Patent Application
20140271531
Systems and methods relating to polymer foams and their use in endoscopic lung volume reduction procedures are generally described.
Lung volume reduction surgery (LVRS) is a known treatment for patients with advanced-stage emphysema. Parts of the lung that are particularly damaged are removed, allowing the remaining lung and surrounding muscles to work more efficiently. After the targeted lung tissue is removed, the remaining lung is resealed with an endoscopic stapler. Conventional LVRS involves surgical resection via either a mini-thoracotomy using video-assisted thoracoscopy (VATS), or a median sternotomy. The alternative to LVRS is medical therapy, which involves smoking cessation, bronchodilators, and oxygen therapy. LVRS has shown to yield a mortality advantage over medical therapy in patients with predominately upper-lobe emphysema. LVRS has also shown to increase exercise capacity in patients, whereas medical treatment may reduce symptoms but cannot improve function.
Despite some promising patient outcomes, there are serious drawbacks with the current approaches to LVRS. The operative mortality rate is 5-8% and many patients are excluded because they are considered too high-risk for surgery. Besides the risk of death, there are known complications both from general surgery and specific to LVRS. The most significant postoperative complications are air leaks from incomplete sealing of the resectioned lung tissue, respiratory failure, especially if re-intubation is necessary, cardiac arrhythmia, and gastrointestinal complications. Air leaks are such a common problem that it is normal procedure to place a chest tube in the patient's chest to prevent the lung from collapsing. In 60% of cases air leaks heal within a week of surgery, but some patients have to remain hospitalized for a longer period of time.
Systems and methods relating to polymer foams are provided. The subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.
In one aspect, the present invention relates to a method of occluding an airway within a patient, comprising: providing a delivery device and a fluid prepolymer material, placing the delivery device within an airway of a patient, delivering the fluid prepolymer material from the delivery device into the airway, and forming a foam within the airway from the fluid prepolymer. In one embodiment the medical device is a catheter. In another embodiment the medical device is a bronchoscope. In one embodiment the airway is a bronchial network of the lung. In another embodiment the airway is a alveolar duct of the lung.
In one aspect, the invention provides methods of occluding airways of a patient, such as the bronchial network of a lung, a bronchus of a lung, or an alveolar duct of a lung. Such methods preferably and effectively result in lung volume reduction for the treatment of, for example, emphysema. In accordance with embodiments of the present invention, methods of occluding airways comprise the step of forming an in-situ forming foam within the airways. The foam is formed from a one-part, two-part, or multi-part system, as defined herein.
In another aspect, the invention provides a system for occluding airways of a patient such as the bronchial network of a lung, a bronchus of a lung, or an alveolar duct of a lung. Such systems are preferably and effectively used to cause lung volume reduction in the patient for the treatment of, for example, emphysema. In accordance with embodiments of the present invention, the system comprises a chamber containing a polymer composition and a delivery device configured to deliver the composition into an airway whereupon the composition reacts to generate a gas and form a foam. In preferred embodiments, the polymer composition is an isocyanate functionalized prepolymer, and the foam is a polyurethane foam.
In other aspects, the invention includes foams, compositions, formulations, products, kits, and systems that are useful for performing the methods described above.
The present invention offers advantages not previously known in the art. For example, the polymers of the invention can be deployed into a closed body cavity without requiring specific knowledge of target site(s) while nonetheless creating conformal contact with target tissues located throughout the cavity. Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.
Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:
Systems and methods related to polymer foams are generally described. Some embodiments relate to compositions and methods for the preparation of polymer foams, and methods for using the polymer foams. In-situ forming foam is deployed as one or more flowable materials that foam and polymerize upon or after deployment. The polymer foams can be applied to a cavity such as an airway, lung, or other suitable structure targeted for reduction such that they occlude the cavity, thus leading to tissue necrosis because the foam prevents oxygenation of the tissue surrounding the duct. As used herein, “cavity”, “duct”, “airway”, “lung” and other similar terms are used synonymously to mean a structure within body tissue into which a foam can be formed, whether naturally-occurring, created by disease or trauma, or made by surgery. The foam need not be applied at an exact location, as foam expansion leads to travel into more distal airways to contact hard to reach areas; if the foam is applied close to a targeted duct, the foam can expand both distally into the alveoli and proximally into the branches. In other embodiments, foams may also be deployed into the vascular network supplying blood to the section of lung to be reduced in volume; in this way, the lung is made necrotic by limiting the blood supply to it (i.e., embolization). The foamed polymers may have surface properties engineered to adhere to the tissue of the airway walls, or to promote cell growth and resorption. Foams of the invention may collapse over the course of days, and fully resorb into the body with necrosed lung tissue over the course of months. Foams of the invention can be used to occlude select distal portions of the airways of the lungs, leading to tissue necrosis and lung volume reduction. Alternatively, certain methods of the invention cause lung necrosis after foam deployment, including thermal ablation, drug delivery, and chemical ablation. Certain compositions of the invention can be deposited within the lungs and retain compliance and elasticity to allow the foam to move with the lungs.
The polymer foams may possess attributes that make them particularly suitable for use within the body. For example, in some embodiments, the polymers used to form the foams described herein are preferably biocompatible. The polymers may also be biodegradable in some cases. In some instances, the polymers may be sufficiently elastic to allow for body movement while being sufficiently stiff to support body tissues. In some embodiments, the foam composition may be adjusted so that it wets tissues effectively. Furthermore, pendant groups may be attached that allow for the targeted adhesion of polymer to tissues or injured or target tissues. As used herein, “tissues” may refer to tissues in general or injured or target tissues. Functionalization of the polymer used to form the foam may also lead to covalent bonding of the foam to a surface inside the body cavity, which may aid, for example, in preventing dislocation of the foam within the cavity or sealing of the tissue.
The materials and methods described herein exhibit several advantages relative to traditional methods of lung volume reduction. As noted above, the current means of performing the surgery are either video assisted thoracoscopy surgery (VATS) or median sternotomy. The in-situ forming foam of the present invention provides an endoscopic alternative to traditional LVRS. One advantage of an endoscopic procedure is that because delivery of an in-situ forming foam via bronchoscope or other minimally-invasive techniques is less invasive than known surgical techniques, it may cause fewer post-procedure complications and reduce operational mortality. Another advantage of an endoscopic procedure is that a wider population of patients may be eligible for the treatment.
Another exemplary advantage of the methods of the present invention is that delivery of an in-situ forming foam via bronchoscope or other minimally-invasive techniques is simpler than known surgical techniques. Therefore, performance of the procedures of the present invention are not limited to thoracic surgeons specializing in specific surgical techniques as is the case with current methods; for example, a pulmonologist could be trained to perform the methods of the present invention. In addition, a bronchoscopy is a quick procedure relative to VATS or sternotomy; the patient may be awake and sedated rather than prepped for an open surgery. These advantages lead to quicker recovery time, decreases in procedure time and hospital stay, therefore reducing the cost and risk of treatment as compared to conventional methods.
As another advantage of the present invention, the use of an in-situ foam to seal off targeted tissue and therefore causing tissue necrosis eliminates the need to physically cut and staple lung tissue, thus eliminating a source of air leaks. The nature of these in situ forming foams and their ability to conform to complex surfaces and volumes makes them particularly useful in this application. As discussed above, air leaks are the most common complication of conventional methods of LVRS.
Preferred embodiments of the invention make use of a polyurethane foam, as further described herein. An in-situ foam with polyurethane chemistry can be engineered to meet certain clinical needs not readily achievable with other chemistries. For example, the kinetics, density, porosity, surface properties, compliance, and degradation profile can all be controlled. In certain embodiments, the expansive nature of the foams described herein allow them to travel to hard to reach spaces, sealing all targeted tissue surface. The complete sealing of the targeted area is important for lung volume reduction, as failure to completely seal the targeted area can lead to collateral ventilation, thus preventing full tissue necrosis. In another example, an in-situ forming foam triggered by environmental conditions in the body such as moisture and heat means the formulation of the foam is not time-sensitive prior to deployment, nor does it require initiation (i.e., whipping with air or blending of multiple phases) by a user such as a physician; the formulation could be stored and delivered as-is. This avoids drawbacks of, for example, a system initiated in the operating room, which if not delivered in a timely manner could polymerize in the catheter before the procedure is complete. Another drawback of similar products of different chemistries or containing biological compounds is that they may require cold storage.
Additional advantages of the polymer foams described herein are described in more detail below.
In some embodiments, in-situ forming foam may be deployed as a liquid via a delivery device such as a catheter or bronchoscope into the desired area of the lung. In some embodiments, a catheter or bronchoscope may not need to positioned at an exact location, as foam expansion leads to travel into more distal airways to contact hard to reach areas. For example, if the catheter or bronchoscope can be positioned close to a targeted alveolar duct, the foam can expand both distally into the alveoli and proximally into the branches. The foam may also be used to seal off more proximal areas of the lung, such as the terminal bronchioles and respiratory bronchioles to prevent oxygenation of the distal alveoli. The expansive nature of the foam may help minimize collateral ventilation. As used herein, “catheter” may refer to a catheter, bronchoscope, or other means of deploying a foam mixture into the lungs. In some embodiments, the foam may be formed from a two-part (or multi-part) system in which at least first and second compositions may be stored stably in a two-part (or multi-part) cartridge prior to deployment from the cartridge through a catheter. The foam is formed upon the placement of the compositions into contact with each other. There may be a mixing element between the cartridge and point of deployment, for example, a catheter; the mixing element may enforce proportions (e.g., ensure homogenization) of the parts or may aerate the material prior to deployment. Alternatively, a one-part foam system may be stored stably in a single cartridge prior to deployment through a catheter from said cartridge, wherein the composition in the one-part system forms a foam upon coming into contact with a water-containing environment (i.e., an aqueous environment) or as a result of being triggered by some other initiator such as heat, pH, electrical current, magnetic field, or other initiator. The polymer foams may also be used to fill a body cavity created by the loss of body tissue. It should be noted that body cavities may be, in some cases, exposed to the external environment surrounding a body, such as, for example, in the case of an open wound or surgical incision. In some embodiments, polymer foams may be formed or located within an enclosed body cavity, for example, by placing a polymer in the body cavity and closing an incision such that the polymer or polymer foam are not exposed to the external environment. While the embodiments described herein may find particularly advantageous use for purposes of lung volume reduction, the use of the in-situ forming foams are not limited to lung volume reduction, and may be used, for example, to seal air leaks in the lung after resection, for necrosis of cancerous tissue, or for delivery of therapeutic agents to areas of the lung.
Examples of polymer foams and methods associated therewith are now provided. In particular, systems and methods for foaming a polymer to form a polymer foam are now described in connection with one set of embodiments.
In-situ foam is deployed as a liquid via catheter or bronchoscope into the desired area of the lung. As used herein, “liquid” is intended to describe a composition that is in a flowable state, such as a liquid, semi-solid, slurry, or viscous material. The material foams and polymerizes in-situ upon or after deployment to seal off alveoli and prevent oxygenation of the surrounding tissue. The catheter does not need to be at an exact location, as foam expansion leads to travel into more distal airways.
Source 14 may comprise any suitable source known to one of ordinary skilled in the art. In some embodiments, source 14 comprises any suitable container through which polymer material 12 may be passed. For example, in some embodiments, the source may comprise a syringe having one or more barrels through which the polymer material is flowed. In some embodiments, the source may comprise a container in which the polymer material is under pressure, and the polymer material is released from the container upon depressurizing the container (e.g., as in an aerosol can). In such embodiments, the polymer material can be applied as a spray, for example. The container may comprise several means for pressurizing known to those of ordinary skill in the art. For example, the container may be pressurized during the filling process in a manufacturing environment, or pressure may be generated immediately prior to use. In one embodiment, one or more pressure-generating chemical reactions may occur within the container, with the user initiating the reaction, waiting for pressure build-up and releasing the material. In another embodiment, pressure may be generated manually, via hand pump, crank, or rotary device. The container may also have an attachment that is introduced into the body that allows the material to flow into the cavity such as an introducer sheath or catheter. The openings on the introducer tip can be multidirectional in order to distribute the polymer in all directions within the cavity. That attachment or introducer may be rigid, soft, straight, flexible or conformable to a tortuous path. The introducer may have various tips for easy entry into the abdominal cavity through the tough abdominal wall and muscles. It may also have a flexible or retractable tip that will protect organs, intestines, bowels from perforations. It may be shaped to be non-coring and atraumatic. A surface finish or coating such as PTFE or silicone may be applied to part of or all of the introducer to make it lubricious and easy to introduce into the body. Additionally, a surface finish or coating can be applied to part or all of the introducer to make it remain in position once it is introduced. The surface finish or coating can be directional, allowing easy insertion but difficult removal.
In some embodiments, the polymers within the polymer material may cross-link within the body cavity. The term “cross-linking” is used to refer to the process whereby a pendant group on a first polymer chain may react with a second polymer chain (e.g., a pendant group on the second polymer) or other molecule or molecules to form a covalent or ionic bond joining the two polymers. Polymers that can undergo cross-linking can comprise straight chains, branched chains having one or more arms (i.e., multi-arm chains), or mixtures of these. In some cases, the polymer (branched and/or non-branched) may contain reactive side chains and/or reactive terminal groups (i.e., groups at the end of a polymer chain), and cross-linking may involve reactions between the side chains, between terminal groups, and/or between a side chain and a terminal group. For example, in
Cross-linking may commence via a variety of mechanisms. In some embodiments, polymer may cross-link once the polymer contacts moisture (e.g., water, blood, aqueous solutions, etc.), for example, within a body cavity. Cross-linking may be achieved via acrylate, methacrylate, vinyl, cinnamic acid, or acrylamide groups in some embodiments. Such groups may be cross-linked via the application of ultraviolet radiation and can be used in conjunction with an external foaming agent. In some instances, a cross-linking initiator may be introduced into the subject in which the body cavity is located (e.g., via the bloodstream, via a separate container in the delivery system such that the initiator and the polymer do not mix before delivery, etc.) to initiate cross-linking of the polymer. For example, a free radical initiator, such as eosin or 2,2-dimethoxy-2-phenylacetophenone, can be used to initiate cross-linking of polymers bearing acrylate, methacrylate, or vinyl groups. Other examples of reactive groups on polymer chains that can be paired to produce cross-linking include, but are not limited to, hydroxyls and isocyanates, amines and NHS-esters, thiols and maleimides, azides and alkynes (i.e., “click chemistry”), acid chlorides and alcohols, and in a preferred embodiment, isocyanates and polyols. It may be desirable, in some embodiments, to keep these paired chemicals separate until they are introduced into the body cavity to prevent unwanted cross-linking outside the body cavity. For example, the polymer may include azide functional groups, and alkynes can be introduced to the body cavity from a container separate from the container used to introduce the polymer. In some embodiments, these chemistries are also employed in conjunction with an external foaming agent. As the polymer material cross-links, its viscosity may be increased. In some cases, the cross-linking proceeds until a substantially solid material (e.g., a solid elastomeric foam) is formed.
Referring back to the example in
In some embodiments, the foaming step is not dependent upon the cross-linking step to form a foaming gas. For example, the foaming step may occur due to an introduction of gas separate from the polymer material. In some cases, gases comprising air, CO2, or other materials may be introduced into the body cavity via an external source (e.g., a syringe or any other suitable container). This gas may then permeate the polymer material (or a cross-linked product) to form bubbles within the material, which may form the voids in the foam as polymeric material cross-links around them. In cases where the gas is supplied via an external source, the source of the gas may be the same as or different from the source of the polymer material (e.g., 14 in
In some embodiments, the gas may be supplied as a product of a chemical reaction of part of the polymer or a cross-linked product. For example, in some embodiments, the foaming step comprises reacting one or more pendant groups on the polymer or cross-linked product to form a gaseous product. The gas-producing pendant groups may react upon contact with another material in the body cavity. For example, in some cases, the gas producing groups may react upon contact with moisture in the body cavity. In some cases, the gas-producing pendant groups may react with a chemical supplied to the body cavity separately from the polymer material (e.g., via the bloodstream, via an external source separate from the polymer material source, etc.). In some embodiments, the gas-producing pendant groups on the polymer chain may react with another component that is supplied to the body cavity. In some embodiments, the polymer or cross-linked product may comprise CO2-producing groups. Examples of CO2-producing groups include, but are not limited to, isocyanate groups, carbonates, bicarbonates, and carbamates. Such groups may produce CO2 gas when reacted with an acid, for example. In some cases, the CO2-producing group may include an N-hydroxysuccinimide carbonate, illustrated below:
CO2-producing groups may include, in some cases, imidazole carbamates, as illustrated below:
As noted above, in some embodiments, the foaming and cross-linking steps occur substantially simultaneously. In some cases, the foaming and cross-linking steps may occur substantially simultaneously, but remain independent of each other. For example, the polymer material may cross-link by reacting with water in the body cavity, and, at substantially the same time, gas may be introduced to the polymer material from an external container. In another embodiment, a first material containing gas generating groups may produce gas by contact with a second agent (e.g., water in the body, water supplied separately, or chemical additive), while contact or interaction with a third material leads to cross-linking. For example, at the time of delivery, polymer A with isocyanate groups can be mixed with water and polymer B, in which the former causes the generation carbon dioxide to foam the material and polymer B can contain hydroxyl groups that react with isocyanates on polymer A to form a cross-linked network between polymers A and B.
The foaming and cross-linking steps may be, in some cases, part of the same reaction process. For example, one or more reactions may produce a gaseous by-product which serves as the supply of gas to form the polymer foam, but concurrently leads to the generation of new functional groups that enable cross-linking. The gaseous by-product can be trapped within the polymer and coalesce to form bubbles. As the reaction progresses, the formation, growth and expansion of the gas bubbles can expand the polymer volume and force it into interstitial areas of the body cavity. As the polymer cross-links, a three-dimensional foam can be formed within the body cavity. The volume expansion and cross-linking can serve to coat and seal surfaces of the body cavity, which may be useful, for example, in ensuring necrosis of tissue, by for example causing hypoxia due to a lack of contact with air. In addition, such a reaction scheme can be combined with an external supply of gas (e.g., CO2 in an external container) to increase the amount of gas contained in the polymer or a cross-linked product of the polymer.
All of the foaming mechanisms described herein may occur before any substantial cross-linking has occurred or during cross-linking of the polymer material or a cross-linked product of the polymer material. For example, in some cases, an external gas may be introduced into and dispersed within a polymer material that has not substantially cross-linked. The polymer material may then cross-link around the bubbles to form the foam. In such cases, the viscosity of the polymer material can be chosen such that the material is able to retain bubbles within the volume without the need for cross-linking In some embodiments, at least some cross-linking may occur before the gas is introduced to the polymer material, and the gas is dispersed within a partially cross-linked polymer material that has not completely solidified to form a foam.
Cross-linking and/or foaming may be achieved, in some instances, using isocyanate chemistry. Isocyanate groups are relatively unstable when exposed to water and moisture. Exposure of isocyanate groups to water or moisture (or other compounds) can lead to the decomposition of the groups, cross-linking of polymers to which they are attached, and release of carbon dioxide, as shown below for a model lysine isocyanate:
In the mechanism above, the isocyanate is partially hydrolyzed to produce amines, which can react with native, non-hydrolyzed isocyanates, as shown above. Not wishing to be bound by any theory, a cross-linked structure can be produced because the rate of the amine-isocyanate reaction may be on the order of or faster than the rate of isocyanate hydrolysis, and inter-chain reactions occur between these functional groups to ultimately form a cross-linked structure. The isocyanates on the polymer can also react with amine groups of the tissue (e.g. lysines in proteins), which can form a covalent bond with the tissue to further strengthen the seal at sites in which fluid is being lost (e.g., at bleeding sites). In addition, the isocyanate hydrolysis reaction produces CO2, enabling simultaneous cross-linking and gas production in a single-reaction scheme.
In certain embodiments, polyurethane foams may be generated by cross-linking polyols with multifunctional isocyanates. Polyols suitable for use in such embodiments include polyether- and polybutadiene-based polyols. Polyols of particular interest include polypropylene glycol (PPG) and polyethylene glycol (PEG), as well as random and block copolymers thereof. Also suitable for use are polycarbonates, polybutadienes, and polyesters. Diols, triols, and tetrols are most preferred, but multifunctional polyols with any suitable number of arms may be used. Molecular weights between 100 and 10,000 Da are preferable, with molecular weights up to 6,000 Da being most preferred, and blends of polymers with different molecular weights, degrees of branching, and composition are often used. Commercial polymers of particular interest include polypropylene glycols (425, 1200 Da), polyethylene glycols (200, 400, 600, 1000, 2000, 3000 Da), Pluracol products (355, 1135i, 726, 816), Arch Poly-G 30-240, Poly-G 76-120, Poly-G 85-29, trimethylolpropane ethoxylate (450, 1014 Da), pentaerythritol ethoxylate (797 Da), UCON 75-H-1400, UCON 75-H-9500, Poly(ethylene glycol)-block-polypropylene glycol)-block-poly(ethylene glycol) copolymers, dipropylene glycol, diethylene glycol, tripropylene glycol, triethylene glycol, tetrapropylene glycol, tetraethylene glycol, trimethylolpropane ethoxylate (170, 450, 730, 1014 Da), hydroxyl terminated polydimethylsiloxanes, and carbinol (hydroxyl) terminated polydimethylsiloxanes. In certain embodiments where the foam is formed from a two part system, it is preferred that polyols used in the present invention comprise an amine catalyst in an amount up to 10 pphp, a water content of up to 20 pphp, a surfactant in an amount up to 10 pphp, and a diluent up to 300 pphp (preferably up to 250 pphp and most preferably up to 15 pphp). Examples of polyurethane foams generated by cross-linking polyols with multifunctional isocyanates, in accordance with the present invention, are listed in Table 1.
In certain embodiments where the foam is formed from a one-part system, it is preferred that polyols used in the present invention comprise an amine or metal catalyst in an amount up to 10 pphp, a surfactant in an amount up to 10 pphp, and a diluent up to 300 pphp (preferably up to 100 pphp and most preferably up to 10 pphp).
Isocyanates suitable for use in such embodiments include any isocyanate with a degree of functionality greater than 2.0. Isocyanate true-prepolymers and quasi-prepolymers may also be used. In this case, a “quasi-” prepolymer, or semi-prepolymer, is a polymer formed by the reaction between a multifunctional isocyanate and polyol, where the isocyanate-to-alcohol ratio is greater than the stoichiometric two-to-one ratio. A “true-” prepolymer, or strict-prepolymer, is a polymer formed by the reaction between a multifunctional isocyanate and polyol, where the isocyanate-to-alcohol ratio is equal to the stoichiometric two-to-one ratio.
In some instances, it may be advantageous to position isocyanate groups in the polymer so that it is accessible for hydrolysis and cross-linking, without inhibiting binding to the tissue. In one set of embodiments, a lysine group in the targeting peptide can be converted to an isocyanate by reaction with diphosgene. In some instances, the isocyanate and peptide chemistries can be completely decoupled by modifying a fraction of the side chains with peptide while the balance are modified with isocyanate.
The polymer that is foamed to form the polymer foams described herein may be formed using a variety of chemistries. In some embodiments, the polymer comprises a synthetic polymer. As used herein, a “synthetic polymer” refers to a polymer that is a product of a reaction directed by human interaction. For example, synthetic polymers can include polymers synthesized by reactions of natural or synthetic monomers or combinations thereof that are directed by human interaction. The formation of synthetic polymers can also include chain elongation of natural or synthetic polymers. In some embodiments, the synthetic polymer is not found in nature. In other cases, the synthetic polymer can be found in nature, but the polymer is synthesized via human interaction (e.g., in a laboratory setting). In some embodiments, the polymer may comprise a poly alpha-hydroxy acid. In some cases, the polymer may comprise a polyester. In some cases, the polymer may comprise a polyether-polyester block copolymer. In some cases, the polymer may comprise a poly(trimethlyene carbonate). In some embodiments, the backbone of the polymer can exclude at least one of polynucleotides, proteins, and polysaccharides.
In some embodiments, the polymer foam is formed by cross-linking a condensation polymer of a polyol and a polyacid. The terms “polyol” and “polyacid” are given their standard meanings in the art, and are used to refer to compounds comprising at least two alcohol groups and at least two acidic groups, respectively. Examples of polyols suitable for use in forming the condensation polymer used to form the polymer foams described herein include, but are not limited to, glycerol, polyethylene glycol, polypropylene glycol, polycaprolactone, vitamin B6, erythritol, threitol, ribitol, arabinitol, xylitol, allitol, altritol, galactritol, sorbitol, mannitol, iditol, lactitol, isomalt, and maltitol, wherein the functional groups present on the polyol are optionally substituted. Examples of polyacids suitable for use in forming the condensation polymer used to form the polymer foams described herein include, but are not limited to, succinic acid, fumaric acid, a-ketoglutaric acid, oxaloacetic acid, malic acid, oxalosuccinic acid, isocitric acid, cis-aconitic acid, citric acid, 2-hydroxy-malonic acid, tartaric acid, ribaric acid, arabanaric acid, xylaric acid, allaric acid, altraric acid, galacteric acid, glucaric acid, mannaric acid, dimercaptosuccinic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, malic acid, or vitamin B5, wherein the functional groups present on the polyacid are optionally substituted.
In some embodiments, the condensation polymer may comprise poly(glycerol-sebacate) (PGS). An exemplary synthesis pathway in which glycerol and sebacic acid are used to form PGS is shown below:
In some embodiments, the polymer foam is formed by cross-linking a polymer comprising the following formula (I):
wherein R1 and Z can be the same or different and each is an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, heterocycle, acyl or carbonyl group, any of which may be optionally substituted, and wherein n is an integer greater than 1. In some embodiments, R1 and/or Z are substituted with a gas producing group. For example, R1 and/or Z may be substituted with a CO2-producing group (e.g., isocyanate).
In some embodiments, the method can comprise cross-linking a polymer comprising the formula (II):
wherein R1 and R2 can be the same or different and each is an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, heterocycle, acyl or carbonyl group, any of which may be optionally substituted; wherein x and y are non-negative integers; wherein R3 may be a hydrogen, gas generating functional group, or tissue binding domain.
In some embodiments, the polymer may comprise the poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and polycaprolactone (PCL) class of polymers and their copolymers, such as poly (lactate-co-caprolactone) or poly (glycolate-caprolactone). Copolymerization of the lactide, glycolide and caprolactone monomers in various ratios can yield materials with a wide range of mechanical properties, thermal characteristics and degradation times. The structure of the PLA/PGA/PCL copolymers (and associated properties such as molecular weight, etc.) can be tailored, in some cases, by adjusting the type of initiator used and its molar ratio with the monomer(s).
In some embodiments, the polymer comprises poly(glycolate caprolactone). In some cases, the PGCL composition includes a ratio of glycolide to caprolactone of about 50:50. An exemplary synthesis pathway for PGCL is shown below, in which pentaerythritol is used as an initiator to form 4-armed, branched structures.
The properties of the polymer used to form the polymer foam may be tailored to achieve a desired result.
For example, in one embodiment, a two part system may use polyurethane chemistry. Kinetics may be controlled with catalyst or the reactivity of the polymer end groups. Viscosity may be controlled with the molecular weight of the polymer backbone or the addition of diluents. Hydrophilicity/hydrophobicity may be controlled by the composition of the polymer backbone. Foam properties may be further controlled by the nature of the isocyanate (NCO) and the isocyanate index.
In another embodiment, a one-part system may be comprised of polyurethane prepolymer with NCO functionality that reacts with heat or moisture. These initiators can be provided by either the body or the delivery system.
In some embodiments, the hydrophilicity/hydrophobicity of the foam may be controlled by the soft segment of the prepolymer. In some embodiments the structural integrity of the foam may be controlled by the hard segment of the prepolymer, the molecular weight of the soft segment, and functionality. In some embodiments the soft segment could be a biodegradable polymer (e.g., polycapralactone, polyglycolide, polylactic acid, or polyanhydrides). In some embodiments a prepolymer formulation may have low enough viscosity to allow the material to move though a surgical catheter (e.g., 5 French) and be deployed by hand.
In some embodiments, the foam is formulated with surface properties engineered to adhere to the tissue of the airway walls. In one example this is achieved by controlling the hydrophobicity of the foam; more hydrophobic materials promote protein adhesion. In another example, this is achieved by functionalizing the surface with mucoadhesives such as poly vinyl pyrrolidone (PVP), methyl cellulose (MC), carboxymethylcellulose (CMC) or other cellulose derivatives. NCO itself at the prepolymer ends can covalently bond to tissue surface.
In some embodiments, the foam is formulated with surface properties that promote cell growth and resorption. For example, a highly porous micro structure provides a three dimensional topography that promotes cell growth. For example, highly porous microstructures where pore volume fraction is greater than 50% or more preferably greater than 80%; pore size is between 10 microns and 500 microns. The porosity can be controlled with the surfactant, blowing catalyst, and NCO index.
In some embodiments, a foam is formulated which collapses over the course of days, and fully resorbs into the body with the necrosed lung tissue over the course of months. This may be achieved, for example, by using a copolymer backbone containing segments that break down quickly and segments with more slowly degrading bonds. For example, anhydride segments degrade quickly as they are very susceptible to hydrolysis, and ester segments are less susceptible and would degrade over a longer period of time.
In some embodiments, a foam may be formulated with enough compliance and elasticity to allow it to move with the lungs. Such a formulation may provide for enhanced patient comfort. As an example, a foam could be described as having a compression force deflection (CFD) between one and 30 kPa at 50% deflection. The CFD can be controlled by the NCO index, polyol functionality and the polyol molecular weight. CFD may be controlled; for example, lowering NCO/polyol functionality and raising the polyol molecular weight will increase the molecular weight between cross-links and result in a foam with a lower CFD.
In some embodiments, a foam is formulated which releases a high exotherm upon reaction to ablate lung tissue and induce distal atelectasis. The oxygen deprived lung tissue would resorb along with the degradable foam over the course of months.
In some embodiments, the foam may incorporate ligands or other molecules to promote tissue adhesion (e.g., fibronectin, cyanoacrylate), tissue ablation (e.g., alcohol, acids, bases), or to promote tissue resorption (e.g., proinflammatories, growth factors). In an additional embodiment, the selected materials for the foam itself can be proinflammatory to promote tissue necrosis and resorption.
In some embodiments, the viscosity of the polymer is tailored such that the polymer is able to permeate the body cavity and create conformal contact. An overly viscous polymer may require excessive pressure to deploy within the body cavity. In addition, an overly viscous polymer may inhibit the polymer from accessing interstitial spaces. An overly low-viscosity polymer might be difficult to contain the material to the target site or may be displaced by the flow of a bodily fluid. One of ordinary skill in the art will be able to produce the desired viscosity for a given polymer type by, for example, adjusting the molecular weight of the polymer. In some embodiments, the viscosity and the molecular weight are related through a power law. The molecular weight of a polymer may be adjusted by, for example, controlling the time of the polymerization reaction used to generate the polymer. In some embodiments, the molecular weight of the polymer is between about 1000 and about 10,000 g/mol or between about 1200 and 6000 g/mol. The viscosity of a polymer may be adjusted by, for example, adding diluents such as any suitable low molecular weight, low viscosity compound, examples of which include triacetin, propylene carbonate, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, dimethyl esters of diacids (e.g., diethyl malonate, dimethyl adipate), dimethyl sulfoxide, and oils (vegetable, olive, castor, etc.). In embodiments that include polyols, it is preferable to add up to about 300 pphp of diluent to control polymer viscosity.
In some embodiments, the polymer is amorphous or semi-crystalline with a glass transition temperature (Tg) below room temperature. Such properties yield, in some cases, polymers with sufficiently low viscosities that they can be dispensed from an external container via pressure-driven flow.
In some embodiments, properties or composition of the polymer may be chosen to achieve a desired hydrophilicity or hydrophobicity. The hydrophilicity of the polymer may be selected, in some instances, such that the surfaces (e.g., tissue surfaces) within a body cavity are appropriately wetted. Generally, a material with increased hydrophilicity will have a greater tendency to wet soft tissues surfaces. However, the polymer and resulting polymer foam may be, in some cases, somewhat hydrophobic such that they do not dissolve into biological fluids. Appropriately hydrophilic polymers are capable of conformally wetting interior surfaces of a body cavity while remaining contained within the cavity. In some embodiments, the composition of the polymer may be selected to achieve a desired hydrophilicity. For example, in some embodiments, the chain length of a monomer used to synthesize the polymer can be varied to change hydrophilicity. As a specific example, the carbon chain length between carbonyl groups of a diacid monomer can be varied from between two and eight aliphatic carbons, producing a range of hydrophilicity in the resulting polymer.
In some embodiments, the polymer foams described herein may have favorable mechanical properties. In some embodiments, the polymer foams are elastomeric. The term “elastomer” as used herein, refers to a polymer that can return to the approximate shape from which it has been substantially distorted by an applied stress. In some cases, the elastomeric polymer foams described herein may comprise a polymer having a bulk modulus of between about 0.05 MPa and about 10 MPa; 0.05 MPa and about 100 MPa; and 0.05 MPa and about 500 MPa. Elastomeric polymers may be particularly suitable for use in making polymer foams because they are capable sustaining stress without permanently deforming, while providing adequate support for body organs and tissues.
The time required to form the polymer foam after exposure to the body cavity and the final mechanical and physicochemical properties of the polymer foam can depend on such factors as the composition of the polymer, the density of pendant groups (e.g., cross-linking groups), and relative positions of the pendant groups (e.g., cross-linking groups). One of ordinary skill in the art will be capable of adjusting the concentration and location of pendant groups to produce polymer foams with desirable physical properties.
In some embodiments, the polymer or polymer foam may be biodegradable. As used herein, “biodegradable” is used synonymously with “bioabsorbable” and “bioerodible” to describe materials that are capable of degrading down to oligomeric or monomeric species under physiological or endosomal conditions. The phrase “physiological conditions,” as used herein, relates to the range of chemical (e.g., pH, ionic strength) and biochemical (e.g., enzyme concentrations) conditions likely to be encountered in the intracellular and extracellular fluids of tissues. In some embodiments, the physiological pH ranges from about 7.0 to 7.4. In some embodiments, biodegradable materials are not hydrolytically degradable but can be fully degraded via enzymatic action to fully degrade. In some cases, biodegradable materials are hydrolytically or enzymatically degradable, or combinations thereof. In some embodiments, the polymer or polymer foam is biodegradable, but it does not biodegrade over the time scale in which it is located within a body cavity. In such cases, the polymer foam can remain structurally stable while being inserted into the body cavity, while ensuring that any remnants of the polymer foam that remain within the body cavity after removal can be biodegraded. For example, in some embodiments, the biodegradable polymer foam does not significantly biodegrade within the body cavity prior to removing the foam via surgical intervention.
The polymer or polymer foam may be biocompatible, in some instances. One of ordinary skill in the art can determine biocompatibility based upon the ISO-10993 standard. For example, PGS is known to satisfy the ISO-10993 standard for biocompatibility. In some embodiments, chemical modifications (e.g., attachment of a pendant group, etc.) to the PGS backbone do not alter its biocompatibility. In some embodiments, a polymer that produces known, but acceptable levels of inflammation may be used. Examples of such polymers include poly-alpha-hydroxyacids (e.g., polylactide, polyglycolide, and polycaprolactone) and poly(trimethylene carbonate).
The polymeric foams described herein may be used, in some embodiments, to prevent or limit the oxygenation of tissue in a cavity, relative to an amount of oxygenation that would occur under essentially identical conditions in the absence of the polymer foam. “Essentially identical conditions,” in this context, means conditions that are similar or identical other than the presence of the polymer foam. For example, otherwise identical conditions may mean that the body cavity is identical, the conditions within the cavity are identical, but where no polymer foam is located within the body cavity.
The oxygenation of tissue may be prevented or limited over a relatively long period of time. For example, in some embodiments, the polymer foam can prevent or limit movement of a bodily fluid within the body cavity for at least about 24 hours, at least about 3 days, at least about 1 week, at least about 3 months, or at least about 6 months.
In some cases, the polymer may be designed to cross-link quickly, for example, by tailoring the polymer to have functional groups that cross-link quickly, by adding catalysts, or by other known means. Suitable catalysts for use in embodiments of the present invention include amine based compounds, preferably tertiary amines, triethylenediamine (TEDA, DABCO, DABCO 33-LV), bis(2-dimethylaminoethyl)ether (Niax A1), trimethylaminoethyl-ethanolamine, 1,2-dimethylimidazole, 1,8-Diazabicycloundec-7-ene, and metallic catalyst, preferably tin octoate, bismuth neodecanoate.
In addition to gas-forming pendant groups, other active agents may also be included as pendant groups on the polymer. For example, the polymer foam can include groups used to stimulate desirable cellular responses such as fibroplasia, angiogenesis and epithelialization. In some embodiments, the polymer or polymer foam may be covalently bonded to a surface within the body cavity, for example, through a pendant group.
In some embodiments, the polymer or cross-linked product may comprise at least one pendant group (e.g., at least one pendant group) that can bind to tissue or injured or target tissue (e.g., diseased tissue, inflamed tissue, bleeding tissue, a wound site, etc.) within the body cavity. The binding of the pendant groups to the tissue can be covalent or non-covalent. The tissue may comprise one or more molecules that would not be present in or near uninjured or non-targeted tissue as is the case, for example, when sub-endothelial or sub-epithelial surfaces are exposed. By including such pendant groups, a polymer or cross-linked product could be made that selectively binds to tissue or injured or diseased tissue, in comparison to uninjured or undiseased tissue. Such binding may limit or prevent the movement of bodily fluid within the body cavity, in some embodiments. Examples of chemicals that may be targeted by pendant groups on the polymer or polymer foam include, for example, von Willebrand Factor, collagen (e.g., collagen I and IV), a fibroblast growth factor, laminin, elastin, localized coagulation factors in their activated form (e.g., fibrin, thrombin, factor X, etc.), among others. Example of types of pendant groups that may be bound to the polymer or polymer foam for such uses include, for example, peptides, carbohydrates (e.g., oligosaccharide sequences) and aptamers.
One of ordinary skill in the art will be able to identify other compounds in tissue and perform screening tests to determine suitable pendant groups that could be used to bind with those compounds. For example, in vivo screening, for example by phage display technology, of a large library of possible pendant groups (e.g., permutations of peptide sequences fused to a phage surface protein, a collection of carbohydrate molecules, etc.) could be performed (e.g., in rodents) to identify pendant groups that bind specifically to diseased luminal surfaces of lung airways. The pendant group could then be identified (e.g., via sequencing for peptides) from each normal and diseased tissue. Subsequent testing (e.g., in vivo testing in uninjured animals) could be performed to verify that the pendant group does not bind to tissue in the absence of injury or disease.
In some cases, human protein targets can be used to find pendant groups that bind selectively to the targeted site. For example, human fibrin, which is generally present where injuries to blood vessels have occurred, can be used for screening, potentially mitigating the risk present in the in vivo approach where there could be sequence and conformational differences between animal and human targets. Binding levels to fibrin can be assessed using, for example, fluorescently tagged molecules, and compared against, for example, fibrinogen, a precursor of fibrin that is ubiquitous in blood plasma. The pendant groups showing highest selectivity to fibrin over fibrinogen could be selected for use in the polymer composition.
In addition to targeting tissues, pendant groups may be used to stabilize tissue. For example, pendant groups (e.g., CO2-forming groups) may covalently bond to tissue, in some cases, which may lead to the sealing of one or more openings within a body cavity. Such binding can aid in limiting or preventing the movement of bodily fluid or gasses within the body cavity, in some cases. In some embodiments, the concentration of isocyanate in the polymer or a cross-linked product can affect the extent to which binding between the polymer and tissue occurs. Specifically, increasing the isocyanate levels can serve to increase and reinforce the polymer-tissue contact area, potentially producing a stronger and longer-lasting seal. Increasing the level of isocyanate in the polymer can also increases the cross-link density, potentially resulting in a more rigid material that may break more easily at the polymer-tissue interface (e.g., when the body is moved). Therefore, the concentration of isocyanate may be selected, in some cases, to balance between these two effects.
In some cases, non-isocyanate pendant groups may be used to stabilize the polymer-tissue interface. For example, the polymer may comprise aldehyde reactive groups, which can be used, for example to bind tissue proteins. Aldehyde groups may be attached by, for example, attaching ethanolamine to the polymer, followed by oxidizing the pendant hydroxyl group to form an aldehyde group.
In some embodiments, the polymer (or the compounds used to make the polymer) is chosen such that they comprise one or more pendant hydroxyl groups. The hydroxyl groups may serve, for example, as sites at which pendant groups are attached to the polymer. For example, glycerol and sebacic acid both contain hydroxyl groups that may be used to impart functionality to PGS. As a specific example, pendant peptides can be introduced onto polymers using a two-step reaction scheme in which the polymer hydroxyl groups are first activated with carbonyldiimidazole (CDI) and then coupled to the amine-terminus of the peptide, as shown below. This chemistry can result in high coupling efficiencies.
In some instances, a drug may be delivered to the body cavity with the polymer. In some embodiments, the polymer may comprise a drug. For example, a drug (or a plurality of particles containing one or more drugs) may be dispersed within the polymer. Example of such drugs include, but are not limited to, antifibrinolytic compounds (e.g., aminocaproic acid, tranexamic acid, etc.), anti-fibrotic compounds, antimicrobial compounds (e.g., antibiotics), anti-inflammatory compounds, proinflammatory compounds, analgesics, pro-coagulant compounds, growth factors, ablative agents (e.g., chemotherapeutics, ethanol) and vasoconstrictors. Drugs that comprise amine groups may, in some cases, be isolated from isocyanates within the polymer, for example, to prevent unwanted reaction during the cross-linking step. Isolation can be achieved by encapsulating drugs into secondary particles and loading them into the polymer at the time of delivery to the body cavity. In addition, encapsulation may be used to release the drugs at a controlled rate. In some embodiments, a drug may be incorporated into a fiber, which may be included in the polymer. The drug release rate from the fiber can be controlled by varying composition and structure (e.g., thickness or other dimension, presence of sheath) of fiber. For example, the fiber can be designed to deliver an initial burst release shortly after the deployment of the polymer, followed by sustained delivery (e.g., over the time period in which the polymer foam will be left in the body cavity).
The polymer may be combined with a second agent (and, optionally, a third agent, fourth agent, etc.), in some cases, before or after the polymer is transported to the body cavity. The second agent may comprise, for example, a compound that accelerates at least one of cross-linking and foaming, relative to a rate of at least one of cross-linking and foaming that would have occurred in the absence of the second agent. For example, in some embodiments, the second agent may comprise an amine (e.g., a polyamine). The amine compound may serve to increase the rate at which the polymer cross-links. The second agent may comprise, in some cases, at least one of lysine, spermine, spermidine, hexamethylenediamine, polylysine, polyallylamine, polyethylenimine, and chitosan. In some cases, the second reagent may comprise a carbonate or a bicarbonate which may be used, for example, to produce CO2 gas in-situ, as described above. In some embodiments, the second reagent can comprise an acid which may be used, for example, as a reactant in the CO2-producing reaction. The acid functionality may comprise, for example, a carboxylic acid pendant group attached to a polymer chain or blended with a polymer to form a mixture. In some cases, the second reagent can be native in the body (e.g., bicarbonate in the blood). In other cases, the second agent may originate from outside the body cavity. For example, the second agent may be, for example, supplied to the body cavity along with the polymer.
In some embodiments, the combination of the second agent with the polymer produces a polymer foam with significantly different mechanical properties (e.g., elastic modulus, yield strength, breaking strength, etc.) than would have been produced in the absence of the second agent. For example, addition of the second agent may lead to increased cross-linking among polymer molecules, potentially producing a stiffer foam.
The second agent may be stored in a container separate from the polymer, for example, to prevent unwanted reaction between the polymer and the second agent outside the body cavity. In some embodiments, a container can be used that keeps the polymer and the second agent separated while stored or transported, but allow for mixing at the outlet nozzle or within the body cavity when the contents are expelled. The outlet nozzle can mix multiple components (>2) including gases in a static or dynamic manner. Examples of static mixers are Low Pressure Drop (LPD) mixers, Bayonet mixers and Interfacial Surface Generator (ISG) mixers. Examples of dynamic mixers are impellers, and rotary static mixers. Nozzles will handle low and high pressure differentials during dispensing. The container may also be designed to mix the components immediately prior to dispensing by breaking the barrier between each of the components and allowing them to mix. Mixing can occur manually such as shaking the canister or chambers can be under vacuum and when the barrier is broken a vortex will be created to mix the components.
In another embodiment, additives can be added to the polymer that absorb the heat generated during the cross-linking reaction. For example, materials in the form of micro or nanoparticles, spheres or fibers can absorb the heat by undergoing a phase change (e.g., melting) or glass transition and thereby reduce the heat absorbed by biological tissues. For example, biodegradable fibers made of polycaprolactone can melt at ˜60° C., absorbing the generated heat. This may control or reduce tissue damage because the maximum temperature is limited and maintained by the incorporated material changing phase.
In some embodiments, the body cavity can be imaged. The ability to image the body cavity can allow for efficient localization and repair of an injury, stabilization of a wound, identification of diseased tissue, etc. In some embodiments, pendant groups on the polymer or polymer foam can be utilized to aid in imaging the body cavity. For example, a contrast agent can be introduced into the blood stream of a subject in which the body cavity is located, and the contrast agent may be capable of selectively binding to pendant groups of the polymer. Examples of contrast agents include, for example, colored, fluorescent, or radio-opaque imaging entities. In some embodiments, the contrast agent is added into the formulation, such as, for example, tantalum particles suspended in the formulation. In some embodiments, the contrast agents emit electromagnetic radiation in the near-infrared range (e.g., about 700 to about 1000 nm) upon interacting with the polymer foam. As a specific example, quantum dots (QD) may be used as contrast agents. In some cases, fluorescent organic tags (e.g., fluorescein isocyanate) or radio-opaque chelating groups (e.g., Gd3+) can be used with appropriate imaging equipment. In another example, the contrast agents listed above may be attached as pendant groups to the polymer or dispersed in the polymer to aid in visualization.
A variety of mechanisms can be employed to remove polymer or polymer foam from the body cavity or from placement on tissue. In some embodiments, at least part of the polymer foam is removed via surgical intervention. For example, the polymer foam may be cut out of the body cavity, in some instances. In some cases, surgical intervention may be sufficient to remove the bulk of the polymer foam material (e.g., at least about 80%, at least about 90%, etc.) from the body cavity. The polymer or the pendant groups bonded to the polymer may be selected, in some cases, such that the resulting polymer foam can be removed from a body cavity. In some embodiments that employ a biodegradable polymer or polymer foam, the foam or the remainder of the foam after surgical removal may biodegrade over time.
In some embodiments, the foam may be degraded by applying an external stimulus to the foam. Such methods may be useful, for example, when some polymer or polymer foam material remains physically inaccessible after surgical removal due to, for example, deep tissue penetration. Examples of external stimuli that may be applied to degrade the polymer foam include, but are not limited to, UV radiation, heat, or a chemical (e.g., a second material is delivered to the site to dissolve the foam after tissue necrosis had been achieved and the implant is no longer needed).
Degradation of the polymer foam may be achieved, in some cases, via reversible cross-links in the polymer or polymer foam. In some cases, the type of cross-link or external stimulus type can be selected such that the polymer foam is selectively and controllably depolymerized. Upon reversion to the uncross-linked state, the polymer or polymer foam can, in some cases, be removed from the cavity using, for example, saline.
Reversible cross-linking can be accomplished by, for example, modifying a pendant group of the polymer to include bis(2-isocyanatoethyl) disulfide. Such chemistry may be particularly useful, for example, when isocyanate chemistry, which may not be reversible using the external stimulus of choice, is used to foam the polymer. The disulfide group can be readily cleaved with, for example, glutathione. In this example, the sulfur-sulfur bond can be broken through a disulfide exchange reaction, enabling selective cleaving at the disulfide bonds by application of, for example, a glutathione solution. As another example, cinnamic acid groups can be attached to the polymer such that reversing the cross-links can be accomplished by application of UV light.
In another embodiment drug-loaded objects are incorporated in the foam at or before administration. Incorporation of drug-loaded objects into a polymer during administration is accomplished by those methods known to those skilled in the medical and pharmaceutical formulation arts. Examples of drug-loaded objects include: microspheres, microfibers, core-sheath microfibers, core-sheath nanofibers, nanoparticles, nanospheres, nanofibers or pure particles of drug. Preferably drug is released from these objects over a period of 7 days. More preferably the drug is released up to 14 days. Drug may be released for up to 30 days or longer. Preferably the kinetic release profile for the drug provides approximately the same dose of drug throughout a given period of time.
In certain embodiments, the invention relates to liquid formulations that are delivered to a body cavity and form foam implants in-situ. The liquid formulation or formulations optionally include an entrained gas or a dissolved gas. In preferred embodiments, the resulting foam implant prevents oxygenation of targeted tissue, ultimately causes tissue necrosis and resorption. Foam implants of the invention are preferably biocompatible and bioabsorbable.
In certain embodiments, the invention is a polyurethane foam that is formed in-situ from a two-part formulation as previously described. The first part of the formulation includes an isocyanate compound such as hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI) or a mixture of MDI isomers, polymeric MDI, isocyanate-functionalized prepolymer, or a polymeric isocyanate having a functionality of preferably between 2.0 and 3.0. The second part of the formulation includes a hydroxyl-functionalized polymer (polyol). The preferred viscosity of the first and second parts of the formulation is 1 to 3,000 cP, and preferably about 2,400 to about 2,600 cP. The polyol phase optionally has multiple polyol species, catalysts, surfactants, chain extenders, cross-linkers, pore openers, fillers, plasticizers and water. Air, carbon dioxide or other auxiliary blowing agents are optionally entrained into either the isocyanate or polyol phases prior to delivery to the patient or, alternatively, are introduced during delivery as a component of the formulation.
In certain embodiments, the invention is a polyurethane foam that is formed in-situ in the presence of a initiator (e.g., moisture) from a one-part formulation as previously described. The initiator may be provided by the body or delivery system. The preferred formulation includes an NCO functionalized prepolymer, and optionally includes catalysts, surfactants, cross-linkers, and diluents. The preferred viscosity is 1 to 3,000 cP, and more preferably about 1 to 1,000 cP. Air, carbon dioxide or other auxiliary blowing agents are optionally entrained into either the isocyanate or polyol phases prior to delivery to the patient or, alternatively, are introduced during delivery as a component of the formulation.
The invention will be better understood in the context of certain advantageous characteristics exhibited by foams and formulations of the invention: (i) storing stably and forming in-situ at target sites; (ii) lack of interference with bodily functions; (iii) travel into more distal airways to contact hard to reach areas; (iv) facilitation of tissue necrosis; and (v) degradation and resorption.
Storing Stably and Forming In-Situ at Target Sites:
In certain embodiments, foams of the invention reach target sites through tortuous/narrow anatomies and located within hard to reach cavities. In these embodiments, the formulation can be deposited at a site within a body cavity, which site is optionally either proximal to or remote from a target site that will be treated; the foam will then travel beyond the site of deposition as foaming and expansion is initiated, for example by moving and expanding along a path of least resistance.
As noted above, a two part foam system may use polyurethane chemistry. Kinetics may be controlled with catalyst or the reactivity of the polymer end groups, viscosity may be controlled with the molecular weight of the polymer backbone or the addition of diluents, and hydrophilicity/hydrophobicity may be controlled by the composition of the polymer backbone. Foam properties may be further controlled by the nature of the isocyanate (NCO) and the isocyanate index. A one-part system may be comprised of polyurethane prepolymer with NCO functionality that reacts with heat or moisture, where initiators can be provided by either the body or the delivery system. The hydrophilicity/hydrophobicity of the foam may be controlled by the soft segment of the prepolymer; the structural integrity of the foam may be controlled by the hard segment of the prepolymer, the molecular weight of the soft segment, and functionality. The soft segment could be a biodegradable polymer (e.g., polycapralactone, polyglycolide, polylactic acid, or polyanhydrides) with a prepolymer formulation having relatively low viscosity.
The formulation and the foam can be miscible with water, and/or hygroscopic. In certain embodiments, miscibility and hygroscopy are improved by tailoring the pore architecture of the foam to induce capillary action, for example by creating an open-pore architecture within the foam, as is discussed more fully below. In certain preferred embodiments, the mobility of the formulation is facilitated by at least one of the following characteristics: expansion of 1-25× (more preferably 1-5×), or low viscosity (less than 3,000 cP (more preferably less than 1,000 cP).
With respect to density and expansion, foams have been developed having densities between 10 and 1,000 kg/m3, or having expansions of between 1 and 95 fold, as shown in
With respect to hygroscopy and miscibility with water, the water absorption characteristics of foams can be tailored as well. Foams have been developed having both high and low water absorption, as tested by a 4-minute water immersion test. Results of this test for certain formulations of the invention are depicted in
In general, the hydrophilicity of the foam may be improved by increasing the amount of polyethylene glycol (PEG)-based polyols used in the formulation relative to hydrophobic polyols such as those based on polypropylene glycol. Water uptake of foams may also be increased as the PEG-based polyol content is increased, though some rebalancing of catalyst, surfactant, isocyanate and other components may be necessary. Small changes to minor ingredients can significantly improve water uptake. For example, by increasing the surfactant level of formulation 122-009-7 by 2.5-fold, water uptake is increased from 6.7 g/g to 21.7 g/g (compare foam 122-009-10).
Transport to target sites may also be improved by providing formulations that can disperse within a body cavity before foaming and/or cross-linking. Delayed foaming and/or cross-linking permits low-viscosity formulations of the invention to penetrate more deeply into tortuous spaces within body cavities. Once the formulation is dispersed, foaming may occur at a moderate rate (on the order of less than 4 minutes) to fully distribute the foam to reach a target site or sites. Formulations have been generated that have a variety of reaction kinetics, as measured by cream time, gel time, and rise time and as shown in
Foaming kinetics can be altered by adjusting the types and levels of catalysts and inhibitors used in the formulation. In general, the addition of weak acids such as acetic acid or citric acid delays the start of foaming, but has a limited effect on the rate of foaming once it begins. The rate of foaming can be controlled by adjusting the relative levels of blowing and gelling catalysts. For example, the start of foaming is significantly delayed in formulation AM096 (cream time of 25 seconds, rise time of 105 seconds), but the rate of foaming remains similar relative to formulation AM099 (cream time of 9 seconds, rise time of 95 seconds), yet the two differ only in that the level of acetic acid is 0.5 pphp higher in AM096 than in AM099. Generally, preferred embodiments of the invention maximize cream time and minimize rise time to yield cream times of 15 seconds and higher, and rise times of up to 150 seconds.
The viscosity of formulations of the invention can also be controlled and, without wishing to be bound to any theory, it is believed that lower viscosity of the liquid precursor improves dispersion within the targeted cavity. Conventionally, polyols used in polyurethane foam formation are multi-functional, OH-terminated polymers with viscosities of between 250 and 5,000 cP. Because high weight percentages are typically used in the art, polyol phases used in foam formulations tend to have similar viscosities. Similarly, polyurethane prepolymers contain urethane bonds and are subject to hydrogen bonding forces, and have viscosities of between 1,000 and 500,000 cP. Formulations of the invention, however, may achieve substantially lower phase viscosities by several means, including (i) using higher quantities of water to dilute high-viscosity polyol components; (ii) using low molecular weight (and hence lower viscosity) polyols; and (iii) using non-reactive diluents to the polyol phase. With respect to diluting high-viscosity polyol components with water, a range of water concentrations of 10-20 pphp may be useful for two-part foaming formulations. With respect to using low molecular weight polyols, preferred compounds include propylene glycol, di- tri- and tetra-propylene glycols, ethylene glycol, di- tri- and tetra-ethylene glycols, and low molecular weight, linear or multi-armed, hydroxyl-terminated polymers preferably containing 1-10 repeat units such as polypropylene glycols, polyethylene glycols, polytetrahydrofurans, polytetramethylene glycols, and polydimethylsiloxanes. As for non-reactive diluents, between 10-200 pphp of diluent may be added to the polyol phase, and it has been found that a level as high as 300 pphp can be added to some formulations to yield stable foams (e.g., formulation AM1042; 5.6× expansion). Preferred properties for diluents include low viscosity (<50 cP; more preferably 0.5-10 cP), lack of reactivity towards hydroxyls, isocyanates, and other components in the formulation, and biocompatibility. Preferred diluents include propylene carbonate (PC), diethyl malonate, tetraethylene glycol dimethyl ether (TEGDME), polyethylene glycol dimethyl ether, dimethyl sulfoxide, acetone, and triacetin.
Using low molecular weight polyols and/or diluents, polyol phases have been engineered with viscosities ranging from 17 cP (AM1045) to 2635 cP (AM735). For example, the hydrophobic polyol phase of formulation AM880 (53 cP) combines a low viscosity polypropylene glycol (1200 Da) and the diluents diethyl malonate (15 pphp) with other ingredients. The more hydrophilic polyol phase of formulation AM759 (50 cP) combines trimethylolpropane ethoxylate (1014 Da) with 70 pphp TEGDME and other ingredients. Even with high levels of diluents, foams with high expansion can still be produced (AM1209; 41 cP; 60 pphp TEGDME; 38× expansion) by increasing the catalyst, water, and isocyanate levels.
Using even higher diluent levels (100-300 pphp) enables further reduction of viscosity (e.g., formulation AM1045; 17 cP; 150 pphp PC; 12.1× expansion). Additionally, added diluents may advantageously act as plasticizers and lead to foams with low compression-force at 50% deflection values (CFD), as discussed below (e.g., AM761; 70 pphp TEGDME; 25.8× expansion, 0.3 kPa CFD).
In some embodiments, the foam of the present invention is described to be “lava like” in that it is viscous yet flowable and hardens from its exterior surface towards its interior. The external skin of the foam forms as a fast-forming, robust, balloon-like outer layer that encases the polymer formulation, promotes material cohesion, and resists deformation and movement into collateral vessels or outside the targeted area. As the foam expands this external skin may deform, exposing some of the interior material which the reacts upon contact with the external environment to reform the external skin. The outer layer may be characterized as a “skin” in some embodiments that consists of a thin exterior layer that is more hard or solid, or less flowable, than the material contained by the outer layer. Moreover, the skin may be characterized as being “robust” because it has mechanical properties (e.g., strength, toughness, etc.) that are different, at least for some period of time, to the material contained by the skin. The interior of the material hardens more slowly via the same or a secondary process, as compared to the skin. In some cases where the skin forms rapidly, the material is not cohesive in-situ, resulting in a continuous, packable polymer, which may tend to form as a coil. Through continued extrusion of the material out of a delivery device such as a catheter or microcatheter, the user can create a long coil to partially or completely fill an aneurysm space or other bodily cavity. The space may be filled with an aneurysm coil or other medical implant and an in-situ forming foam or an aneurysm coil that is coated with a material that expands to form a foam coating in-situ. The continuous, long aspect ratio of the coil and cured outer surface prevents the coil from entering the collateral vessels to a significant degree, which could lead to adverse events. These and other factors are important distinctions and advantages of in-situ forming foams over systems and methods that make use of pre-formed foams.
In a preferred embodiment, the foam is formed by a fast cross-linking reaction that can be surface triggered by in-situ water. Multi-functional moisture sensitive silanes are one example of materials susceptible to such reactions especially when formulated with tin, titans or other metal-organic catalysts. One-part cross-linking systems can be created by a two-step process. In the first step, hydroxyl containing siloxanes (either silanols or carbinols) are reacted with an excess of multifunctional silane containing acetoxy, oxime, alkoxy (e.g., methoxy, ethoxy), isopropenoxy, amide, amine, aminoxy, or other functional groups containing silane with the hydrolytically susceptible Si—O—C bond. The resulting prepolymers have multiple groups that are susceptible to hydrolysis. In the second step, such prepolymers are exposed to in-situ water to result in a rapidly cross-linking elastic solid. The reaction proceeds from the outside-in, resulting in a quickly formed outer skin and, in some cases, the formation of the foam into a coil-like configuration. The slower permeation of water or alternative reaction trigger can be used to slowly cure the material inside of the skin. The proteins and pH of the blood can be used to support coil formation by modifying the rate of the skin-forming reaction as well as in coating the formed coil and preventing coil sticking and agglomeration upon self-contact.
Additionally, hydride functional (Si—H) siloxanes or isocyanate functionalized carbinols can be introduced into silanol elastomer formulations to generate gas and produce expanding foamed structures. Expansion of the material can be used to increase the size of the formed coil effectively decreasing coil embolization potential. Expansion of the material can also be critical to increase material size without delivery of more material, in adding porosity and in generating sealing or pressure. Additional formulation ingredients such as surfactants can be used to the impact of generated gas on porosity and expansion.
Alternatively, isocyanate-containing prepolymers are a second example of materials that may be used to generate in-situ forming coils or lava-like foams. Isocyanate groups are relatively unstable when exposed to water and moisture. One-part isocyanate based cross-linking systems can be created by a two-step process. In the first step, polyols, diols, diamines, polyamines, diepoxides, silanols, carbinols or polyepoxides are capped with aliphatic or aromatic diisocyanates such as isophorone diisocyanate (IPDI), hexamethylene diisocyanate (HDI) and methylene diphenyl diisocyanate (MDI). Additionally, multifunctional isocyanates such as HDI biuret, HDI trimer, and polymeric MDI can be combined with diols or diamines. The resulting prepolymers have multiple distant isocyanate groups that are able to react with water and amines found in blood. In the second step, such prepolymers are exposed to in-situ blood resulting in rapid cross-linking and foam formation. The reaction is water-triggered and proceeds from the outside-in, forming a porous outer skin, lava-like shell core structure that assists in coil formation. The expansion of such materials can be important in generating coils of a large diameter while maintaining a small cross-sectional area of the delivery device. Such materials can be used to form stand-alone foaming or gelling coils or combined with each other such that one material is coaxially formed on top the other. For example, a coaxial delivery device can deploy a coil forming formation surrounded by a highly expandable coating formulation. The two formulations may be from different chemistry classes. Alternatively, the two formulations may be selected to be immiscible such that upon delivery the formulations phase separate (e.g., oil miscible and water miscible formulations) to naturally form a coaxial structure. Additionally, the interaction with the catheter wall and/or the density differential of the two fluids can be used to further drive the phase separation. Additionally, two part formulations may be designed such that the two parts are not fully miscible. A surfactant system may be used to formulate the two part formulation into a single stable emulsion. Such an emulsion could be delivered via single chamber delivery device and does not require mixing. The emulsion can be destabilized by shear during delivery or in-situ factors (pH, temperature, ionic strength). Upon such destabilization, the internal phase of the emulsion would spill out and trigger the reaction with the external phase resulting in in-situ foam formation
The solidification of interior portions of foams that form with an exterior skin can be controlled, for example, by altering the permeability of the material to solidification trigger. In the case that the trigger is water, permeability can be controlled by adjusting material hydrophobicity. Additional ingredients can be added to adjust material radiopacity, density, and/or contact angle with blood, tissue, or other biological matrices.
An experiment has been developed in which a one-part polyurethane prepolymer is injected into the bronchial network of an explanted lung. The quasi-prepolymer is composed of MDI in excess of a hydrophilic polyol (UCON), and formulated with diluent (propylene carbonate), catalyst (DABCO 33LV), and surfactant (Tegostab). The formulation was successfully delivered through a 9 French needle into the bronchus and traveled to distal airways. An explanted foam cast of the airways is shown in
After the foam had formed in-situ, a solution of bromothymol blue was introduced into the same injection point to ensure that the foam had formed a seal. Some solution flowed back out of the injection site, while the remainder shunted into non-foam filled vessels or was absorbed by the foam immediate to the injection site (
An in vitro test to evaluate dispersion and movement of formulations of the invention has been developed, and is shown schematically in
A range of formulations have been successful or partially successful in this transport test. Low viscosity, delayed reaction kinetics, and high expansion are all correlated with success in the test. The majority of formulations that have been successful in the test (conformal or near-conformal contact with the flow orifice) have had a viscosity of less than 1200 cP, cream time of more than 10 seconds, and expansion greater than 12×. Finally, hydrophobic formulations have generally performed better in the test than hydrophilic formulations.
Lack of Interference with Bodily Functions:
Foams of the invention are preferably soft and easily compressed so that they do not interfere with physiological functions. For example, in preferred embodiments the foams are adhesive and expansive such that they seal the targeted tissue and promote tissue necrosis, but also sufficiently soft such that they do not interfere with respiration. In some embodiments, the foams are characterized by CFD values greater than 1 kPa but less than 25 kPa are preferred.
The foams preferably apply less than 20 mmHg of pressure during long-term use, though the foams may transiently apply pressures in excess of 20 mmHg during the generation and subsequent dissolution of CO2 gas from the isocyanate-water reaction without negative long-term consequences on bodily functions.
Foams have been developed having CFD values between 0.3 and 100 kPa, as shown in
Travel into More Distal Airways to Contact Hard to Reach Areas:
Foams of the invention are preferably low viscosity (between 1 and 1,000 cP) and expansive in nature (between 0.5 and 10×) to fill distal airways and complex anatomies. A low viscosity formulation allows the use of a low profile delivery device, which can travel through narrow or tortuous airways to the desired cavity. Without wishing to be bound to theory, a low viscosity formulation allows the liquid precursor to travel into more distal anatomies and spread throughout the cavity. Without wishing to be bound to theory, the expansive nature of the foam allows it to travel further and better fill the cavity, as it will expand in the direction of least resistance.
The ability of the low viscosity liquid precursor to spread and the foam to expand gives the operator a greater margin for delivery. The delivery device need not be placed in a precise location, as the foam has the ability to spread and expand into the available space. This is advantageous in an endoscopic surgery where the anatomies are complex and visibility is likely limited.
Facilitation of Tissue Necrosis:
Foams of the invention can seal off targeted areas of tissue and promote tissue necrosis. In preferred embodiments, foams of the invention have properties such that the foam adheres to targeted tissue to ensure a good seal and limit oxygenation. In one example this is achieved by controlling the hydrophobicity of the foam; more hydrophobic materials promote protein adhesion. In another example, this is achieved by functionalizing the foam surface with mucoadhesives such as poly vinyl pyrrolidone (PVP), methyl cellulose (MC), carboxymethylcellulose (CMC) or other cellulose derivatives. In another example, NCO itself at the prepolymer ends can bind nonspecifically and non-selectively to tissue surfaces.
In preferred embodiments, the foam fills the targeted cavity and contacts all available tissue surfaces. In order to achieve tissue necrosis, all collateral ventilation to the targeted section of lung should be eliminated. The ability of the foam to travel as a precursor and expand as a polymer foam to fill complex geometries, in conjunction with its ability to seal off tissue, will limit collateral ventilation and promote tissue necrosis.
In some embodiments, foams of the invention are formulated which collapse over the course of days, and fully resorbs into the body with the targeted lung tissue over the course of months. This may be achieved, for example, by using a copolymer backbone containing segments that break down quickly and segments with more slowly degrading bonds. For example, anhydride segments degrade quickly as they are very susceptible to hydrolysis, and ester segments are less susceptible and would degrade over a longer period of time. In some embodiments, foams of the invention comprise of prepolymers with biodegradable soft segments (e.g., polycapralactone, polyglycolide, polylactic acid, or polyanhydrides). In this way, the material initially forms a cross-linked foam in-situ to seal a cavity and promote tissue necrosis, but resorbs into the body with the lung tissue once tissue necrosis has been achieved.
In some embodiments, foams of the invention have surface properties that promote cell growth and resorption. For example, a highly porous micro structure provides a three dimensional topography that promotes cell growth. Pore density (defined as the number of open pores per unit area) can be controlled by adjusting the types and levels of ingredients in the formulation. In general, pore density can be altered by balancing the isocyanate index, surfactant levels, catalyst levels controlling both blowing and gelling rates, and the polyol viscosity. In many cases, subtle changes to a single ingredient level can drastically change the pore density. For example, it has been found that decreasing the isocyanate index from 45 (in formulation 126-52-4, which has 7 pores/mm2) to 35 (in formulation AM368 which has 19 pores/mm2) while leaving other component concentrations essentially unchanged results in a significantly higher pore density and openness to the structure. In a similar fashion, the pore density of formulation 126-52-2 (12 pores/mm2) can be increased to 19 pores/mm2 (AM368) by adding 0.37 pphp of the pore opening agent Ortegol 501 to formulation.
Similar to pore density, pore size is affected by a number of ingredient types and levels. For example, the pore size of formulation AM375 (average pore size of approximately 120 μm) can be increased almost three-fold (in AM376; average pore size of approximately 350 μm) by adjusting the relative ratio of Pluracol 816 to TMPEO (17.5:1 to 1:1) while leaving other concentrations essentially unchanged.
In some embodiments, a kit including one or more of the compositions previously discussed (e.g., a kit including a polymer that can be foamed in-situ, a kit including a polymer foam, a device comprising a polymer or polymer foam and any other additive (e.g., external gas, second agent, etc.), a kit comprising a polymer or polymer foam and a delivery system) that can be used to create and/or deploy a polymer foam, or the like, is described. A “kit,” as used herein, typically defines a package or an assembly including one or more of the compositions of the invention, and/or other compositions associated with the invention, for example, as previously described. Each of the compositions of the kit may be provided in liquid form (e.g., in solution, as a liquid-phase polymer, etc.), or in solid form (e.g., a reversibly cross-linked polymer). In certain cases, some of the compositions may be constitutable or otherwise processable, for example, by the addition of a suitable solvent, other species, or source of energy (e.g., UV radiation), which may or may not be provided with the kit. Examples of other compositions or components associated with the invention include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binding agents, bulking agents, preservatives, drying agents, antimicrobials, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps, patches, containers, tapes, adhesives, and the like, for example, for using, administering, modifying, assembling, storing, packaging, preparing, mixing, diluting, and/or preserving the compositions components for a particular use, for example, to a sample and/or a subject.
A kit of the invention may, in certain cases, include different compositions that can be mixed to form a product. In certain embodiments, the kit may include physically separated chambers to hold the compositions, and a mechanism that is activated by a user or a machine for discharging the compositions and/or mixing them together. As a non-limiting example, the kit may include a dual barrel syringe having first and second chambers that contain first and second compositions, wherein the first and second chambers are physically separated, for example by a wall. In this example, the user may depress the plunger of the dual-barrel syringe to eject the first and second compositions from the first and second chambers. In certain embodiments, the kit also includes a static mixing nozzle, a dynamic mixing nozzle, an impeller, or a mixing chamber to permit the components to mix prior to or during discharge.
A kit of the invention may include a catheter. A delivery catheter to infuse in-situ forming foam may contain a balloon or flap to prevent foam proximal foam expansion. For example, a balloon may be attached on the distal end of the catheter and be inflated to contact the airway lumen prior to foam expansion; the inflated balloon then prevents proximal movement. A similar effect may be achieved with a flap, cuff, membrane or similar mechanism to contact the airway lumen. A delivery catheter may have a distal end designed to control the dispersion of the foam as it is delivered, (i.e., spray tip, multidirectional holes). A kit of the invention may be designed to work in conjunction with a bronchoscope. The catheter may be fed through the same introducer, or be connected to the bronchoscope to streamline the procedure.
A kit of the invention may, in some cases, include instructions in any form that are provided in connection with the compositions of the invention in such a manner that one of ordinary skill in the art would recognize that the instructions are to be associated with the compositions of the invention. For instance, the instructions may include instructions for the use, modification, mixing, diluting, preserving, administering, assembly, storage, packaging, and/or preparation of the compositions and/or other compositions associated with the kit. In some cases, the instructions may also include instructions for the delivery and/or administration of the compositions, for example, for a particular use, e.g., to a sample and/or a subject, or to deliver the compositions of the invention into contact with bodily tissues to prevent, limit, or otherwise control bleeding or the flow of other bodily fluids. The instructions may be provided in any form recognizable by one of ordinary skill in the art as a suitable vehicle for containing such instructions, for example, written or published, verbal, audible (e.g., telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) or electronic communications (including Internet or web-based communications), provided in any manner.
In the compositions of the invention, the term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, a straight chain or branched chain alkyl may have 30 or fewer carbon atoms in its backbone, and, in some cases, 20 or fewer. In some embodiments, a straight chain or branched chain alkyl may have 12 or fewer carbon atoms in its backbone (e.g., C1-C12 for straight chain, C3-C12 for branched chain), 6 or fewer, or 4 or fewer. Likewise, cycloalkyls may have from 3-10 carbon atoms in their ring structure, or 5, 6 or 7 carbons in the ring structure. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, hexyl, cyclochexyl, and the like.
The term “heteroalkyl” refers to an alkyl group as described herein in which one or more carbon atoms is replaced by a heteroatom. Suitable heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of heteroalkyl groups include, but are not limited to, alkoxy, amino, thioester, and the like.
The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The terms “heteroalkenyl” and “heteroalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the heteroalkyls described above, but that contain at least one double or triple bond respectively.
As used herein, the term “halogen” or “halide” designates —F, —Cl, —Br, or —I.
The terms “carboxyl group,” “carbonyl group,” and “acyl group” are recognized in the art and can include such moieties as can be represented by the general formula:
wherein W is H, OH, O-alkyl, O-alkenyl, or a salt thereof. Where W is O-alkyl, the formula represents an “ester.” Where W is OH, the formula represents a “carboxylic acid.” The term “carboxylate” refers to an anionic carboxyl group. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiolcarbonyl” group. Where W is a S-alkyl, the formula represents a “thiolester.” Where W is SH, the formula represents a “thiolcarboxylic acid.” On the other hand, where W is alkyl, the above formula represents a “ketone” group. Where W is hydrogen, the above formula represents an “aldehyde” group.
The term “aryl” refers to aromatic carbocyclic groups, optionally substituted, having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings in which at least one is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). That is, at least one ring may have a conjugated pi electron system, while other, adjoining rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The aryl group may be optionally substituted, as described herein. “Carbocyclic aryl groups” refer to aryl groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds (e.g., two or more adjacent ring atoms are common to two adjoining rings) such as naphthyl groups. In some cases, the The term “alkoxy” refers to the group, —O-alkyl.
The term “aryloxy” refers to the group, —O-aryl.
The term “acyloxy” refers to the group, —O-acyl.
The term “aralkyl” or “arylalkyl”, as used herein, refers to an alkyl group substituted with an aryl group.
The terms “heteroaryl” refers to aryl groups comprising at least one heteroatom as a ring atom.
The term “heterocycle” refers to refer to cyclic groups containing at least one heteroatom as a ring atom, in some cases, 1 to 3 heteroatoms as ring atoms, with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. In some cases, the heterocycle may be 3- to 10-membered ring structures or 3- to 7-membered rings, whose ring structures include one to four heteroatoms. The term “heterocycle” may include heteroaryl groups, saturated heterocycles (e.g., cycloheteroalkyl) groups, or combinations thereof. The heterocycle may be a saturated molecule, or may comprise one or more double bonds. In some case, the heterocycle is a nitrogen heterocycle, wherein at least one ring comprises at least one nitrogen ring atom. The heterocycles may be fused to other rings to form a polycylic heterocycle. The heterocycle may also be fused to a spirocyclic group. In some cases, the heterocycle may be attached to a compound via a nitrogen or a carbon atom in the ring.
Heterocycles include, for example, thiophene, benzothiophene, thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole, pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, oxazine, piperidine, homopiperidine (hexamethyleneimine), piperazine (e.g., N-methyl piperazine), morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, other saturated and/or unsaturated derivatives thereof, and the like. The heterocyclic ring can be optionally substituted at one or more positions with such substituents as described herein. In some cases, the heterocycle may be bonded to a compound via a heteroatom ring atom (e.g., nitrogen). In some cases, the heterocycle may be bonded to a compound via a carbon ring atom. In some cases, the heterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine, acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline, benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or the like.
The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the 30 general formula: N(R′)(R″)(R′″) wherein R′, R″, and R′″ each independently represent a group permitted by the rules of valence. An example of a substituted amine is benzylamine.
Any of the above groups may be optionally substituted. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds, “permissible” being in the context of the chemical rules of valence known to those of ordinary skill in the art. It will be understood that “substituted” also includes that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In some cases, “substituted” may generally refer to replacement of a hydrogen with a substituent as described herein, e.g., a drug or a peptide. However, “substituted,” as used herein, does not encompass replacement and/or alteration of a key functional group by which a molecule is identified, e.g., such that the “substituted” functional group becomes, through substitution, a different functional group. For example, a “substituted phenyl group” must still comprise the phenyl moiety and cannot be modified by substitution, in this definition, to become, e.g., a pyridine ring. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaruomatic moieties, —CF3, —CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halide, alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. The peptides described herein are inclusive of at least two amino acids connected by amide bond.
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This application claims priority to U.S. Provisional Patent Application Ser. No. 61/852,172 filed Mar. 15, 2013, titled “In-Situ Forming Foam for Endoscopic Lung Volume Reduction.” This application also claims priority to U.S. Provisional Application Ser. No. 61/852,072 filed Mar. 15, 2013, titled “In-situ Forming Foams For Embolization.” Each of the foregoing applications is incorporated herein by reference for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 61852172 | Mar 2013 | US | |
| 61852072 | Mar 2013 | US |
