyclosporine A, into cured fish oil encapsulated coatings and alter the drug dissolution release profile by using temperature to control the cross-linking properties of that coating.
In view of the above examples, the following method can be implemented to effect different outcomes based on the variance of the curing process.
In general, a higher temperature will result in a greater number of cross-links than a lower temperature. Furthermore, in general, a relatively longer duration of cure time will result in a greater number of cross-links than a relatively shorter duration of cure time. However, as evidenced by the examples described herein, a higher temperature but shorter cure time can result in a greater number of cross-links than a lower temperature with a longer cure time. Thus, a more dominating factor in considering the desired amount of cross-links is temperature, and a lesser impacting factor in considering the desired amount of cross-links is the cure time.
The oil component itself, in the form of fish oil for example, can provide therapeutic benefits in the form of reduced inflammation, and improved healing, if the fish oil composition is not substantially modified during the process that takes the naturally occurring fish oil and forms it into the cross-linked gel 10. Some prior attempts to use natural oils as coatings have involved mixing the oil with a solvent, or curing the oil in a manner that destroys the beneficial aspects of the oil. The solvent utilized in the example cross-linked gel 10 embodiment of the present invention (NMP) does not have such detrimental effects on the therapeutic properties of the fish oil. Thus the benefits of the omega-3 fatty acids, and the EPA and DHA substances are substantially preserved in the cross-linked gel of the present invention.
Therefore, the cross-linked gel 10 of the present invention includes the bio-absorbable naturally occurring oil (i.e., fish oil). The cross-linked gel 10 is thus able to be absorbed by the cells of the body tissue. With the present invention, because of the lipophilic action enabled by the bio-absorbable lipid based cross-linked gel 10 of the present invention, the intake by the tissue cells of the cross-linked gel 10, and any therapeutic agent component, is substantially controlled by the cells themselves. In configurations using polymer based materials, the drugs were released at a rate regardless of the reaction or need for the drug on the part of the cells receiving the drug. With the cross-linked gel 10 of the present invention, the cells can intake as much of the cross-linked gel 10, and correspondingly the therapeutic agent, as is needed by the damaged cell requiring treatment.
In addition, the bio-absorbable nature of the cross-linked gel 10 results in the cross-linked gel 10 being completely absorbed over time by the cells of the body tissue. There is no break down of the cross-linked gel 10 into sub parts and substances that are inflammatory and are eventually distributed throughout the body and in some instances disposed of by the body, as is the case with biodegradable synthetic polymer coatings. The bio-absorbable nature of the cross-linked gel 10 of the present invention results in the cross-linked gel 10 being absorbed, leaving only the medical device structure, if the cross-linked gel 10 is not implanted alone. There is no inflammatory foreign body response to the cross-linked gel 10.
In addition, the cross-linked gel 10 provides a lubricious or anti-adhesive surface against tissue. The cross-linked gel 10 itself can provide an anti-adhesion barrier between two sections of tissue, or the cross-linked gel 10 can form an anti-adhesion surface on a medical device, such as the mesh 40. The use of the naturally occurring oil, such as fish oil, provides extra lubrication to the surface of the medical device, which helps to reduces injury. With less injury, there is less of an inflammatory response, and less healing required. Likewise the fatty acid derived cross-linked gel that makes up the cross-linked gel maintains anti-inflammatory properties and non-inflammatory properties, which also substantially lowers the inflammatory response of the tissue. The reduced inflammation also reduces adhesions.
Numerous modifications and alternative embodiments of the present invention will be apparent to those skilled in the art in view of the foregoing description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the best mode for carrying out the present invention. Details of the structure may vary substantially without departing from the spirit of the invention, and exclusive use of all modifications that come within the scope of the appended claims is reserved. It is intended that the present invention be limited only to the extent required by the appended claims and the applicable rules of law.
This application is a continuation of United States Non-Provisional application Ser. No. 11/237,263, filed Sep. 28, 2005, which claims priority to, and the benefit of, U.S. Provisional Application No. 60/613,808, filed Sep. 28, 2004, for all subject matter common to both applications. The disclosure of said provisional application is hereby incorporated by reference in its entirety. This application also relates to co-pending U.S. patent application Ser. No. 11/237,420, filed concurrently with the parent application on Sep. 28, 2005, which application is hereby incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1948959 | Croce | Feb 1934 | A |
| 2368306 | Kiefer et al. | Jan 1945 | A |
| 2403458 | Ransom | Jul 1946 | A |
| 2555976 | Keenan et al. | Jun 1951 | A |
| 2735814 | Hodson et al. | Feb 1956 | A |
| 2986540 | Posnansky | May 1961 | 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 |
| 4447418 | Maddoux | May 1984 | A |
| 4557925 | Lindahl et al. | Dec 1985 | A |
| 4664114 | Ghodstain | May 1987 | A |
| 4813210 | Masuda et al. | Mar 1989 | A |
| 4814329 | Harsanyi et al. | Mar 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 |
| 4947840 | Yannas et al. | Aug 1990 | A |
| 4952419 | de Leon | Aug 1990 | A |
| 4968302 | Schluter et al. | Nov 1990 | A |
| 5017229 | Burns et al. | May 1991 | A |
| 5061281 | Mares et al. | Oct 1991 | 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 |
| 5202310 | Levy et al. | Apr 1993 | A |
| 5176956 | Jevne et al. | May 1993 | A |
| 5254105 | Haaga | Oct 1993 | 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 |
| 5464650 | Berg et al. | Nov 1995 | A |
| 5480653 | Aguadish et al. | Jan 1996 | A |
| 5509899 | Fan et al. | Apr 1996 | A |
| 5547677 | Wright | Aug 1996 | A |
| 5549901 | Wright | Aug 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 |
| 5612074 | Leach | Mar 1997 | A |
| 5614284 | Kranzler et al. | Mar 1997 | A |
| 5627077 | Dyllick-Brenzinger et al. | May 1997 | A |
| 5629021 | Wright | May 1997 | A |
| 5637113 | Tartagalia et al. | Jun 1997 | A |
| 5665115 | Cragg | Sep 1997 | A |
| 5695525 | Mulhauser et al. | Dec 1997 | A |
| 5700286 | Tartagalia et al. | Dec 1997 | A |
| 5731346 | Egberg et al. | Mar 1998 | A |
| 5736152 | Dunn | Apr 1998 | A |
| 5747533 | Egberg 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 |
| 5817343 | Burke | Oct 1998 | A |
| 5824082 | Brown | Oct 1998 | A |
| 5837313 | Ding et al. | Nov 1998 | A |
| 5843919 | Burger | Dec 1998 | A |
| 5874470 | Nehne et al. | Feb 1999 | A |
| 5879359 | Dorigatti et al. | Mar 1999 | A |
| 5898040 | Shalaby et al. | Apr 1999 | A |
| 5906831 | Larsson et al. | May 1999 | A |
| 5931165 | Reich et al. | Aug 1999 | A |
| 5955502 | Hansen et al. | Sep 1999 | A |
| 5986043 | Hubbell et al. | Nov 1999 | A |
| 6005004 | Katz et al. | Dec 1999 | A |
| 6010766 | Braun et al. | Jan 2000 | A |
| 6010776 | Exsted et al. | Jan 2000 | A |
| 6015844 | Harvey et al. | Jan 2000 | A |
| 6028164 | Loomis | Feb 2000 | A |
| 6040330 | Hausheer et al. | Mar 2000 | A |
| 6048725 | Shimada et al. | Apr 2000 | A |
| 6056970 | Greenawalt et al. | May 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 |
| 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 |
| 6203551 | Wu | Mar 2001 | B1 |
| 6206916 | Furst | Mar 2001 | B1 |
| 6211315 | Larock et al. | Apr 2001 | B1 |
| 6228383 | Hansen et al. | May 2001 | B1 |
| 6229032 | Jacobs et al. | May 2001 | B1 |
| 6245366 | Popplewell et al. | Jun 2001 | B1 |
| 6245811 | Harrobin et al. | Jun 2001 | B1 |
| 6254634 | Anderson 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 |
| 6299604 | Ragheb 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 |
| 6358556 | Ding et al. | Mar 2002 | B1 |
| 6364893 | Sahatjian et al. | Apr 2002 | B1 |
| 6368658 | Schwarz et al. | Apr 2002 | B1 |
| 6369039 | Palasis et al. | Apr 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 |
| 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 |
| 6500453 | Brey et al. | Dec 2002 | B2 |
| 6503556 | Harish et al. | Jan 2003 | B2 |
| 6525145 | Gavaert et al. | Feb 2003 | B2 |
| 6527801 | Dutta | Mar 2003 | B1 |
| 6534693 | Fischell et al. | Mar 2003 | B2 |
| 6548081 | Sadozai et al. | Apr 2003 | B2 |
| 6565659 | Pacetti et al. | May 2003 | B1 |
| 6569441 | Kunz et al. | May 2003 | B2 |
| 6599323 | Melican et al. | Jul 2003 | B2 |
| 6610035 | Yang et al. | Aug 2003 | B2 |
| 6610068 | Yang et al. | Aug 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 |
| 6696583 | Koncar et al. | Feb 2004 | B2 |
| 6730064 | Ragheb et al. | May 2004 | B2 |
| 6753071 | Pacetti | Jun 2004 | B1 |
| 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 |
| 6833004 | Ishii et al. | 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 |
| 6918927 | Bates et al. | Jul 2005 | B2 |
| 6996952 | Gupta et al. | Feb 2006 | B2 |
| 7070858 | Shalaby et al. | Jul 2006 | B2 |
| 7101381 | Ford et al. | Sep 2006 | B2 |
| 7152611 | Brown et al. | Dec 2006 | B2 |
| 7323178 | Pathak | Jan 2008 | B1 |
| 7415811 | Gottlieb et al. | Aug 2008 | B2 |
| 7854958 | Kramer | Dec 2010 | B2 |
| 7947015 | Herweck et al. | May 2011 | B2 |
| 8124127 | Faucher et al. | Feb 2012 | B2 |
| 8263102 | Labrecque et al. | Sep 2012 | B2 |
| 8308684 | Herweck et al. | Nov 2012 | B2 |
| 8312836 | Corbeil et al. | Nov 2012 | B2 |
| 8367099 | Herweck et al. | Feb 2013 | B2 |
| 8722077 | Labrecque et al. | May 2014 | B2 |
| 9000040 | Faucher et al. | Apr 2015 | B2 |
| 9012506 | Faucher et al. | Apr 2015 | B2 |
| 20010025034 | Arbiser | Sep 2001 | A1 |
| 20010025196 | Chinn et al. | Sep 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 |
| 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 |
| 20020098278 | Bates et al. | Jul 2002 | A1 |
| 20020116045 | Eidenschink | Aug 2002 | A1 |
| 20020120333 | Keogh et al. | Aug 2002 | A1 |
| 20020122877 | Harish et al. | Sep 2002 | A1 |
| 20020142089 | Koike et al. | Oct 2002 | A1 |
| 20020193829 | Kennedy et al. | Dec 2002 | A1 |
| 20030003125 | Nathan et al. | Jan 2003 | A1 |
| 20030003221 | Zhong et al. | Jan 2003 | A1 |
| 20030004564 | Elkins et al. | Jan 2003 | A1 |
| 20030009213 | Yang | Jan 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 |
| 20030008374 | Pathak | May 2003 | A1 |
| 20030086958 | Arnold et al. | May 2003 | A1 |
| 20030094728 | Tayebi | May 2003 | A1 |
| 20030108588 | Chen et al. | Jun 2003 | A1 |
| 20030130206 | Koziak et al. | Jun 2003 | A1 |
| 20030015260 | 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 |
| 20030020416 | Bosma et al. | Oct 2003 | A1 |
| 20030191179 | Joshi-Hangal 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 |
| 20030220297 | Berstein et al. | Nov 2003 | A1 |
| 20040000629 | Fischell et al. | Jan 2004 | A1 |
| 20040001822 | Fischell et al. | Jan 2004 | A1 |
| 20040014810 | Horrobin | Jan 2004 | A1 |
| 20040039441 | Rowland et al. | Feb 2004 | A1 |
| 20040007175 | Fischell et al. | Apr 2004 | A1 |
| 20040007328 | Bates et al. | Apr 2004 | A1 |
| 20040060260 | Gottlieb et al. | Apr 2004 | A1 |
| 20040072849 | Schreiber et al. | Apr 2004 | A1 |
| 20040117007 | Whitbourne et al. | Jun 2004 | A1 |
| 20040131755 | Zhong et al. | Jul 2004 | A1 |
| 20040133275 | Mansmann | Jul 2004 | A1 |
| 20040137066 | Jayaraman | Jul 2004 | A1 |
| 20040137179 | Shojiro et al. | Jul 2004 | A1 |
| 20040142094 | Narayanan | Jul 2004 | A1 |
| 20040146546 | Gravett et al. | Jul 2004 | A1 |
| 20040016757 | Roth et al. | Aug 2004 | A1 |
| 20040156879 | Muratoglu et al. | Aug 2004 | A1 |
| 20040161464 | Domb | 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 |
| 20040241211 | Fischell | Dec 2004 | A9 |
| 20040256264 | Israelsson et al. | Dec 2004 | A1 |
| 20050010078 | Jamiolkowski et al. | Jan 2005 | A1 |
| 20050008451 | Shebuski et al. | Apr 2005 | A1 |
| 20050095267 | Campbell et al. | May 2005 | A1 |
| 20050100655 | Zhong et al. | May 2005 | A1 |
| 20050106209 | Ameri et al. | May 2005 | A1 |
| 20050112170 | Hossainy et al. | May 2005 | A1 |
| 20050113849 | Popadiuk et al. | May 2005 | A1 |
| 20050124062 | Subirade | Jun 2005 | A1 |
| 20050129787 | Murad | Jun 2005 | A1 |
| 20050015836 | Dhondt et al. | Jul 2005 | P1 |
| 20050159809 | Hezi-Yamit et al. | Jul 2005 | A1 |
| 20050165476 | Furst et al. | Jul 2005 | A1 |
| 20050165477 | Anduiza et al. | Jul 2005 | A1 |
| 20050018737 | Pacetti | Aug 2005 | A1 |
| 20050182485 | Falotico et al. | Aug 2005 | A1 |
| 20050203635 | Hunter et al. | Sep 2005 | A1 |
| 20050203636 | McFetridge | Sep 2005 | A1 |
| 20050023297 | Hossainy et al. | Oct 2005 | A1 |
| 20050223679 | Gottlieb et al. | Oct 2005 | A1 |
| 20050249775 | Falotico et al. | Nov 2005 | A1 |
| 20050283229 | Dugan et al. | Dec 2005 | A1 |
| 20060000850 | Dhont et al. | Jan 2006 | A1 |
| 20060003631 | Nakayama et al. | Feb 2006 | A1 |
| 20060051544 | Goldmann | Mar 2006 | A1 |
| 20060058881 | Trieu | 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 | Apr 2006 | A1 |
| 20060083768 | Labrecque et al. | Apr 2006 | A1 |
| 20060088596 | Labrecque et al. | Apr 2006 | A1 |
| 20060093643 | Stenzel | May 2006 | A1 |
| 20060110467 | Labrecque et al. | May 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 |
| 20060246105 | Molz et al. | Dec 2006 | A1 |
| 20070015893 | Hakuta et al. | Jan 2007 | A1 |
| 20070071798 | Herweck et al. | Mar 2007 | A1 |
| 20070084144 | Labrecque et al. | Apr 2007 | A1 |
| 20070093894 | Darouiche | Apr 2007 | A1 |
| 20070202149 | Faucher et al. | Aug 2007 | A1 |
| 20070212411 | Fawzy et al. | Sep 2007 | A1 |
| 20070264460 | Del Tredici | Nov 2007 | A1 |
| 20070275074 | Holm et al. | Nov 2007 | A1 |
| 20070280986 | Gil et al. | Dec 2007 | A1 |
| 20070286891 | Kettlewell et al. | Dec 2007 | A1 |
| 20070299538 | Roeber | Dec 2007 | A1 |
| 20080038307 | Hoffmann | Feb 2008 | A1 |
| 20080044481 | Harel | Feb 2008 | A1 |
| 20080045557 | Grainger et al. | Feb 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 |
| 20080279929 | Devane et al. | Nov 2008 | A1 |
| 20080286440 | Scheer et al. | Nov 2008 | A1 |
| 20080289300 | Gottlieb et al. | Nov 2008 | A1 |
| 20090011116 | Herweck et al. | Jan 2009 | A1 |
| 20090047414 | Corbeil et al. | Feb 2009 | A1 |
| 20090092665 | Mitra et al. | Apr 2009 | A1 |
| 20090181074 | Makower et al. | Jul 2009 | A1 |
| 20090181937 | Faucher et al. | Jul 2009 | A1 |
| 20090208552 | Faucher et al. | Aug 2009 | A1 |
| 20100183697 | Swanick et al. | Jul 2010 | A1 |
| 20100209473 | Dhont et al. | Aug 2010 | A1 |
| 20100233232 | Swanick et al. | Sep 2010 | A1 |
| 20110045050 | Elbayoumi et al. | Feb 2011 | A1 |
| 20110274823 | Labrecque et al. | Nov 2011 | A1 |
| 20120016038 | Faucher et al. | Jan 2012 | A1 |
| 20120213839 | Faucher et al. | Aug 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| 0471566 | Feb 1992 | EP |
| 0610731 | Aug 1994 | EP |
| 0623354 | Nov 1994 | EP |
| 0730864 | Sep 1996 | EP |
| 0790822 | Aug 1997 | EP |
| 0873133 | Oct 1998 | EP |
| 0917561 | May 1999 | EP |
| 1140243 | Oct 2001 | EP |
| 1181943 | Feb 2002 | EP |
| 1270024 | Jan 2003 | EP |
| 1273314 | Jan 2003 | EP |
| 1364628 | Nov 2003 | EP |
| 1520795 | Apr 2005 | EP |
| 1557183 | Jul 2005 | EP |
| 2083875 | Aug 2009 | EP |
| 1402906 | Jun 2011 | EP |
| WO 03039612 | May 2003 | FR |
| 20080025986 | Mar 2008 | KR |
| WO 1986000912 | Jul 1984 | WO |
| WO 1990001969 | Mar 1990 | WO |
| 90008544 | Aug 1990 | WO |
| WO 1995026715 | Oct 1995 | WO |
| WO 1997002042 | Jan 1997 | WO |
| WO 1997009367 | Mar 1997 | WO |
| WO 1997013528 | Apr 1997 | WO |
| WO 1998030206 | Jul 1998 | WO |
| 9846287 | Oct 1998 | WO |
| WO 1998054275 | Dec 1998 | WO |
| WO 1999025336 | May 1999 | WO |
| WO 200040278 | Jul 2000 | WO |
| WO 200062830 | Oct 2000 | WO |
| WO 2001024866 | Apr 2001 | WO |
| WO 2001026585 | Apr 2001 | WO |
| WO 2001037808 | May 2001 | WO |
| WO 2001060586 | Aug 2001 | WO |
| WO 2001066036 | Sep 2001 | WO |
| WO 2001076649 | Oct 2001 | WO |
| WO 2002049535 | Jun 2002 | WO |
| WO 2002100455 | Dec 2002 | WO |
| WO 2003000308 | Jan 2003 | WO |
| WO 2003015748 | Feb 2003 | WO |
| WO 2003028622 | Apr 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 |
| WO 2003092741 | Nov 2003 | WO |
| WO 2003092779 | Nov 2003 | WO |
| WO 2004004598 | Jan 2004 | WO |
| WO 2004006976 | Jan 2004 | WO |
| WO 2004006978 | Jan 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 |
| WO 2006024488 | Mar 2006 | WO |
| WO 2006036967 | Apr 2006 | WO |
| WO 2006102374 | Sep 2006 | WO |
| WO 2007047028 | Apr 2007 | WO |
| 2008010788 | Jan 2008 | WO |
| 2008016664 | Feb 2008 | WO |
| WO 2008057328 | May 2008 | WO |
| 2010042134 | Apr 2010 | WO |
| 2010042241 | Apr 2010 | WO |
| WO 2012009707 | Jan 2012 | WO |
| Entry |
|---|
| Stenberg, Cecilia. “Influence of the fatty acid pattern on the drying of linseed oils” (2004). |
| Champagne et al., Microencapsulation for teh improved delivery of bioactive compounds into foods; Current Opinion in Biotechnology 2007, 18:184-190. |
| David Schardt, Just the Flax, Nutrition Action Healthletter; Dec. 2005. |
| Ackman, R.G., “Fish Oils”, Bailey's Industrial Oil and Fat Products, 6th Edition, 279-317 (2005). |
| Ahuja et al. Journal of Indian Pediatric Surgery 2002 7:15-20. |
| Andes, et al. “Antiproliferative Strategies for the Treatment of Vascular Proliferative Disease”, Current Vascular Pharmacology, 1)1): 85-98 (2003). |
| 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. |
| Autosuture, “ParietexTM Composite OS Series Mesh,” retrieved online at http://www.autosuture.com/AutoSuture/pagebuilder.aspx?topicID=135734&breadcrumbs=135601:0 (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.” |
| Cecw-Ee, “Ch. 4: Coating Types and Characteristics,” Engineering and Design—Painting: New Construction and Maintenance, pp. 4-1 to 4-24 (1995). |
| Crivello et al., “Epoxidized triglycerides as renewable monomers in photoinitiated cationic polymerization,” Chem. Mater, 1992:692-699. |
| 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). |
| Encylopedia Britannica Online, “Surface Coating,” available online at http://www.britannica.com/Ebchecked/topic/575029/surface-coating>, date accessed Jun. 17, 2011. |
| 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). |
| 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). |
| Jorge, N., “Grasas y Aceites”, 48(1): 17-24, (1997). |
| Lipids, Chapter 19, pp. 1-12 (2002). |
| 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). |
| Ogunniyi, D.S., “Castor oil: A vital industrial raw material,” Biosource Technology, vol. 97: 1086-1091 (2006). |
| Polymerization Merriam-Webster Online Dictionary, retrieved from <www.merriam-webster.com> on Dec. 13, 2009; Merriam-Webster's Inc. 2009; pp. 1. |
| 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). |
| Rutkow, Ira M. et al., “‘Tension-free’ inguinal herniorrhaphy: A preliminary report on the ‘mesh plug’ technique,” Surgery, vol. 114:3-8 (1993). |
| 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). |
| 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. |
| Timar-Balizsy et al., “Chemical Principals of Textile Conservation,” Oxford: Elsevier Science Ltd., 1998:117-119. |
| 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). |
| Websters Dictionary Online, Accessed on Feb. 13, 2009, entry for “polymer” p. 1 of 1. |
| Wikipedia, “Sirolimus,” pp. 1-13, available online at http://en.wikipedia.org/wiki/Sirolimus, date accessed May 11, 2011. |
| Winter, et al., “Physical and Chemical Gelation” Encyclopedia of Materials—Science and Technology, vols. 1-11: 6691-6999 (2001). |
| 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). |
| 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; 1216-1222 (1997). |
| 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. |
| Supplementary European Search Report for Application No. EP 12004057, dated Apr. 10, 2013. |
| International Search Report for International Application PCT/US2013/044653, dated Sep. 4, 2013. |
| Supplementary European Search Report for Application No. EP 10825447, dated Mar. 31, 2014. |
| 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 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 2010-0183697,), 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-2010-0233232,), dated Jun. 11, 2012. |
| Notice of Allowance for U.S. Appl. No. 12/182,261 (listed on SB/08 as US US-2009-0047414,), 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. |
| Advisory Action for U.S. Appl. No. 12/581,582 (listed on SB-08 as U.S. Publication No. 2010-0183697,), dated Nov. 14, 2012. |
| Notice of Allowance for U.S. Appl. No. 11/525,390 (listed on SB-08 as U.S. Publication No. US-2007-0071798,), dated Nov. 20, 2012. |
| Non-Final Office Action for U.S. Appl. No. 13/404,487 (listed on SB-08 as US 2012-0213839),), dated Dec. 20, 2012. |
| Non-Final Office Action for U.S. Appl. No. 13/184,512 (listed on SB-08 as 2012-0016038),), dated Jan. 31, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/978,840 (listed on SB-08 as U.S. 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. 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. No. US-2012-0213839,), dated Apr. 2, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/236,943 (listed on SB-08 as U.S. No. US-2006-0067975,), dated Apr. 22, 2013. |
| Final Office Action for U.S. Appl. No. 13/184,512 (listed on SB-08 as U.S. No. U.S. 2012-0016038,), date Jun. 25, 2013. |
| Non-Final Office Action for U.S. Appl. No. 11/237,264 (listed on SB-08 as U.S. 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. 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Final Office Action for U.S. Appl. No. 12/075,223, dated Jul. 22, 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. 13/184,512, dated Oct. 10, 2014. |
| Non-Final Office Action for U.S. Appl. No. 12/075,223, dated Oct. 29, 2014. |
| 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. |
| 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. |
| Final Office Action for U.S. Appl. No. 11/701,799, dated Mar. 12, 2015. |
| Final Office Action for U.S. Appl. No. 13/843,068, dated Apr. 23, 2015. |
| Final Office Action for U.S. Appl. No. 13/184,512, dated Apr. 28, 2015. |
| Wicks et al. Organic Coatings:Science and Technology 1999 New York:Wiley Interscience p. 258-267. |
| Mills et al. Oils and Fats. “The Organic Chemistry of Museum Objects” London:Buttersworth and Co. 1987, p. 26-40. |
| Erhardt Paints Based on Drying Oil Media. Painted Wood: History & Conservation. Ed. Berland Singapore: The J. Paul Getty Trust 1998. p. 17-32. |
| Wexler et al. Chemical Reviews 1964 64(6):591-611. |
| Polymer—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 11:3-8. |
| Bimbo (Inform 1998 9(5):473-483. |
| Oxford Reference, A Dictionary of Chemistry, 6th edition, John Daintith, 2008, 3 pages. |
| Fats & Oils (2008) at http://scifun.chem.wisc.edu/chemweek/pdf/fats&oils.pdf (downloaded Sep. 24, 2015). |
| “Lead”, Article by Centers for Disease Control and Prevention (CDC), Nov. 2009, 2 pages. |
| “Cure” in Academic Press Dictionary of Science and Technology, 1992. |
| 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). |
| Hutlin, 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: sessionid=33N2RBQDV0DZKCQPCCEGU3AKB2IIWTT1 (2006). |
| Orthovisc, “What is ORTHOVISC®?” retrieved online at http://www.orthovisc.com/xhtmmlbgdisplay.jhtml?itemname=about_orthovisc (2005). |
| Orthovisc, “Your Knees and Osteoarthritis”, retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.jtml?itemname=understanding_knee_oa (2003). |
| Orthovisc, “What to expect from your treatment,” retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.jtml?itemname=what_to_expect (2007). |
| Orthovisc, “Tools and Resources for Managing Your Osteoarthritis”, retrieved online at http://www.orthovisc.com/xhtmlbgdisplay.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. |
| 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). |
| Triglycerides, 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). |
| Hawley's Condensed Chemical Dictionary—pp. 425 and 426 (2001), which corresponds to “Exhibit A1.” |
| Hydrogenated Castor Oil, at http://www.acme-hardesty.com/product/hydrogenated-castor-oil/ (downloaded Jun. 2, 2017), which corresponds to “Exhibit B1.” |
| Wikipedia, Sunflower oil, https://en.wikipedia.org/wiki/Sunflower_oil, accessed Jul. 23, 2015 in related U.S. Appl. No. 14/252,671, pp. 1-7. |
| Esoteric Oils, Peppermint essential oil information, http://www.essentialoils.co.za/essential-oils/peppermint.htm, accessed Jul. 23, 2015 in related U.S. Appl. No. 14/252,671, pp. 1-7. |
| Orthomolecular, Fish Oil, Jun. 29, 2004, http://orthomolecular.org/nutrients/fishoil.html, accessed Jul. 22, 2015 in related U.S. Appl. No. 14/252,671, p. 1. |
| Number | Date | Country | |
|---|---|---|---|
| 20150079191 A1 | Mar 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60613808 | Sep 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11237263 | Sep 2005 | US |
| Child | 14511765 | US |
