Patent ID: 12201556

DETAILED DESCRIPTION

Described herein are therapeutic devices for extended release drug delivery. The devices include one or more porous structures for the delivery of one or more therapeutics for the treatment of diseases. The devices and systems described herein can deliver therapeutics to select regions and structures of the body over a variety of periods of time. The therapeutic devices and systems described herein can be used for extended release drug delivery of one or more therapeutic agents. The therapeutic device can include a refillable reservoir configured to receive a bolus injection the therapeutic agent(s). The reservoir can have an outlet for delivery of the bolus injection of the therapeutic agent(s) to a patient from the reservoir over an extended period of time. The device can include a porous structure coupled near the outlet of the reservoir. The porous structure can be formed of a sintered material and will be described in more detail below. The device can include a barrier layer coupled to the reservoir on or adjacent a surface of the porous structure such that the therapeutic agent passes through both the porous structure and the barrier layer upon delivery from the reservoir through the outlet. The porous structure is tuned to deliver the therapeutic agent at a predetermined diffusion rate and the barrier layer is adapted to retain particles having an average particle size range that is different from or outside the average particle size range retained by the porous structure. Thus, the barrier layer is configured to block passage of contaminants from entering the eye through the porous structure, or block passage of contaminants from entering the reservoir through the porous structure, or both. The contaminants can vary including, for example, one more microbes, bacteria, fungal spores, immune cells, cellular products such as antibodies. The barrier layer can also mitigate bolus release of the therapeutic agent upon an increase in pressure within the reservoir.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. All patents, patent applications, published applications and publications, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there are pluralities of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go. but equivalent information is known and can be readily accessed, such as by searching the internet and/or appropriate databases. Reference thereto evidences the availability and public dissemination of such information.

As used herein, relative directional terms such as anterior, posterior, proximal, distal, lateral, medial, sagittal, coronal, transverse, etc. are used throughout this disclosure. Such terminology is for purposes of describing devices and features of the device and is not intended to be limited. For as used herein “proximal” generally means closest to a user implanting a device and farthest from the target location of implantation, while “distal” means farthest from the user implanting a device in a patient and closest to the target location of implantation.

As used herein, a disease or disorder refers to a pathological condition in an organism resulting from, for example, infection or genetic defect, and characterized by identifiable symptoms.

As used herein, treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the devices described and provided herein.

As used herein, amelioration or alleviation of the symptoms of a particular disorder, such as by administration of a particular pharmaceutical composition, refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.

As used herein, an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such an amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. The amount can cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Repeated administration can be required to achieve the desired amelioration of symptoms. Pharmaceutically effective amount, therapeutically effective amount, biologically effective amount and therapeutic amount are used interchangeably herein to refer to an amount of a therapeutic that is sufficient to achieve a desired result, i.e. therapeutic effect, whether quantitative or qualitative. In particular, a pharmaceutically effective amount, in vivo, is that amount that results in the reduction, delay, or elimination of undesirable effects (such as pathological, clinical, biochemical and the like) in the subject.

As used herein, sustained release encompasses release of effective amounts of an active ingredient of a therapeutic agent for an extended period of time. The sustained release may encompass first order release of the active ingredient, zero order release of the active ingredient, or other kinetics of release such as intermediate to zero order and first order, or combinations thereof. The sustained release may encompass controlled release of the therapeutic agent via passive molecular diffusion driven by a concentration gradient across a porous structure.

As used herein, a subject includes any animal for whom diagnosis, screening, monitoring or treatment is contemplated. Animals include mammals such as primates and domesticated animals. An exemplary primate is human. A patient refers to a subject such as a mammal, primate, human, or livestock subject afflicted with a disease condition or for which a disease condition is to be determined or risk of a disease condition is to be determined.

As used herein, a therapeutic agent referred to with a trade name encompasses one or more of the formulation of the therapeutic agent commercially available under the trade name, the active ingredient of the commercially available formulation, the generic name of the active ingredient, or the molecule comprising the active ingredient. As used herein, a therapeutic or therapeutic agents are agents that ameliorate the symptoms of a disease or disorder or ameliorate the disease or disorder. Therapeutic agent, therapeutic compound, therapeutic regimen, or chemotherapeutic include conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art and described elsewhere herein. Therapeutic agents include, but are not limited to, moieties that are capable of controlled, sustained release into the body.

As used herein, a composition refers to any mixture. It can be a solution, a suspension, an emulsion, liquid, powder, a paste, aqueous, non-aqueous or any combination of such Ingredients.

As used herein, fluid refers to any composition that can flow. Fluids thus encompass compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams and other such compositions.

As used herein, a kit is a packaged combination, optionally, including instructions for use of the combination and/or other reactions and components for such use.

As used herein, “nano”, “nano-sized”, “nano-scale”, “nano-particle” or “nano-channel” relates to an average particle size or dimension of less than about 1000 nm, particularly less than about 200 nm, more particularly between about 1 nm to about 100 nm. As used herein, “micro”, “micro-sized”, “micro-scale”, “micro-particle” or “micro-channel” relates to an average particle size or dimension of less than about 1000 um, particularly less than about 200 um, more particularly between about 1 um to about 100 um. In some instances, a dimension is provided herein in microns that is less than 1 um (e.g. 0.2 microns or 200 nm). Thus, “nano” and “micro” as used herein to refer to size are not necessarily mutually exclusive.

The devices and systems described herein can incorporate any of a variety of features described herein and the elements or features of one implementation of a device and system described herein can be incorporated alternatively or in combination with elements or features of another implementation of a device and system described herein as well as the various implants and features described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO 2012/019136; PCT Pat. Publication No. WO 2012/019047; and PCT Pat. Publication No. WO 2012/065006. For example, the porous structures described herein may be used with any of the various implementations of a device or system. For the sake of brevity, explicit descriptions of each of those combinations may be omitted although the various combinations are to be considered herein. Additionally, described herein are different methods for implantation and access of the devices. The various implants can be implanted, filled, refilled etc. according to a variety of different methods and using a variety of different devices and systems. Provided are some representative descriptions of how the various devices may be implanted and accessed, however, for the sake of brevity explicit descriptions of each method with respect to each implant or system may be omitted.

The porous structures (also referred to herein as a release control element, RCE, frit, filter, membrane, or substrate) as described herein can be used with a number of various different implantable therapeutic devices including one or more of those devices described U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO 2012/019136; PCT Pat. Publication No. WO 2012/019047; and PCT Pat. Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto.

The porous structures described herein can be incorporated into an implantable therapeutic device that is positioned in a variety of locations in the body. The devices and systems described herein can be used to deliver therapeutic agent(s) for an extended period of time to one or more of the following tissues: intraocular, intravascular, intraarticular, intrathecal, pericardial, intraluminal, intraperitoneal, central nervous system, intraosseous, intramuscular, intradermal, intralesional, intrarterial, and others. The devices and systems described herein can be used to deliver one or more therapeutic agents locally or systemically.

Although specific reference may be made below to the delivery of treatments to a particular region of the body, such as the eye or another region, it also should be appreciated that delivery of treatments to other regions of the body to treat various medical conditions besides ocular conditions are considered herein. For example, conditions that may be treated and/or ameliorated using the drug delivery devices and methods described herein may include at least one of the following: hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, Alzheimer's, hereditary diseases such as cerebrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Grave's disease, systemic lupus erythematosus and rheumatoid arthritis, shock and wasting disorders, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, gastrointestinal or other cancers, degenerative diseases, trauma, multiple systemic conditions such as anemia, and ocular diseases such as, for example, retinal detachment, proliferative retinopathy, proliferative diabetic retinopathy, degenerative disease, vascular diseases, occlusions, infection caused by penetrating traumatic injury, endophthalmitis such as endogenous/systemic infection, post-operative infections, inflammations such as posterior uveitis, retinitis or choroiditis and tumors such as neoplasms and retinoblastoma, angiogenesis, neoplasm, abnormal new cell growth, cancerous growths, tumors and the like. Any number of drug combinations can be delivered using any of the devices and systems described herein.

The release of a therapeutic agent from a therapeutic device can follow Fick's Law of Diffusion that yields a release rate decay that follows a first order profile.FIG.1illustrates a hypothetical example of a Fickian release profile andFIG.2illustrates a corresponding plot of drug concentration in a target body location (e.g. the vitreous of an eye). In general, the therapeutic device can maintain a therapeutic level of the drug in the target body location for an extended period of time. Often therapeutic devices have a first order release rate profile. However, in order to maintain the desired therapeutic levels even at the later time points, the device is “tuned” to release more than therapeutic levels at the earlier time points. Alternate mechanism(s) of release via diffusion may be effective in mitigating the early release of drug that is in excess of that needed for therapeutic benefit. For example, the rate of molecular diffusion can be inhibited by limiting the size of the pores through which drug molecules pass, otherwise known as “constrained diffusion.” In constrained diffusion systems, a high concentration gradient can exist and be sustained. Such a system can be “tuned” to release at a more uniform, therapeutically targeted rate. Ideally, a therapeutic device has a “zero order” release rate rather than a first order release such that it releases consistently at a rate to maintain a target body concentration of drug this is slightly above the therapeutic level. Various materials can have a molecule-to-pore size ratio that may be suitable to yield a constrained diffusion release rate profile. Incorporation of such materials into a therapeutic device may be feasible, but can require explicit evaluation and iterative development for each molecule/clinical target of interest.

The implantable therapeutic devices considered herein can include a hollow, non-porous or nun-permeable housing having an inner surface defining, at least in part, a reservoir chamber for holding therapeutic material. The implantable therapeutic device can also include one or more porous structures for controlled sustained release of the therapeutic agent from the reservoir chamber via passive molecular diffusion driven by a concentration gradient across the porous structure.

FIGS.3A-3Fshows an implementation of an implantable therapeutic device100having a hollow housing130, a reservoir chamber160for holding therapeutic material and one or more porous structures150for controlled sustained release of the therapeutic material from the reservoir chamber160. It should be appreciated that the configuration of the therapeutic device100can vary and the device100shown is just one implementation. The housing130can have a proximal end region and a distal end region. The housing130can extend between the proximal end region and the distal end region along a longitudinal axis100A such that the reservoir chamber160is symmetrically disposed about the axis. The reservoir chamber160can also be eccentrically disposed about the axis. The reservoir chamber160can be a fixed volume chamber or an expandable chamber. The reservoir chamber160can have a non-porous, non-permeable wall suitable for containing one or more therapeutic materials or agent(s) (seeFIG.3F). A penetrable barrier140can be positioned within a proximal end region of the housing130such as within an opening180in an access portion of the device that leads into a reservoir chamber160of the device. The porous structure150can be positioned within another region of the housing130a distance away from the penetrable barrier140such as within an opening152leading out of the reservoir chamber160of the device. For example, the porous structure150can be positioned near a distal end region of the housing130opposite the location of the more proximal penetrable barrier140. It should also be appreciated that additional porous structures can be disposed along the Musing, for example the distal end of the housing can include a first porous structure, and one or more additional porous structures can be disposed along a portion of the housing proximal to the distal end, for example, along a tubular sidewall of the housing. The reservoir chamber160can have a volume sized to deliver therapeutic amounts of therapeutic agent to the eye for an extended period of time and the porous structure150can be configured to release therapeutic agent contained within the reservoir chamber160over the extended period of time, as will be described in more detail below.

The housing130can include a retention structure120that can protrude outward from the proximal end region of the housing130. The access portion opening180can be an opening in the device100that extends into the reservoir chamber160. The penetrable barrier140can be positioned, at least in part, within the access portion opening180such that it forms a seal with the proximal end region of the housing130and also allows access to refill or flush the device.

Again with respect toFIGS.3A-3Fand as mentioned above, a distal end region of the housing130can include another opening152, for example, positioned near a distal end region of the housing130opposite the proximal access portion opening180into the reservoir chamber160, that extends between the inside of the reservoir chamber160out of the housing130. The porous structure150can be coupled to or positioned, at least in part, within the opening152. The porous structure150can be affixed within opening152in distal end of housing130, for example with glue or other material(s). Alternatively or in combination, the distal end of the housing130can include an inner diameter sized to receive the porous structure150, and the housing130can include a stop to position the porous structure150at a predetermined location on the distal end so as to define a predetermined size of reservoir chamber160. It should be appreciated that the porous structure150can be coupled to or positioned within other regions besides the distal end region of the housing130. It should also be appreciated that more than one porous structure150can be coupled to, positioned within, or disposed along the housing130. For example, the distal end of the housing130can include a first porous structure, and one or more additional porous structures can be disposed along a portion of the housing proximal to the distal end, for example, along a tubular sidewall of the housing. The one or more additional porous structures can be disposed in series such that the therapeutic device100has a first porous structure150acting as a release control element metering the diffusion of the therapeutic agent from the reservoir chamber and a second porous structure providing a barrier function, for example, by retaining immune cells, bacterial cells, and other undesired material within the reservoir and limiting or preventing such contaminants from exiting the reservoir and entering the eye. Additionally or alternatively, the second porous structure can provide a barrier function limiting or preventing contaminants from entering the device from inside the eye. A first type of porous structure can be positioned in series with another type of porous structure. For example, a sintered release control element having a particular thickness, porosity, and tortuosity can be positioned adjacent a filter membrane having a different thickness, porosity, and/or tortuosity. A first type of porous structure can be positioned in a distal opening of the reservoir chamber and a filter can be bonded on an inner surface of the porous structure, an outer surface of the porous structure or both an inner and an outer surface of the porous structure.

Still with respect toFIGS.3A-3F, therapeutic formulations injected into device100can be released from the reservoir chamber160in accordance with the volume of the reservoir chamber160and a release characteristic or release rate index of the porous structure150, which is described in more detail herein. The volume of the reservoir chamber160can be sized to deliver therapeutic amounts of a therapeutic agent to the patient for an extended period of time. The volume of the reservoir chamber160can be substantially determined by an inner cross sectional area of the housing130, such as the distance between the proximal, penetrable barrier140and the porous structure150.

One or more regions of the housing130of the devices described herein can be formed of a substantially rigid, biocompatible material. In some implementations, the walls of the housing130including at least the proximal retention structure120down to and including the porous structure150are substantially rigid such that the reservoir chamber160has a substantially constant volume when the therapeutic agent is released from the device so as to maintain a stable release rate profile, for example when the patient moves. The reservoir chamber160can remain substantially rigid and have a substantially constant volume even during injection of the therapeutic agent into the device, for example a device already implanted in the patient. It should be appreciated that the therapeutic devices described herein can incorporate an expandable reservoir chamber160such as described in U.S. Publication No. 2016/0128867, which is incorporated herein by reference.

One or more regions of the housing130, one or more regions of the retention structure120as well as other portions of the devices described herein, alone or in combination, can be formed of one or more of many biocompatible materials including, but not limited to materials such as acrylates, polymethylmethacrylate, siloxanes, metals, titanium stainless steel, polycarbonate, polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate (PET), polyimide, polyamide-imide, polypropylene, polysulfone, polyurethane, polyvinylidene fluoride, polyphenylene polyphenylsulfone or PTFE, and others. The material can also include biocompatible, optically transmissive materials such as one or more of acrylate, polyacrylate, methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate, glass or siloxane.

The reservoir chamber160can be filled and re-filled as needed, such as after implantation of the device in the patient. As mentioned above, the penetrable barrier140can be positioned, at least in part, within an access portion opening180sealing the reservoir chamber160on a proximal end region of the device100. The penetrable barrier140can be a septum configured to receive and be repeatedly penetrated by a sharp object such as a needle for injection of the therapeutic agent into the reservoir chamber160. The penetrable barrier140can be configured to re-seal when the sharp object is removed. The penetrable barrier140can be a pre-molded soft, high strength material. In some implementations, the penetrable barrier140can be formed from one or more elastic materials such as siloxane, rubber, or another liquid injection molding silicone elastomer such as NUSIL MED-4810, NUSIL MED-4013, and others (NuSil Silicone Technology, Carpinteria, CA). In some implementations, the penetrablebarrier140can include an opaque material and/or a colored material such that it can be visualized by the treating physician. In other implementations, the penetrable barrier can be a translucent material such that the penetrable barrier appears dark when the therapeutic device is implanted in the eye and viewed from outside the eye by a treating physician. The dark region forms a penetration target for refilling of the device when the device is still implanted in tho eye.

As mentioned above, the implantable therapeutic device100can include a porous structure150for controlled release of the therapeutic agents from the reservoir chamber160. The porous structure150can allow for controlled release of the therapeutic agent via passive molecular diffusion driven by a concentration gradient across the porous structure150. Porous structures considered herein are described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Publication No. WO 2012/019136; PCT Publication No. WO2012/019047; and PCT Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto.

FIGS.3A-3C,3F, and4A-4Dshow implementations of a porous structure150configured to release the therapeutic material from the reservoir chamber160. The porous structure150can be configured in many ways to release the therapeutic agent in accordance with an intended release profile. The porous structure150may include one or more of a permeable membrane, a semi-permeable membrane, a material having at least one hole disposed therein, nano-channels, nano-channels etched in a rigid material, laser etched nano-channels, a capillary channel, a plurality of capillary channels, one or more tortuous channels, tortuous microchannels, sintered nano-particles, an open cell foam or a hydrogel such as an open cell hydrogel. The porous structure150can be the release control element configured to meter drug delivery to the patient.

In some implementations, the porous structure150can be composed of interconnected particles or grains of material. Minute spaces or void space can extend throughout the porous structure150between the sintered material. The void space within the sintered material can contribute to the porosity of the porous structure150. Without limiting this disclosure to any particular theory or mode of operation, the porous structure150can be designed to have a pore size that retains or inhibits passage of molecules, cells, or solid particles of a certain size range and allows for passage of molecules, cells, or solid particles of another size range through the porous structure150. The porous structures may be described herein as having an average pore size or void space dimension to define the porous structure utility for allowing a molecule to substantially pass through a porous structure or to substantially limit a molecule from passing through the porous structure. As such, the molecules of a particular size range (e.g. therapeutic agent) can passively diffuse from within the reservoir chamber160within the porous structure outward along a concentration gradient from one side of the porous structure150to another side of the porous structure150such that therapeutic quantities of the therapeutic agent are delivered for the extended time.

The material forming the porous structure150can include sintered material including at least one of a metal, a ceramic, a glass or a plastic. The sintered material can include a sintered composite material, and the composite material can include two or more of the metal, the ceramic, the glass or the plastic. The metal can include at least one of Ni, Ti, nitinol, stainless steel including alloys such as304,304L,316or316L, cobalt chrome, elgiloy, hastealloy, c-276 alloy or Nickel 200 alloy. The plastic can include a wettable coating to inhibit bubble formation in the channels, and the plastic can include at least one of polyether ether ketone (PEEK), polyethylene, polypropylene, polyimide, polystyrene, polycarbonate, polyacrylate, polymethacrylate, or polyamide.

In some implementations, the porous structure150is formed from an all-metal filter media. The all-metal filter media can be metal fiber or metal powder based media. In some implementations, the powder or grains of material used to form the porous structure150can have an average size of no more than about 20 um, or no more than about 10 um, an average size of no more than about 5 um, or an average size of no more than about 1 um, or an average size of no more than about 0.5 um. The all-metal filter media can be sintered porous metal media (Mott Corporation. Farmington, Conn.) The filter media can have a grade that can substantially stop solid particles having a nominal solid particle size from penetrating the media. In some implementations, the sintered material includes grains of material corresponding to a Media Grade of no more than about 0.1, or no more than about 0.2, or no more than about 0.3, or no more than about 0.5 (Media Grade as determined by ISO 4003 or ASTM E128). In some implementations, the starting raw material for the porous structure150can be metal powder particles sintered together. The particle size distribution of the starting raw material can be between about 50 nm and about 350 nm or between about 50 nm to about 50 um, as well as any number microns in between depending on the powder particle size distribution desired. In other implementations, the particle size distribution of the starting raw material can be no more than about 20 um, no more than about 10 um, no more than about 5 um, no more than about 1 um, or nor more than about 0.5 um, or no more than about 0.3 um, or no more than about 0.2 um.

In some implementations, the sintered material allows passage during filtration solid particles having a size of about 0.1 microns or less, about 0.2 microns or less, about 0.3 microns or less, and about 0.5 microns or less. In some implementations, the porous structure150has pores having a diameter or pore size of approximately 0.2 um, 0.3 um, 0.4 um, 0.5 um, 1 um, 2 um, 3 um, 4 um, or 5 um. In some implementations, the porous structure150has an average pore size of about 5 um up to about 50 um. In some implementations, the porous structure150allows for passage of particles smaller than a size ranging between 0.1 um-100 um and largely blocks passage of particles having a size greater than this size range. The pores of the porous structure150can be substantially larger than the molecules of interest that are to diffuse through the porous structure150. For example, the pores of the porous structure150can be 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100 times larger than the molecules of interest to diffuse through the porous structure150. In some implementations, therapeutic compounds in the size range of IgG (150 kDa or 10.5 nm hydrodynamic diameter) or BSA (69 kDa or 7.2 nm hydrodynamic diameter) can diffuse relatively easily through the void space of the porous structure150. The pore size can be representative of the dimension of the void space extending throughout the porous structure150. However, It should be appreciated that some regions within the void space can neck down to a smaller size than a neighboring pore or can widen into a larger size than a neighboring pore. Generally as used herein, average pore size refers to a dimension of the porous structure150that provides information as to whether or not a particle of a particular size range can largely pass through the porous structure150or be largely captured, retained, blocked, and/or rejected by the porous structure150.

The porous structure150can have a fixed tortuous, porous material such as a sintered metal, a sintered glass, or a sintered polymer with a defined porosity and tortuosity that controls the rate of delivery of the at least one therapeutic agent to the target body. The void space within the porous structure150can be characterized as having a plurality of channels (e.g. micro-channels and/or nano-channels) extending between pores or openings in the first side and pores or openings in the second side. The diameter of the channels may have a dimension across that allows for, impairs or prevents movement of molecules having a particular size through them. In some implementations, the diameter of the channels are about 10 nm across to about 1000 nm across, or larger. The channels can be substantially straight or can be tortuous. The porosity or percentage of void space throughout the porous structure150can be within a range from about 3% to about 70%. In other embodiments, the porosity or percentage of void space is within a range from about 5% to about 10% or from about 10% to about 25%, or, for example, from about 15% to about 20%. Porosity can be determined from the weight and macroscopic volume or can be measured via nitrogen gas adsorption.

Microbes including bacteria and/or fungal spores as well as immune cells and cellular products such as antibodies can be inhibited from filtering through the void space within the sintered material of the porous structure150. For example, the pore size or dimension of the channels through the porous structure can be of a particular small size range to retain such material. In some implementations, pore sizes for the porous structure150are, for example, between 3 and 5 microns, or 3 and 10 microns, up to about 50 microns. However, pore sizes in this range can allow certain microbes to pass through the porous structure150. If a microbe is inadvertently introduced into the reservoir chamber160of the implantable device100, the microbe can eventually pass through the device into the surrounding tissue region of the patient. In addition, if bacteria exists in the eye of the patient from another source unrelated to the implant, it may filter into the implant during diffusion. Thus, pore sizes of a certain range pose a risk of infection to the patient. Microbes as well as immune cells such as macrophages, cellular products, or other molecules from the patient, bacteria can pass into the reservoir chamber160through the porous structure150having pore sizes of a certain range. Porous structures having a pore size that is approximately 0.2 microns or smaller generally inhibit microbial and immune cell infiltration. However, a porous structure150having a pore size in this range can inhibit target release rate of the therapeutic agent from the reservoir. Further, implantable therapeutic devices having porous structures can release an amount of drug through the porous structure during in situ filling or refilling due to a transient increase in pressure inside the device associated with resistance of fluid being forced through the refill needle system. In the case of a therapeutic device that is already implanted in a patient prior to filling, this bolus release of drug during filling can be undesirable. It can be useful to control whether and how much of a bolus is released during filling.

As will be described in more detail below, the therapeutic devices described herein can incorporate a porous barrier layer155that allows the therapeutic agent of interest to pass through, but inhibits microbial and cellular infiltration. As will be described in more detail below, the porous barrier layer155can also mitigate bolus release during refilling of the reservoir by providing a dense pressure barrier. Mitigating bolus release can be useful, for example, during flushing of a device exhibiting signs of contamination. The reservoir chamber of the device can be flushed with an anti-bacterial agent (or other type of agent) prior to refilling the device with a therapeutic for treating of the eye disease without fear of pushing the contamination into the eye.

The porous structures150can be covered on at least a first surface by the porous barrier layer155. The porous barrier layer155can be a coating over a distal end region of the device or on one or more surfaces of the porous structure150. The barrier layer155can also be a discrete porous structure positioned in series with the porous structure150. The barrier layer155can be bonded on, positioned internal to or formed on an inner-facing surface of the porous structure150(i.e. a surface that faces internal to the reservoir of the device) or an outer-facing surface (i.e. a surface that faces external to the reservoir of the device), or both an inner and an outer facing surface when the porous structure150is assembled with the therapeutic device100within the opening152.

The porous structure150can be configured to control the diffusion rate of the therapeutic agent from the reservoir chamber160and the barrier layer155can inhibit passage of certain contaminants (e.g. microbes, bacteria, cellular material, cell types, macrophages, cellular products, fungal spores, etc.) from exiting and/or entering the reservoir chamber160through the porous structure150. Release rate is described in more detail below, but generally is a function of the concentrations of the therapeutic on either side of the porous structure (i.e. inside the reservoir and outside the reservoir), the diffusion coefficient of the therapeutic in the solution, porosity of the porous structure, tortuosity of the channels or void spaces in the porous structure, area of the porous structure, and thickness of the porous structure. The barrier layer155can inhibit penetration of contaminants without substantially impacting the metered diffusion rate of the drug that would otherwise be achieved by the porous structure150in absence of the barrier layer155. Alternatively, the porous structure150and/or the barrier layer155can be selected based on certain characteristics (e.g. porosity, thickness, tortuosity, area) such that the desired diffusion rate or release rate of the therapeutic agent from the reservoir chamber160is achieved even in spite of the barrier layer155.

The porous structure150acts as the release control element providing predictable metering of the drug diffusion into the eye whereas the barrier layer155limits or prevents contaminants from passing through the porous structure150along with the drug. The barrier layer155can have a substantially different porosity compared to the porosity of the porous structure150alone. As described above, the porous structure150can have minute spaces or void space forming channel structures disposed between pores in a first surface and pores in a second surface of the porous structure150. The channel structures can be within the micro-channel and/or nano-channel size range. The porous structure150can have a first pore size or void space dimension that allows for molecules having a first size to pass through the porous structure150, such as the therapeutic agent as well as molecules significantly larger than the therapeutic agent such as bacteria. The barrier layer155can have a pore size or void space dimension that is smaller than the pore size or void space dimension of the porous structure150. The pore size or void space dimension of the barrier layer155is large enough to allow the therapeutic agent to penetrate the barrier layer155, but limits or prevents larger sized molecules such as bacteria or immune cells or other contaminants from being able to penetrate the barrier layer155. Thus, the pore size or void space dimension of the barrier layer155can retain a larger range of molecules including those that are sized smaller than would otherwise be retained by the porous structure150alone. The barrier layer155on or adjacent the first and/or second surface of the porous structure150can effectively reduce the size of the molecule that can enter the porous structure150without impacting the channel dimension such that the permeability of a drug molecule through the void space of the porous structure150is maintained substantially the same.

The barrier layer155is adapted to reject or substantially block passage of particles having an average particle size within an average particle size range that is greater than about 1 nm-10 nm, or greater than about 0.01 um—0.1 um, or greater than about 0.1 um-1 um such that the barrier layer155rejects or blocks passage of particles having an average particle size within an average particle size range that is greater than about 0.001 um to about 1 um. In some implementations, the porous structure150allows passage of particles having a size range up to about 3 um or up to about 50 um whereas the barrier layer155rejects or blocks passage of particles having an average particle size greater than about 0.1 um to about 1 um. As such, the barrier layer155rejects or blocks passage of particles having a size that would otherwise be allowed to pass through the porous structure150. For example, the barrier layer155may reject or block passage of particles having an average particle size greater than about 0.1 um up to greater than about 3 um, or particles having an average particle size greater than about 0.1 um up to greater than about 4 um, or particles having an average particle size greater than about 0.1 um up to greater than about 5 um.

As mentioned, the barrier layer155can be a discrete porous structure positioned in series with another porous structure. Each porous structure150can be configured to release the therapeutic agent for an extended period while having certain diffusion characteristics. The one or more porous structures150coupled together in series can be coupled together in any of a number of configurations. For example, a first porous structure150can be positioned within an interior of the reservoir chamber160proximal to the opening152leading out of the reservoir chamber160and a second porous structure can be positioned within the opening152. Alternatively, a first porous structure150can be positioned within the opening152and a second porous structure can be positioned at a distal end of the first porous structure150outside the reservoir chamber160. In either version, the two porous structures positioned in series can be in direct contact with one another or can be separated a distance away from one another. The porous structures positioned in series can be two or more porous structures formed of the same material or different materials. The porous structures positioned in series generally have different porosity in that a first porous structure retains molecules having a size range that would not be retained by the second porous structure. For example, the first porous structure may have a porosity that allows for bacterial cells to penetrate therethrough and the second porous structure may have a porosity that limits or substantially prevents molecules in this size range from penetrating therethrough. Each of the first and second porous structures, however, would allow for the therapeutic agent to be delivered to the patient to penetrate at a predictable diffusion rate. In some implementations, the first porous structure150can be a sintered release control element and the barrier layer155can be a separate filter membrane formed of a different material. The release control clement may have certain defined parameters such as thickness, area, porosity, tortuosity and allow for drug delivery according to a particular release rate index as described elsewhere herein. The filter membrane may have defined parameters that are different from the release control element such that the filter membrane acts as a barrier to certain molecules, but has minimal impact on the release rate index of the release control element. For example, the filter membrane may have a significantly smaller thickness compared to the release control element. The filter membrane may have smaller porosity and/or tortuosity. Regardless, the combination of the release control element and the filter membrane may maintain the particular release rate index as if the filter membrane were not present.

FIG.7Ashows a distal end of an implementation of a therapeutic device100. The device100has a hollow housing130with walls formed of a non-permeable material and defining a reservoir chamber160for holding therapeutic material. A first porous structure150for sustained release of the therapeutic material from the reservoir chamber160is positioned within an opening152leading out of the reservoir chamber160.FIG.7Bshows the distal end of the therapeutic device ofFIG.7Aand having a barrier layer155formed by a discrete porous structure coupled within the reservoir chamber160in series with the first porous structure150. The barrier layer155in this implementation can be a filter membrane separate from the first porous structure150.

Still with respect toFIG.7B, the chamber160can taper down towards the opening152such that a region162at a distal end of the reservoir chamber160is formed having a narrower diameter than a more proximal region of the reservoir chamber160. A distal ledge164can surround the opening152within with the porous structure150is positioned. The barrier layer155can be positioned within the region162between the porous structure150positioned within the opening152and the distal end region of the reservoir chamber160. The distal ledge164surrounding the opening152can be sized to receive a perimeter edge157of the barrier layer155such that a central region of the barrier layer155aligns with the opening152and thus, the porous structure150positioned within the opening152. The barrier layer155can be fixed in place by a bushing158or capture ring. The bushing158can be positioned over the perimeter edge157of the barrier layer155capturing the barrier layer155against the distal ledge164. The bushing158can be an annular element formed of PMMA. The inner aperture159of the bushing158allows for communication between the reservoir chamber160and the barrier layer155. The outer surface of the bushing158can be shaped to conform to the inner wall130of the reservoir chamber160within which it is positioned. The outer surface of the bushing158can be generally cylindrical to fit within region162at the distal end of the reservoir chamber160.FIG.7Cshows another implementation of the therapeutic device100having a barrier layer155captured by a bushing158. In this implementation, the barrier layer155is positioned within the distal end of the reservoir chamber160and the outer surface of the annular bushing158captures the perimeter edge157of the barrier layer155against the wall130of the reservoir chamber160as well as the distal ledge164formed around the opening152. Thus, the diameter of the barrier layer155in this implementation can be larger than the inner diameter of the distal end of the reservoir chamber160. The outer surface of the bushing158can be shaped to conform to the inner wall130of the reservoir chamber160such that the bushing158can engage and be press-fit into the reservoir chamber160to capture the perimeter edge157of the harrier layer155.

FIG.7Dillustrates a distal end region of a reservoir chamber160of a therapeutic device100having a double bushing158. The perimeter edge157of the barrier layer155can be captured between two bushings158a,158b.As with other implementations, a distal ledge164can be formed around the opening152from the reservoir chamber160. The double bushing can include a first bushing158bpositioned against the distal ledge164and a second bushing158apositioned towards the reservoir chamber160. The perimeter edge157of the barrier layer155can be captured between the first bushing158band the second bushing158bsuch that the central region of the barrier layer155is positioned over the opening152. Each of the first and second bushings158a,158bcan be annular or ring-shaped such that they can capture the perimeter edge157between them while maintaining the central region of the barrier layer155to freely communicate with the reservoir chamber160. The annulus can have any of a variety of shapes. Each of the double bushings can have a generally cylindrical annulus like the bushing158shown inFIG.7B. The double bushings can be toroid-shaped or otherwise rounded such as the bushing158shown inFIG.7C. The annulus of each of the double bushings can also have a frusto-conical shape, a tunnel shape, toroid, flattened toroid, or a bowl shape. The perimeter region157can be captured between flattened sides of the annulus and the central region of the barrier layer155can align with the central aperture of the bushing158. The double bushing158can be pre-fused and bonded in place with an adhesive or solvent.

It should be appreciated that the barrier layer155can be positioned relative to the porous structure150such that it is positioned on the reservoir side of the porous structure150or on the external side of the reservoir and porous structure150. The barrier layer155can be positioned in contact with the porous structure150such as shown inFIG.7Bor the barrier layer155can be spaced apart from the porous structure150such as shown inFIG.7D. It should also be appreciated that the barrier layer155can be coupled to the device using any of a number of techniques. The barrier layer155can be heat-fused, ultrasonically bonded, or adhered. Further, the barrier layer155can be formed of any of a variety of materials including porous metal as described elsewhere herein. In some implementations, the barrier layer155can be a membrane disc filter formed of silver metal, cellulose acetate, ceramic, glass fiber, borosilicate fiber, MCE (mixed cellulose ester), nylon, polyacrylonitrile (PAN), polycarbonate track etch (PCTE), polyethersulfone (PES), polyester track etch (PETE), polypropylene (PP), PTFE, PVDF, or other filter material such as those provided by Sterlitech Corp. (Kent, Wash.).

The barrier layer155, whether it is a discrete porous structure such as the filter membranes described above or a coating on the porous structure, can contain contaminants introduced into the system from exiting into the eye and/or limit or substantially prevent contaminants from entering the system from the eye. Contaminants may be introduced into the system when the reservoir chamber is initially filled with therapeutic agent or refilled while the therapeutic device is still implanted in the eye. The barrier layer155can limit or prevent the release of these contaminants from the reservoir chamber160into the eye thereby reducing the risk of eye infections at least until the contamination is identified and the therapeutic device can be removed from the eye. In some implementations, the barrier layer155can limit or prevent the passage of contaminants from the reservoir into the eye for at least about 1 week, 1 month, or indefinitely. Contaminants can cause a change in the appearance of the contents in the reservoir chamber (e.g. cloudy) or result in irritation to the patient. The therapeutic device can be visually inspected by a physician following implantation such as by indirect ophthalmoscope or on a slit lamp.

In addition to limiting reservoir contamination and reducing the risk of an eye infection by containing contaminants within the system and limiting the release into the eye, the barrier layer155allows for flushing of the reservoir chamber without the need to remove the device from the eye. As described elsewhere herein, the barrier layer155can mitigate bolus release through the porous structure150during injections of fluid into the reservoir. Contamination of the reservoir chamber can be treated by flushing the system or injecting the system with antibiotics. Because bolus release is mitigated, the flushing and/or injection can be performed while the device is still implanted in the eye without fear of the contaminants being urged from the reservoir chamber through the porous structure into the eye. For example, a refill needle system such as that described in U.S. Pat. No. 9,033,911 filed Aug. 5, 2011, or U.S. Publication No. 2013-0165860, filed Sep. 13, 2012, can be used to flush the system with saline followed by refilling the device with an antibiotic to eliminate the contaminant from the system. Once the system is treated for the contamination, the system can be further flushed with saline and the original therapeutic drug can be refilled into the system so the patient can continue treatment.

In some implementations, the porous structure150can have an average pore size that is between about 0.2 um to about 5 um and a porosity that is between about 10% to about 30%. The barrier layer155can have an average pore size that is approximately 0.2 microns or less, approaching the size of the therapeutic being delivered. As such, the barrier layer155retains molecule that are smaller than would otherwise be retained by the porous structure150. Or said another way, certain sized molecules retained or blocked by the barrier layer155would not be retained or blocked by the porous structure150. The porosity P of the barrier layer155can be substantially less than the porosity of the porous structure150alone. The substantially reduced porosity of the barrier layer155can result in an overall denser material as compared to the porous structure150. In some implementations, the porosity of the barrier layer155can be between about 1% to about 15%. Despite the smaller pore size and lower porosity of the barrier layer155compared to the porous structure150relative to which it is applied or used in conjunction with, in some implementations the release rate through the porous structure150and the barrier layer155can be maintained or comparable to the release rate through the porous structure150alone as if the barrier layer155were not present. For example, the porous structure150alone can have a release rate index that is between about 0.06 mm to about 0.1 mm. In other implementations, the porous structure150alone can have a release rate index as low as 0.002 and as a high as 0.15. The porous structure150having a barrier layer155can have a release rate index that is between about 0.06 mm to about 0.1 mm. In still further implementations, the release rate index of the porous structure150in the presence of the barrier layer155may be significantly different compared to the release rate index of the porous structure150alone, but certain parameters of the porous structure150can be optimized to achieve the desired release rate index in the presence of the barrier layer155. For example, the porous structure150may be selected based on a greater porosity or a smaller tortuosity or smaller thickness or a combination thereof.

It should be appreciated that the ranges provided herein are examples and that one or more characteristics can be modified and/or optimized to achieve a desired effect in drug delivery. For example, a porous structure150alone prior to combining with a barrier layer155can be selected based on its gas flow rate. The gas flow rate can vary, for example, between about 10 standard cubic centimeters per minute (seem) to about 250 sccm. The gas flow rate can be between 1.5 sccm and 320 sccm. In some implementations, the gas flow rate can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 135, 140, 145, 150, 200, 250, or 400 sccm. The release rate index (mm) of the porous structure150alone can be about 0.01 to about 0.10, or from about 0.06 to about 0.04, or from about 0.002 to about 1.5. Generally, the mean pore size of the barrier layer155is equal to or less than 0.2 um approaching the size of the drug molecule being delivered. The mean pore size of the porous structure150can be increased relative to the mean pore size of the barrier layer155. For example, the mean pore size of the porous structure150can be between about 0.2 microns to about 9 microns. The thickness of the porous structure150and the barrier layer155can vary as well. The porous structure150can have a thickness that is between about 70 microns to about 5000 microns and an outer diameter between about 700 microns to about 1200 microns. The barrier layer155can have a thickness that is significantly less than the porous structure150. In some implementations, the barrier layer155is a coating and can have a thickness on the order of a few nanometers up to about 250 microns. The barrier layer155, whether a coating deposited on the surface as shown inFIG.4Dor a discrete structure in series with the porous structure150, eau have a minimal thickness so as to maintain effectively the same thickness (length L) of the porous structure150alone. In some implementations, the barrier layer155can be a filter membrane having a nominal thickness of between about 10 um to about 200 um, or between about 110 um to about 150 um. In some implementations, the combination of the barrier layer155and the porous structure in series (e.g. a “composite” release control element) can have a thickness that is greater than a thickness of the porous structure alone while having a minimal impact on the drug diffusion characteristics of the porous structure. Alternatively, the diffusion properties of the porous structure150can be adjusted in order to remove any actual or incidental impact caused by the barrier layer155on drug release through the porous structure.

As described above with respect to the porous structure150, the barrier layer155can be designed to have a pore size that retains or inhibits passage of molecules, cells, or solid particles of a certain size range and allows for passage of molecules, cells, or solid particles of another size range through the barrier layer155.

The barrier layer155may be described herein as having an average pore size or void space dimension or molecular weight cut off to define the utility of the barrier layer155for allowing a molecule to substantially pass through the barrier layer155or to substantially limit or prevent a molecule from passing through the barrier layer155. As such, the molecules of a particular size range (e.g. therapeutic agent) can pass from one side of the barrier layer155to another side of the barrier layer155such that they are released from the reservoir.

In some implementations, the porous structure150can be between Media Grade 0.2 and Media Grade 0.5 porous material and the barrier layer155can be a mass of particles having an average particle size of 50 nanometers to 350 nanometers. In some implementations, the porous structure150can include316L stainless steel substrate (Mott Corporation) and the barrier layer155can be a mass of particles that are predominantly stainless steel. The porous substrate and the mass of particles can be sintered. In some implementations, a suspension of sinterable particles in a carrier fluid is applied as a barrier layer155to the substrate150using an ultrasonic spray nozzle and the sinterable particles sintered to the substrate150in an ultrasonic spray deposition process. The suspension of particles can be a suspension of particles that are applied to the porous substrate150. The porous structure150can be manufactured according to the process described in U.S. Patent Application No. 2012/0183799, which is incorporated by reference herein in its entirety. The porous structure150can be a substrate having pores with a first mean pore size and the barrier layer155can be a coating on at least one surface of the substrate having pores with a second mean pore size. The pore size of the porous structure150can be equal to or greater than the second mean pore size. The barrier layer155can have a mean pore size effective to capture microbes greater than 0.2 microns as evaluated by Microbial retention ASTM F838-05 or equivalent as described in more detail below.

In other implementations, the porous structure150can be a sintered titanium element having a thin film titanium coating deposited by physical vapor deposition (PVD) or Plasma Enhanced Chemical Vapor Deposition (PECVD) (Acree Technologies Inc., Concord, Calif.). In some implementations of the sputtering method of forming the barrier layer155, a source target such as a titanium target is activated so as to vaporize the target material into the surrounding atmosphere such as a vacuum environment in a plasma plume. The vapor can condense onto one or more surfaces of the porous substrate150forming the barrier layer155as a thin film. The process can take place in ultra-high vacuum or in the presence of a background gas, such as oxygen. The chamber can include fixturing, such as a rotating basket, inside the chamber to allow all surfaces of the porous structure150to receive a coating forming the barrier layer155. Alternatively, a single surface of the porous structure150can be coated. Energetic Deposition Process (EDP) can also be used to form a barrier layer155on the porous structure150. EDP is characterized by a high ionization rate and higher add-atom energy than PVD, for example, 50%-100% for EDP compared to about 5% ionization rate for PVD. The add-atom energy in sputtering can be between 1 eV to 3 eV, whereas for EDP the add-atom energy can be from about 30 eV to about 100 eV, depending on the material being deposited and the process conditions. Higher ionization potential and energy can generally lead to denser films deposited. Standard sputtering tends to produce coatings that are somewhat porous with columnar morphology, whereas EDP tends to produce non-porous, denser coatings without columnar structures. As described above, the relative thicknesses of the substrate and the coatings can vary. In some implementations, the porous structure150can be between about 700 microns to about 5000 microns, or between about 200 microns and about 1300 microns. In some implementations, the barrier layer155can be about 1, 2, 3, 4, 5 microns up to about 10 microns thick. In some implementations, the barrier layer155can be about 10, about 20, about 30, about 40, about 50, about 60, or about 70 microns thick. In some implementations, the barrier layer155can be between about 5 microns to about 40 microns thick.

Therapeutic quantities of the one or more therapeutic agents can pass through the porous structure150and the barrier layer155of the therapeutic devices described herein for the extended period of time whereas other particles are inhibited from passing through the porous structure and/or the barrier layer. The therapeutic devices described herein can have a porous structure150and/or a barrier layer155sized to pass the at least one therapeutic agent comprising molecules having a molecular weight of at least about 100 kDa, 75 kDa, 50 kDa, 25 kDa, 10 kDa, 5 kDa, 2.5 kDa, 1 kDa, 500 Daltons (D), 250 D, 200 D, 150 D, or 100 D. A variety of therapeutic agents are considered herein. Table 1 provides representative therapeutic agents that can be delivered and their molecular weights.

The therapeutic devices described herein can have a porous structure150and/or a barrier layer155sized to inhibit passage of microbes. Microbes can include, but are not limited to, fungi, fungal spores, protists, as well as bacterial cells includingBrevundimonas diminuta, Propionibacterium acnes, Actinomycesspecies.Bacillus cereus, Clostridium, Enterococcus, Escherichia coli, Haemophilus influenza, Klebsiella pneumoniae, Mycobacterium tuberculosis, Neisseria meningitides, Nocardia asteroids, Pseudomonas aeruginosa, Serratia species, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus viridansand others. The therapeutic devices described herein can have a porous structure150and/or a barrier layer155sized to inhibit passage of immune cells and/or cellular material from the patient into and/or out of the therapeutic device. Immune cells can include, but are not limited to monocytes, lymphocytes, neutrophils, eosinophils, basophils, macrophages, erythrocytes, platelets, and other cells. The therapeutic devices described herein can have a porous structure150and/or a barrier layer155sized to inhibit passage of any of these unwanted molecules (e.g. microbes, cells, cellular materials) while allowing for passage of the one or more therapeutic agents from the therapeutic device into the eye.

The release rate of therapeutic agent through a porous structure150alone, such as a sintered porous metal structure described above, may be described by the following equation: Release Rate=(D P/F) A (cR−cv)/L, where: cR=Concentration in reservoir, cv=Concentration outside of the reservoir or in the target body volume, D=Diffusion coefficient of the therapeutic agent in the reservoir solution, P=Porosity of porous structure, F=Channel parameter that may correspond to a tortuosity parameter of channels of porous structure, A=Area of porous structure, L=Thickness (length) of porous structure. Cumulative Release=1—cR/cR0=1=exp((−D PA/FL V R)t), where t=time and Vr=reservoir volume.

The parameters of the porous structure150that affect the passive molecular diffusion of the drug from the reservoir chamber160due to the concentration gradient are the porosity (P), tortuosity (T), area (A), and length or thickness (L) of the porous structure150. These parameters are encompassed by a release rate index (RRI), which can be used to determine the release of the therapeutic agent. The RRI may be defined as (PA/FL), where P is the porosity of the porous structure, A is an effective area of the porous structure, F is a curve fit parameter corresponding to an effective length, and L is a length or thickness of the porous structure150.

As described above, the grains of material sintered together to form the porous structure150can define interconnected channels of void space through the porous structure150. The channel parameter (F) can correspond to an elongation of the path of the therapeutic agent released through the porous structure150. The porous structure150can include many of these interconnecting channels and the channel parameter (F) can correspond to an effective length that the therapeutic agent travels along the interconnecting channels of the porous structure150, such as from the reservoir side to the external side of the device100.

The diffusion coefficient (D) can be estimated by the following equation from the measured value of DBSA,20C=6.1 e−7 cm2/s for bovine serum albumin (BSA) in water at 20° C. (Molokhia et al, Exp Eye Res 2008): DTA,37C=DBSA,20C(η20C/η37C)(MWBSA/MWTA)1/3where MW refers to the molecular weight of either BSA or the test compound and η is the viscosity of water. Small molecules have a diffusion coefficient (D) similar to fluorescein (MW=330, D=4.8 to 6 e-6 cm2/s from Stay, M S et al.Pharm Res2003, 20(1), pp. 96-102). For example, the small molecule may comprise a glucocorticoid such as triamcinolone acetonide having a molecular weight of about 435.

The porous structure150has a porosity, thickness, channel parameter and a surface area configured to release therapeutic amounts for the extended time. Porosity of the porous structure150can be determined from the weight and macroscopic volume or can be measured via nitrogen gas adsorption. As mentioned above, the porous structure150can include a plurality of porous structures. The area A used in the above equation may include the combined area of the plurality of porous structures.

The channel parameter (F) may be a fit parameter corresponding to the tortuosity of the channels. For a known porosity (P), surface area (A) and thickness (L) of the surface parameter, the curve fit parameter (F), which may correspond to tortuosity of the channels, can be determined based on experimental measurements. The parameter PA/FL can be used to determine the desired sustained release profile, and the values of P, A, F and L determined. The rate of release of the therapeutic agent corresponds to a ratio of the porosity to the channel parameter, and the ratio of the porosity to the channel parameter can be less than about 0.5 such that the porous structure releases the therapeutic agent for the extended period. For example, the ratio of the porosity to the channel parameter (F) is less than about 0.1 or for example less than about 0.2 such that the porous structure releases the therapeutic agent for the extended period. The channel parameter (F) can be a value of at least about 1, such as at least about 1.2. For example, the value of the channel parameter (F) can be at least about 1.5, for example at least about 2, and can be at least about 5. The channel parameter (F) can be within a range from about 1.1 to about 10, for example within a range from about 1.2 to about 5. The channel parameter (F) to release the therapeutic agent for an intended release rate profile can be determined empirically.

The area (A) in the model originates from the description of mass transported in units of flux; i.e., rate of mass transfer per unit area. For simple geometries, such as a porous disc mounted in an impermeable sleeve of equal thickness, the area (A) corresponds to one face of the disc and the thickness (L) is the thickness of the disc. For more complex geometries, such as a porous structure in the shape of a truncated cone, the effective area (A) can be a value in between the area where therapeutic agent enters the porous structure and the area where therapeutic agent exits the porous structure.

A model can be derived to describe the release rate as a function of time by relating the change of concentration in the reservoir to the release rate described above. This model assumes a solution of therapeutic agent where the concentration in the reservoir is uniform. In addition, the concentration in the receiving fluid is considered negligible (cv=0). Solving the differential equation and rearrangement yields the following equations describing the concentration in the reservoir as a function of time, t, and volume of the reservoir, VR, for release of a therapeutic agent from a solution in a reservoir though a porous structure. cR=cR0exp ((−D PA/FL VR) t) and Cumulative Release=1—cR/cR0

The model and determination of parameters in the above equations as well as the tuning of the therapeutic devices to release therapeutic amounts above a minimum inhibitory concentration for an extended time based on bolus injections of the therapeutic agent are described in more detail, for example, in U.S. Pat. No. 8,399,006, which is incorporated by reference herein.

Release rates of a therapeutic agent from the therapeutic devices can be assessed by measuring diffusion of size-matched molecules in vitro through a porous structure over an extended period of time. For example, solutions of BSA or fluorescein or other molecules representative of a drug of interest and having a known concentration can be used to till a reservoir chamber of a therapeutic device and allowed to diffuse over time from the reservoir through a porous structure coupled to the device. The diffusion experiments can be continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks and samples collected at various time-points throughout to assess release rate of the therapeutic agent through the porous structure. The samples allow for plotting the cumulative amount of drug released from the device over time. The amount of test molecule within the reservoir chamber and/or outside the reservoir chamber can be measured as is known in the art, for example, by absorbance, fluorescence, ELISA, and other tests.

The measured release rates can be compared to predicted release rates using the model described above relating to the change in concentration in the reservoir to the release rate from the reservoir based upon Fick's Law of Diffusion. As described in U.S. Pat. No. 8,399,006, the release from the device agrees with the trend predicted by the model.

The porosity P can be determined by nitrogen adsorption and is typically provided by the manufacturer along with the area A and length L. The measured cumulative release of a molecule through the porous structure and a prediction from the model describing release through the porous structure can be used to determine the channel parameter F. Thus, upon determination of the channel parameter F, the release rate index (RRI) can be determined. The RRI is determined by fitting the rate data from a device. The determined RRI can be used to determine the release of the therapeutic agent, and the porous structure can be further characterized with gas flow as described herein to determine the RRI prior to placement in a patient.

The porous structure can be subjected to a gas flow test to determine the release rate of a therapeutic from the device. These tests can be used with a porous structure positioned on the therapeutic device or before the porous structure is assembled with the therapeutic device, so as to quantify flow through the porous structure of the device. Flow of gas such as oxygen or nitrogen through the porous structure can be measured with a decay time of the gas pressure. The flow rate and RRI can be determined based on the material of the porous structure. The therapeutic agent can be measured through the porous structure or a similar test molecule. The correspondence of the flow rate with a gas to the release rate of the therapeutic agent is determined empirically. In some implementations, a correlation can be made between the “flow” tests, which are dependent upon a pressure gradient and is a forced gas flow and the actual drug release test, which is dependent upon in vitro passive diffusion through the porous structure. The correlation is described in more detail in U.S. Pat. No. 8,399,006, which is incorporated by reference herein.

The extended release of therapeutic from the reservoir chamber through the porous structure relies on passive, concentration gradient driven molecular diffusion. To measure this type of extended release directly can be time-consuming and prevents the porous structure from being used again. Thus, testing a porous structure using active pressure gradient response as a substitute for characterizing the passive molecular diffusion mechanism is described. In some implementations, the forced gas flow test involving a pressure gradient can correlate with the drug release test that relies upon passive transport of a therapeutic agent via diffusion from the reservoir chamber through the tortuous interconnected channels of the porous structure into the target volume.

The testing described herein and also in U.S. Pat. No. 8,399,006 allows for testing that would suggest performance of porous materials relative to a molecular diffusion mechanism. Fick's Law of Molecular Diffusion says that diffusion through a porous element can be described via a linear concentration gradient over the thickness of the element, L, with the diffusion coefficient reduced by a ratio of porosity, P. over tortuosity, T, yielding the equation:

VR*∂cR∂t=(-D⁢PT)*(cR-cV)L*A

where cv=drug concentration in the receiver fluid.

The elements of this equation that are specific to the porous structure can be isolated and combined into the RRI. The porous structure controls drug delivery via its macroscopic dimensions, area and thickness, and its microscopic properties, porosity and tortuosity. These four parameters can be grouped into a single parameter referred to as the Release Rate Index (RRI), which has units of length and is as follows:

RRI=P⁢ATL

The RRI parameters can correlate for various porous structures with the quick and easy non-destructive gas flow vs. pressure behavior. This allows for 100% QC testing of devices to ensure long-term sustained drug release performance without so much as getting the porous structures wet. This also allows for intelligent selection of porous structures not currently in inventory based on interpolation of the correlation. Further, the RRI curves and an understanding of device properties (e.g. reservoir volume capacity) and drug properties (e.g. drug concentration and drug molecular diffusivity), allow for one to project the release behavior of systems that are not yet built. This correlation allows for projections of a variety of drug release parameters that may be of interest such as daily release rates over time, estimated resultant concentrations in the target volume, cumulative amounts or percent of amount of drug released, as well as forecasting expected duration of efficacy for a known therapeutic dose requirement.

FIG.6is a flow chart demonstrating a method of manufacturing600a therapeutic device with a porous structure configured for sustained release of a therapeutic agent. It should be appreciated that the steps described need not be performed exactly in the order shown. A porous structure150having specified characteristics can he selected (box605). The specified characteristics or parameters can include characteristics that impact drug diffusion rate through the porous structure such as material type, solid particle size retained, porosity P, area A, length or thickness L, mean pore size, and the like. The specified characteristics are encompassed by a release rate index (RRI), which can be used to determine the release of the therapeutic agent. The RRI may be defined as (PA/FL), where F is a curve fit parameter corresponding to an effective length. For example, the porous structure can be a316L stainless steel substrate having a porosity of between about 10%-20%, a Media Grade of 0.2. a thickness of between about 0.50 mm to about 1.50 mm, and a mean pore size of about 3 um to about 5 um, to upwards of 50 um. A non-destructive gas flow test can be performed on a porous structure having the specified characteristics (box610) to obtain a performance result. For example, the performance result can be a gas flow rate of about 100 sccm to about 150 sccm. A drug diffusion test can be performed on a porous structure having the specified characteristics to measure diffusion rate of a molecule through the porous structure (box615). For example, the measured diffusion rate of bovine serum albumin (BSA) through the porous structure. The measured diffusion rate of the molecule through the porous structure allows for the RRI to be calculated. The data from the non-destructive gas flow tests and the destructive gas flow tests can be analyzed to generate a correlation between the two test types (box620), the correlation being between a pressure gradient, forced gas flow test and an actual drug release test, which is dependent upon passive diffusion through the porous structure. The correlation can be generated using more than one pair of test results. The correlation generated can be used to predict a measured diffusion rate of the molecule through a porous structure having the same specified characteristics based on a test result of the porous structure during a non-destructive gas flow test (box625). The correspondence of the flow rate with a gas to the release rate of a therapeutic agent is thus determined empirically. Thus, the porous structure150can be subjected only to a non-destructive test and a prediction made as to the result that would be achieved by performing a destructive test so as to quantify diffusion of drug through the porous structure. When the porous structure150is coated as described herein or is combined with a barrier layer such as a discrete filter membrane positioned adjacent the porous structure150the predictions with regard to diffusion of drug through the porous structure based on the non-destructive test result remain accurate.

The effects of the barrier layer on drug diffusion, whether the barrier layer is a coating or a discrete filter membrane positioned in series with the porous structure, can be minimal. Thus, the method of manufacturing described above can be applicable whether the barrier layer is used or not.

The therapeutic devices described herein can be implanted for as long as is helpful and beneficial to the patient. For example the device can be implanted for at least about 1 year, 2 years, 3 years, 4 year, 5 years and up to permanently for the life of the patient. Alternatively or in combination, the device can be removed when no longer helpful or beneficial for treatment of the patient. In other implementations, the device can be implanted for at least about 4 ears to 10 years, for example a duration of treatment period for a chronic disease such as diabetic macular edema or age-related macular degeneration. The device can be periodically refilled in the physician's office with new therapeutic agent as indicated by disease progression. For diseases such as age-related macular degeneration, the device can be refilled as frequently as once every week, bi-weekly, monthly, bi-monthly, every 3 months, every 4 to 6 months, every 3 to 9 months, every 12 months, or any other period as indicated to treat a disease.

It should be appreciated that a variety of diseases and/or conditions can be treated with the devices and systems described herein, for example: glaucoma, macular degeneration, retinal disease, proliferative vitreoretinopathy, diabetic retinopathy, uveitis, keratitis, cytomegalovirus retinitis, cystoid macular edema, herpes simplex viral and adenoviral infections and other eye diseases, eye infections (including, but not limited to, infections of the skin, eyelids, conjunctivae, and/or lacrimal excretory system), orbital cellulitis, dacryoadenitis, hordeolum, blepharitis, conjunctivitis, keratitis, corneal infiltrates, ulcers, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis herpes zoster ophthalmicus, viral conjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis, retinal disease, vitreoretinopathy, diabetic retinopathy, cytomegalovirus retinitis, cystoids macular edema, herpes simplex viral and adenoviral injections, scleritis, mucormycosis, canaliculitis, acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmanisis, malaria, helminth infection, etc. It also should be appreciated that medical conditions besides ocular conditions can be treated with the devices and systems described herein. For example, the devices can deliver drugs for the treatment of inflammation, infection, cancerous growth. It should also be appreciated that any number of drug combinations can be delivered using any of the devices and systems described herein.

The devices described herein can be used to deliver agent or ants that ameliorate the symptoms of a disease or disorder or ameliorate the disease or disorder including, for example, small molecule drugs, proteins, nucleic acids, polysaccharides, biologics, conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art. Examples of therapeutic agents suitable for use in accordance with embodiments of the therapeutic devices described herein are listed throughout as well as in Table 1.

Therapeutic agents include, but are not limited to, moieties that inhibit cell growth or promote cell death, that can be activated to inhibit cell growth or promote cell death, or that activate another agent to inhibit cell growth or promote cell death. Optionally, the therapeutic agent can exhibit or manifest additional properties, such as, properties that permit its use as an imaging agent, as described elsewhere herein. Exemplary therapeutic agents include, for example, cytokines, growth factors, proteins, peptides or peptidomimetics, bioactive agents, photosensitizing agents, radionuclides, toxins, anti-metabolites, signaling modulators, anti-cancer antibiotics, anti-cancer antibodies, angiogenesis inhibitors, radiation therapy, chemotherapeutic compounds or a combination thereof The drug may be any agent capable of providing a therapeutic benefit. In an embodiment, the drug is a known drug, or drug combination, effective for treating diseases and disorders of the eye. In non-limiting, exemplary embodiments, the drug is an antiinfective agent (e.g., an antibiotic or antifungal agent), an anesthetic agent, an anti-VEGF agent, an anti-inflammatory agent, a biological agent (such as RNA), an intraocular pressure reducing agent (i.e., a glaucoma drug), or a combination thereof Non-limiting examples of drugs are provided below.

The therapeutic agent can include a macromolecule, for example an antibody or antibody fragment. The therapeutic macromolecule can include a VEGF inhibitor, for example commercially available Lucentis™. The VEGF (Vascular Endothelial Growth Factor) inhibitor can cause regression of the abnormal blood vessels and improvement of vision when released into the vitreous humor of the eye. Examples of VEGF inhibitors include Lucentis™ Avastin™, Macugen™, and VEGF Trap. The therapeutic agent can include small molecules such as of a corticosteroid and analogues thereof. For example, the therapeutic corticosteroid can include one or more of trimacinalone, trimacinalone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, or analogues thereof. Alternatively or in combination, the small molecules of therapeutic agent can include a tyrosine kinase inhibitor comprising one or more of axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, or vatalanib, for example. The therapeutic agent can include an anti-VEGF therapeutic agent. Anti-VEGF therapies and agents can be used in the treatment of certain cancers and in age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in accordance with the embodiments described herein include one or more of monoclonal antibodies such as bevacizumab (Avastin™) or antibody derivatives such as ranibizumab (Lucentis™), or small molecules that inhibit the tyrosine kinases stimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™), sorafenib (Nexavar™), axitinib, or pazopanib. The therapeutic agent can include a therapeutic agent suitable for treatment of dry AMD such as one or more of Sirolimus™ (Rapamycin), Copaxone™ (Glatiramer Acetate), Othera™, Complement C5aR blocker, Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis. The therapeutic agent can include a therapeutic agent suitable for treatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™ (Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor (POT-4), complement factor D inhibitors. The therapeutic agent can include a kinase inhibitor such as one or more of bevacizumab (monoclonal antibody), BIBW 2992 (small molecule targeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (small molecule), trastuzumab (monoclonal antibody), gefitinib (small molecule), ranibizumab (monoclonal antibody), pegaptanib (small molecule), soratenib (small molecule), dasatinib (small molecule), sunitinib (small molecule), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), panitumumab (monoclonal antibody), vandetanib (small molecule) or E7080 (targeting VEGFR2/NEGFR2, small molecule commercially available from Esai, Co.).

The therapeutic agent can include inhibitors of VEGF receptor kinase; inhibitors of VEGFA, VEGFC, VEGFD, bFGF, PDGF, VEGF/PDGF, VEGFA/Ang2, Ang-2, PDGFR, cKIT, FGF, BDGF, BDGFNEGF/FGF, mTOR, αvβ3, αvβ5, α5β1 integrins, αvβ3/αvβ5/α5β1 integrins, alpha2 adrenergic receptor; inhibitors of complement factor B (e.g. TA106), inhibitors of complement factor D (CFD) (Lampalizumab/TNX-234), inhibitors of C3 (e.g. APL-2, novel compstatin analogs), inhibitors of C5 (e.g. Eculizumab, Zimura, ARC1905, ALN-CC5), inhibitors of C5a (e.g. JPE-1375), and related targets; tubulin; AAV-CD56. The therapeutic agent can also include Complement Factor II (CFII), engineered inini-CFH, or recombinant CFH (rCFH).

A variety of therapeutic agents can be delivered using the drug delivery implants described herein, including: anesthetics, analgesics, cell transport/mobility impending agents such as colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma drugs including beta-blockers such as timolol, betaxolol, atenolol, and prostaglandins, lipid-receptor agonists or prostaglandin analogues such as bimatoprost, travoprost, latanoprost, unoprostone etc; alpha-adrenergic agonists, brimonidine or dipivefrine, carbonic anhydrase inhibitors such as acetazolamide, methazolamide, dichlorphenamide, diamox; and neuroprotectants such as nimodipine and related compounds.

Additional examples include targets affecting angiopoietin and angiopoietin receptors that bind angiopoietin including, but not limited to TIE-1, TIE-2, Ang1, Ang2, Ang3, Ang4, including but not limited to pazopanib (Votrient) or any other therapeutic described in US Publication No. 2014/0276482 and PCT Application Ser. No. PCT/US2015/043921, which are each incorporated by reference herein.

Additional examples include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antibacterials such as sulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole; anti-fungal agents such as fluconazole, nitrofurazone, amphotericin B, ketoconazole, and related compounds; anti-viral agents such as trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscamet, vidarabine, trifluorouridine, idoxuridine, ribavirin, protease inhibitors and anti-cytomegalovirus agents; antiallergenics such as methapyriline; chlorpheniramine, pyrilamine and prophenpyridamine; anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and triamcinolone; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics, muscarinics and anti-cholinesterases such as pilocarpine, carbachol, di-isopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine; sympathomimetics such as epinephrine and vasoconstrictors and vasodilators; Ranibizumab, Bevacizamab, and Triamcinolone.

Antiinflammatories, such as non-steroidal anti-inflammatories (NSAIDs) may also be delivered, such as cyclooxygenase-1 (COX-1) inhibitors (e.g., acetylsalicylic acid, for example ASPIRIN from Bayer AG, Leverkusen, Germany; ibuprofen, for example ADVIL from Wyeth, Collegeville, Pa.; indomethacin; mefenamic acid), COX-2 inhibitors (CELEBREX from Pharmacia Corp., Peapack, N.J.; COX-1 inhibitors), including a prodrug NEPAFENAC; immunosuppressive agents, for example Sirolimus (RAPAMUNE, from Wyeth, Collegeville, Pa.), or matrix metalloproteinase (MMP) inhibitors (e.g., tetracycline and tetracycline derivatives) that act early within the pathways of an inflammatory response. Anticlotting agents such as heparin, antifibrinogen, fibrinolysin, anti clotting activase, etc., can also be delivered.

Antidiabetic agents that may be delivered using the disclosed implants include acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, insulin, aldose reductase inhibitors, etc. Some examples of anti-cancer agents include 5-fluorouracil, adriamycin, asparaginase, azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine, etoposide, etretinate, filgrastin, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, goserelin, hydroxyurea, ifosfamide, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin, mitotanc, pentostatin, pipobroman, plicamycin, procarbazine, sargramostin, streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard, vinblastine, vincristine and vindesine.

Hormones, peptides, steroids, nucleic acids, saccharides, lipids, glycolipids, glycoproteins, and other macromolecules can be delivered using the present implants. Examples include: endocrine hormones such as pituitary, insulin, insulin-related growth factor, thyroid, growth hormones; heat shock proteins; immunological response modifiers such as muramyl dipeptide, cyclosporins, interferons (including α, β, and γ interferons), interleukin-2, cytokines, FK506 (an epoxy-pyrido-oxaazcyclotricosine-tetrone, also known as Tacrolimus), tumor necrosis factor, pentostatin, thymopontin, transforming factor bcta2, crythopoetin, antineogenesis proteins (e.g., anti-VEGF, Interferons), among others and anticlotting agents including anticlotting activase. Further examples of macromolecules that can be delivered include monoclonal antibodies, brain nerve growth factor (BNGF), ciliary nerve growth factor (CNGF), vascular endothelial growth factor (VEGF), and monoclonal antibodies directed against such growth factors. Additional examples of immunomodulators include tumor necrosis factor inhibitors such as thalidomide.

In addition, nucleic acids can also be delivered wherein the nucleic acid may be expressed to produce a protein that may have a variety of pharmacological, physiological or immunological activities. Thus, the above list of drugs is not meant to be exhaustive. A wide variety of drugs or agents may be used with the devices described herein, without restriction on molecular weight, etc.

Other agents include anti-coagulant, an anti-proliferative, imidazole antiproliferative agent, a quinoxaline, a phsophonylmethoxyalkyl nucleotide analog, a potassium channel blocker, and/or a synthetic oligonucleotide, 5-[1-hydroxy-2-[2-(2-methoxyphenoxyl) ethylamino]ethyl]-2-methylbenzenesulfonamide, a guanylate cyclase inhibitor, such as methylene blue, butylated hydroxyanisole, and/or N-methylhydroxylamine, 2-(4-methylaminobutoxy) diphenylmethane, apraclonidine, a cloprostenol analog or a fluprostenol analog, a cross linked carboxy-containing polymer, a sugar, and water, a non-corneotoxic serine-threonine kinase inhibitor, a nonsteroidal glucocorticoid antagonist, miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase inhibitors), sympathomimetics (e.g., epinephrine and dipivalylepinephxine), beta-blockers (e.g., betaxolol, levobunolol and timolol), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), and prostaglandins (e.g., metabolite derivatives of arachidonic acid, or any combination thereof.

Additional examples of beneficial drugs that may be employed and the specific conditions to be treated or prevented are disclosed in Remington, supra; The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 19th edition, published by the MacMillan Company, London; and The Merck Index, 13th Edition, 1998, published by Merck & Co., Rahway, N.J., which is incorporated herein by reference.

EXAMPLES

Example 1

Gas Flow Test of Porous Structures With and Without a Barrier Layer

As described above, the RRI parameter is a conjunction of the parameters of the porous element that affect molecular diffusion rates per Fick's Law of Molecular Diffusion. Specifically, RRI=PA/TL where: P=porosity, A=Surface area, T=Tortuosity, L=Length. The addition of a barrier layer having decreased porosity and providing additional thickness to the porous structure was expected to cause a decrease in the release rate and/or affect the correlation between the gas flow test and the diffusion test.

The porous structures tested varied. In some tests, the porous structure were316L stainless steel sintered substrates (Mott corporation) and the barrier layer was a coating on the porous structure. The substrates were coated by a particle coating and compared to uncoated controls from the same lot. The substrates were 0.2 Media Grade according the measurements of bubble point. The particle coating included a mass of predominantly stainless steel particles formed as described in U.S. 2012/0183799, which is incorporated by reference herein. The particles were nano-particles. The pore size of the coating was <0.2 um in order to provide anti-bacterial protection and considerably smaller than the pore size of the “naive” uncoated substrates.

In other tests, the porous structure included titanium sintered release control elements (RCEs) (Acree Technologies, Inc., Concord, Calif.) and the barrier layer was a coating on the porous structure. The RCEs were coated by a particle coating and compared to uncoated controls from the same lot. The particle coating was performed by Plasma Enhanced Chemical Vapor Deposition (PECVD), using Cathodic Arc, Magnetron Sputtering, and HiPIMS technologies as is known in the art. The particles were nano-particles. The pore size of the coating was <0.2 um in order to provide anti-bacterial protection and considerably smaller than the pore size of the “naïve” uncoated RCEs. The target coating was between about 10um to about 40 um.

In still further tests, the barrier layer was a discrete filter membrane positioned adjacent a surface of the sintered substrate. The membrane was a 0.2 uM PES filter.

The gas flow tests were performed and combined with RRI so as to determine the release profile of the substrates. Each test was performed on the porous substrate with the barrier layer prior to mounting it on a therapeutic device. The porous substrate with the barrier layer test specimen were mechanically connected to the test hardware. A controllable source of a working fluid such as nitrogen or air was coupled to the test hardware to deliver the working fluid. A manometer or other pressure measurement device as well as one or more transducers was used to measure pressure, flow, etc. within the test system. The source pressure was constantly regulated to a known pressure and the flow of the working fluid allowed to flow through a mass flow meter and then through the fixture porous substrate test specimen. The specific characteristics of the porous substrate specimen determined the rate at which the working fluid flowed through the system. Pressure at the open end of the fixture test specimen was regulated to control the backpressure and therefore the pressure drop across the specimen. A regulated compressed cylinder supplied the test system with a constant source pressure of 30 psig and a constant back pressure of 1 psig. The test fluid flowed through the test specimen at a characteristic rate dependent on the pressure as measured by the mass flow meter. Generally the range was between 10-100 standard cubic centimeters per minute (sccm). The gas flow test was relatively instantaneous in nature. Flow through a test specimen stabilized quickly allowing for a large number of samples to be performed in a rapid fashion.

The results of the gas flow tests were analyzed showing gas flow (sccm) as a function of RRI (mm). The release rate index of the porous structures with the barrier layer were compared to the uncoated control RCEs. Similarly, the gas flow performance of the porous structures with the barrier layer were compared to the controls having no barrier layer.

Example2

Drug Diffusion Through Porous Structures With and Without a Barrier Layer

The porous structures were used to construct therapeutic devices or device prototypes suitable for characterization of drug release behavior by measuring drug diffusion as described herein. To construct the device prototypes, the reservoirs were fabricated from syringes and porous structures, which can be the same porous structures used in the gas flow tests described above. The porous structures (referred to as RCEs) were press-fit into sleeves machined from Delrin. The sleeves were exposed on one entire planar face to the solution in the reservoir and the other entire planar face to the receiver solution in the vials. The tips were cut off of 1 mL polypropylene syringes and machined to accept a polymer sleeve with an outer diameter slightly larger than the inner diameter of the syringe. The porous RCE/sleeve was press-fit into the modified syringe. In some tests, the barrier layer was a 0.2 uM PES filter membrane mounted above the porous structure,

A solution was prepared containing 300 mg/mL BSA (Sigma, A2153-00G) in PBS (Sigma, P3813). Solution was introduced into the therapeutic device, or if syringe prototypes were used into the syringes by removing the piston and dispensing approximately 200 ul into the syringe barrel. Bubbles were tapped to the top and air was expressed out through the RCE. The BSA solution was expressed through the RCE until the syringe held 100 uL as indicated by the markings on the syringe. The expressed BSA solution was wiped off and then rinsed by submerging in PBS. The reservoirs were then placed into 4 mL vials containing 2 mL PBS at room temperature. Collars cut from silicone tubing were placed around the syringe barrels to position the top of the reservoir to match the height of PBS. The silicone tubing fit inside the vials and also served as a stopper to avoid evaporation. At periodic intervals, the reservoirs were moved to new vials containing PBS. The amount of BSA transported from the reservoir through the RCE was determined by measuring the amount of BSA in the vials using a BCA™ Protein Assay kit (Pierce, 23227).

The cumulative amount released into the vials were measured over time. The percent of cumulative release of BSA through the RCEs were measured at 1 week, 2 weeks, 3 weeks, 4 weeks and beyond. The percent cumulative release of the RCEs with a barrier layer were compared to the controls having no barrier layer to assess whether there was an impact on drug release. Gas flow and pressure decay tests were used to identify specified characteristics of the RCEs that may be correlated to other test results such as chemical or pharmacologic performance.

Example3

Microbial Retention Testing

Porous structures with a barrier layer were tested for their ability to remove microbes from a liquid or gas medium and compared to porous structures having no barrier layer. Generally, to remove microbes such as bacterial cells from a liquid or gas medium a pore size of approximately 0.2 microns or less is needed. Porous structures prepared as described above were tested for their effectiveness to remove bacteria by using Microbial Retention ASTM F838-05 or equivalent. For microbial retention testing per ASTM F838-05, all equipment was sterilized/disinfected prior to use. All testing was conducted in a laminar flow hood. Each porous structure, including those having a barrier coating and those not having a barrier coating, were prepared by filtering a minimum of 100 mL of sterile buffer through it as a control. One hundred milliliters of filtrate was aseptically collected downstream of the controls in a sterile container. The filtrate was filtered using microbial retentive filters. The microbial retentive filters were placed onto Plate Count Agar and allowed to incubate at 30±2° C. for 7 days. A 48 hour pre-count was performed on each filter. It should be appreciated that other microbial retention tests are contemplated herein. For example, microbial retention can be tested in a way that does not involve forced flow through the container. For example, tests can be performed to assess effectiveness of a container to inhibit bacterial infiltration upon immersion similar to the diffusion test set-up.

After the controls were processed, each porous structure were challenged with approximately 3×107to 5×107CFU/100 mL ofB. diminuta.One hundred milliliters of filtrate were aseptically collected downstream of the porous structures in a sterile container. The filtrate was filtered using a microbial retentive filter. The microbial retentive filter was placed onto Plate Count Agar and allowed to incubate at 30±2° C. for 7 days. A 48 hour pre-count was performed on each filter. Analyzing the colony forming units (CFU)/100 mL provides information regarding which porous structures inhibited bacterial infiltration (pass) and which allowed for bacteria to make its way through the porous structure (fail).

Example4

Mitigation of Bolus Release Through Porous Structures With and Without a Barrier Layer

During initial filling or refilling of a reservoir chamber of a fixed volume therapeutic device there can occur a transient increase in pressure within the reservoir chamber. This increase in pressure within the reservoir chamber can create a pressure gradient across the porous structure that can cause the reservoir solution being delivered to be expressed through the porous structure into the surrounding tissues. The porosity of the porous structure, among other factors (e.g. delivery rate), can affect the magnitude of bolus expressed. Generally, a higher porosity porous structure has a lower pressure drop and a higher bolus is released upon filling.

A subjective assessment of the impact of the barrier layer on bolus release through the porous structures was conducted. A therapeutic device having a coated RCE and a therapeutic device having an uncoated RCE as described in the examples above were connected to a bifurcated line attached to a single pressure source to simulate filling of the reservoir chamber of the device.FIG.5is a still frame capture of a video recording of the filling of the coated RCE (top device) compared to the uncoated control (lower device). The coated RCE significantly inhibited bolus release of fluid through the RCE upon application of a pressure gradient compared to the uncoated control. RCE in combination with a discrete porous structure, such as a PES filter membrane (Sterlitech Corp., Kent, Wash.), also significantly inhibited bolus release of fluid through the RCE upon application of a pressure gradient. Bolus release of therapeutic fluid is associated with an “active” application of a pressure gradient whereas drug release is associated with “passive” concentration gradient driving force. The porous barrier layer having minimal thickness (or length L) has a decreased porosity compared to the porous structure such that drug release via diffusion is negligibly affected but fluid flow via a pressure gradient is more substantially impacted. Thus, the less porous, dense extra layer inhibits the release of a bolus during filling by forming a pressure barrier.

While this specification contains many specifics, these should not be construed as limitations on the scope of what is claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. Only a few examples and implementations are disclosed. Variations, modifications and enhancements to the described examples and implementations and other implementations may be made based on what is disclosed.

In the descriptions above and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of elements or features. The term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one of A and B;” “one or more of A and B;” and “A and/or B” are each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” arc each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.”

Use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible.

TABLE 1Therapeutic Agent ListMolecularGeneric NameBrands (Companies)CategoryIndicationWeight2-Methoxyestradiol(Paloma Pharmaceuticals)Angiogenesis inhibitorsAMDanalogs3-aminothalidomide13-cis retinoic acidAccutane TM (RochePharmaceuticals)A0003(Aqumen BioPharmaceuticals)A0003AMDA5b1 integrin inhibitor(Jerin Ophthalmic); (Ophthotech)nhibitors of a5b1 integrinAMDAbarelixPlenaxis ™ (PraecsAnti-Testosterone Agents;For palliative treatment of advanced37731Pharmaceuticals)Antineoplastic Agentsprostate cancer.AbataceptOrencia ™ (Bristol-Myers Squibb)Antirheumatic AgentsFor the second line reduction of the37697signs and symptoms of moderate-to-severe active rheumatoid arthritis,inducing inducing major clinicalresponse, slowing the progression ofstructural damage, and improvingphysical function in adult patients whohaveAbciximabReoPro ™; ReoPrc ™ (Centocor)Anticoagulants; AntiplateletFor treatment of myocardial42632Agentsinfarction. adjunct to percutaneous1oronary intervention, unstableanginaABT-578(Abbot Laboratories)Limus ImmunophilinBinding CompoundsAcetonideAdalimumabHumira ™ (Abbott Laboratories)Antirheumatic Agents;Uveitis, AMD25645Immunomodulatory AgentsAldesleukinProleukin ™, Proleukin ™ (ChironAntineoplastic AgentsFor treatment of adults with61118Corp)metastatic renal cell carcinomaAlefaceptAmevive ™ImmunomodulatoryFor treatment of moderate to severe42632Agents;chronic plaque psoriasisImmunosuppressiveAgentsAlemtuzumabCampath ™; Campath ™ (ILEXAntineoplastic AgentsFor treatment of B-cell chronic6614Pharmaceuticals LP);lymphocytic leukemiaMabCampath ™Alpha-1-proteinaseAralast ™ (Baxter); Prolastin ™Enzyme ReplacementFor treatment of panacinar28518inhibitor(Talecris Biotherapeutics C formerlyAgentsemphysemaBayer)AlteplaseActivase ™ (Gener tech Inc)Thrombolytic AgentsFor management of acute myocardial54732infarction acute ischemic strok andfor lysis of acute pulmonary emboliAMG-1470AnakinraKineret ™ (Amgen nc)Anti-Inflammatory Agents,For the treatment of adult rheumatoid65403Non-Steroidal;arthritis.Antirheumatic Agents;Immunomodulatory AgentsAnecortave acetateAngiostatinAnistreplaseEminase ™ (Wulfing Pharma GmbH)Thrombolytic AgentsFor lysis of acute pulmonary emboli,54732intracororary emboli andmanagement of myocardial infarctionAnti-angiogenesis(Eyecopharm)Anti-angiogenesis peptidesAMDpeptidesAnti-angiogenesis(TRACON Pharma)Anti-angiogenesisAMDantibodies, TRC093,antibodiesTRC105Anti-angiogericIcon-1 ™ (Iconic Therapeutics)Anti-angiogeric bifunctionalAMDbifunctional proteinprotein, Icon-1Anti-endothelialgrowth factorAntihemophilic FactorAdvate ™; Alphanate ™; Bioclate ™;Coagulants; ThromboticFor the treatment of hemophilia A,70037Helixate ™; Helixate FS ™; HemofilAgentsvon Willebrand diseae and Factor XIIIM ™; Humate-P ™; Hyate:C ™;deficiencyKoate-HP ™; Kogenate ™; KogenateFS ™; Monarc-M ™; Monoclate-P ™;ReFacto ™; Xyntha ™AntithymocyteGenzyme); Thymoglobulin ™Immunomodulatory AgentsFor prevention of renal transplant37173globulin(SangStat MedicalrejectionAnti-hypertensive(MacuCLEAR)Anti-hypertensive MC1101AMDMC1101Anti-platelet deviredgrowth factorAnti-VEGF(Neurotech); Avasin ™ (NeoVista)Anti-VEGFAMDAP23841(Ariad)Limus ImmunophilinBinding CompoundsARC1905OphthotechComplement CascadeInhibitor (Factor C5)AprotininTrasylol ™Antifibrinolytic AgentsFor prophylactic use to reduce90569perioperative blood loss and the needfor blood transfusion in patientsundergoing cardiopulmonary bypassin the course of coronary arterybypass graft surgery who are at anincreased risk for blood loss andblood transfusioArcitumomabCEA-Scan ™Diagnostic Agents; ImagingFor imaging colorectal tumors57561AgentsAsparaginaseElspar ™ (Merck & Co. Inc)Antineoplastic AgentsFor treatment of acute lympocytic132.118leukemia and non-HodgkinslymphomaAxitinibTyrosine Kinase Inhibitors386BasiliximabSimulec ™ (NovarisImmunomodulatoryFor prophylactic treatment of kidney61118Pharmaceuticals)Agents;transplant rejectionImmunosuppressiveAgentsBecaplerminRegranex ™, Regranex ™ (OMJAnti-Ulcer Agents; TopicalFor topical treatment of skin ulcers123969Pharmaceuticals)(from diabetes)BevacizumabAvastin ™, Avastin ™ (GenentechAntiangiogenesis Agents;For treatment of metastatic colorectal27043Inc)Antineoplastic AgentscancerBivalirudinAngiomax ™; Angiomax ™Anticoagulants;For treatment of heparin-induced70037(Medicines Co or MDCO); Angiox ™Antithrombotic AgentsthrombocytopeniaBortezomibProteosome InhibitorsBosutinibTyrosine Kinase Inhibitors530Botulinum Toxin TypeBOTCX ™ (Allegran Inc); BOTOXAnti-Wrinkle Agents;For the treatment of cervical dystonia23315ACosmetic ™ (Allegran Inc); Botox ™;Antidystonic Agents;in adults to decrease the severity ofDysport ™Neuromuscular Blockingabnormal head position and neckAgentspain associated with cervicaldystonia. Also for the treatment ofsevere primary axillary hyperhidrosisthat is inadequately managed withtopicalBotulinum Toxin TypeMyobloc ™ (Solstice Neurosciences);Antidystonic AgentsFor the treatment of patients with12902BNeurobloc ™ (Solsticecervical cystonia to reduce theNeuro sciences)severity of abnormal head positionand neck, pain associated withcervical cystonia.C5 inhibitor(Jerini Ophthalmic; (Ophthotech)Inhibitors of C5AMDCal101CalistgaPI3Kdelta InhibitorAMD, DMECanstatinCapromabProstaScint ™ (Cytogen Corp)Imaging AgentsFor diagnosis of prostate cancer and84331detection of intra-pelvic metastasesCaptoprilACE InhibitorsCCI-779(Wyeth)Limus ImmunophilinBinding CompoundsCediranibTyrosine Kinase Inhibitors450CelecoxibCyclooxygenase InhibitorsCetrorelixCetrotide ™Hormone Antagonists;For the inhibition of premature LH78617Infertility Agentssurges in women undergoingcontrolled ovarian stimulationCetuximabErbitux ™, Erbitux ™ (ImCloneAntineoplastic AgentsFor treatment of metastatic colorectal42632Systems Inc)cancer.ChoriogonadotropinNovarel ™; Ovidrel ™; Pregnyl ™,Fertility Agents;For the treatment of female infertility78617alfaProfasi ™GonadotropinsCilary neurotrophic(Neurotech)Cilary neurotrophic factorAMDfactorCoagulation Factor IXBenefix ™ (Genetics Institute)Coagulants; ThromboticFor treatment of hemophilia267012Agents(Christmas disease).Coagulation factorNovoSeven ™ (Noro Nordisk)Coagulants; ThromboticFor treatment of hemorrhagic54732VIIaAgentscomplications in hemophilia A and BColchicinesCollagenaseCordase ™; Santyl ™ (AdvanceAnti-Ulcer Agents; TopicalFor treatment of chronic dermal138885Biofactures Corp); Xiaflextm ™ulcers and severe skin burnsComplement factor H(Optherion); (Taligen Therapeutics)Complement factor HAMD, Geographic AtrophyrecombinantrecombinantCompstatin derivative(Potentia Pharmaceuticals)Complement Factor C3AMDpeptide, POT-4Inhibitors; CompstatinDerivative PeptidesCorticotropinACTH ™; Acethropan ™, Acortan ™;Diagnostic AgentsFor use as a diagnostic agent in the33927Actha- ™; Exacthir ™; H.P. Actharscreening of patients presumed toGel ™: Isactid ™: Purified cortrophinhave adrenocortical insufficiency.gel ™; Reacthin ™; Solacthyl ™;TubexCosyntropinCortrcsyn ™; Synacthen depot ™Diagnostic AgentsFor use as a diagnostic agent in the33927screening of patients presumed tohave adrenocortical insufficiency.CyclophilinsLimus ImmunophilinBinding CompoundsCyclosporineGengraf ™ (Abbott labs); Neoral ™Antifungal Agents;For treatment of transplant rejection,32953(Novartis); Restass ™; Restasis ™Antirheumatic Agents;rheumatoid arthritis, severe psoriasis(Allergan Inc); Sandimmune ™Dermatologic Agents;(Novartis); Sangoya ™Enzyme Inhibitors;ImmunomodulatoryAgents;ImmunosuppressiveAgentsDaclizumabZenapax ™ (Hoffmann-La RocheImmunomodulatoryFor prevention of renal transplant61118Inc)Agents;rejection UveitisImmunosuppressiveAgentsDarbepoetin alfaAranesp ™ (Amgen Inc.)Antianemic AgentsFor the treatment of anemia (from55066renal transplants or certain HIVtreatment)DasatinibTyrosine Kinase Inhibitors488DefibrotideDasovas ™, Noravid ™, Prociclide ™Antithrombotic AgentsDefibrotide is used to treat or prevent36512a failure of normal blood flow(occlusive venous disease, OVD) inthe liver of patients who have hadbone marrow transplants or receivedcertain drugs such as oral estrogens,mercaptopurine, and many others.Denileukin diftitoxOntak ™Antineoplastic AgentsFor treatment of cutaneous T-cell61118lymphomaDesmopressinAdiuretin ™; Concentraid ™;Antidiuretic Agents;For the management of primary46800Stimate ™Hemostatics; Renal Agentsnocturnal enuresis and indicated asantidiuretic replacement therapy inthe management of central diabetesinsipidus and for the management ofthe temporary polyuria and polydipsiafollowing head trauma or surgery inthe pituDexamethasoneOzurdex ™ (Allergan)GlucocorticoidDME, inflmmation, macular edema392following branch retinal vein occlusion(BRVO) or central retinal veinocclusion (CRVO)DiclofenacCyclooxygenase InhibitorsDithiocarbamateNFκB InhibitorDornase AlfaDilor ™; Dilor-400 ™; Lufyllin ™,Enzyme ReplacementFor the treatment of cystic fibrosis.7656Lufyllin-400 ™; Neothylline ™,Agents(doublePulmozyme ™ (Genentech Inc)strand)Drotrecogin alfaXigris ™; Xigris ™, Eli Lilly & Co)Antisepsis AgentsFor treatment of severe sepsis267012EculizumabSoliris ™, Soliris ™ (AlexionComplement CascadeAMD188333Pharmaceuticals)Inhibitor (Factor C5)EfalizumabRaptiva ™; Raptiva ™ (GenentechimmunomodulatoryFor the treatment of adult patients128771Inc)Agents;with moderate to severe chronicimmunosuppressiveplaque psoriasis, who are candidatesAgentsfor phototherapy or systemic therapy.EndostatinEnfuvirtideFuzeon ™; Fuzeon ™ (RocheAnti-HIV Agents; HIVFor treatment of HIV AIDS16768Pharmaceuticals)Fusion InhibitorsEpoetin alfaEpogen ™ (Amgen Inc.); Epogin ™Antianemic AgentsFor treatment of anemia (from renal55066(Chugai); Epcmax ™ (Elanex);transplants or certain HIV treatment)Eprex ™ (Janssen-Cilag. OrthoBiologies LLC); NeoRecormon ™(Roche); Procrit ™ (Ortho Biotech);Recormon ™ (Roche)EptifibatideIntegrilin ™; Integrilin ™ (MillenniumAnticoagulants; AntiplateletFor treatment of myocardial infarction7128Pharm)Agents; Plateletand acute coronary syndrome.Aggregation InhibitorsErlotinibTyrosine Kinase Inhibitors393EtanerceptEnbrel ™; Enbrel ™ (Immunex Corp)Antirheumatic Agents;Uveitis, AMD25645Immunomodulatory AgentsEverolimusNovartisLimus ImmunophilinAMDEinding Compounds,mTORExenatideByetta ™, Byetta ™ (Amylin/Eli Lilly)Indicated as adjunctive therapy to53060improve glycemic control in patientswith Type 2 diabetes mellitus who aretaking metformin, a sulfonylurea, or acombination of both, but have notachieved adequate glycemic control.FCFD4514SGenentech/RocheComplement CascadeAMD, Geographic AtrophyInhibitor (Factor D)FelypressinFelipresina ™ [INN-Spanish];Renal Agents;For use as an alternative to46800Felipressina ™ [DCIT]; Felypressin ™Vasoconstrictor Agentsadrenaline as a 10ocalizing agent,[USAN:BAN:INN]; Felypressine ™provided that local ischaemia is not[INN-French]; Felypressinum ™essential.[INN-Latin]; Octapressin ™FenretinideSirion/reVision TherapeuticsBinding Protein AntagonistAMD, Geographic Atrophyfor Oral Vitamin AFilgrastimNeupogen ™ (Amgen Inc.)Anti-Infective Agents;Increases leukocyte production, for28518Antineutropenic Agents;treatmen: in non-myeloidImmunomodulatory Agentscancer,neutropenia and bone marrowtransplantFK605-bindingLimus Immunophilinproteins, FKBPsBinding CompoundsFluocinoloneRetisert ™ (Bausch & Lomb);GlucocorticoidRetinal inflammation, diabetic453AcetonideIluvien ™ (Alimera Sciences, Inc.)macular edemaFollitropin betaFollistim ™ (Organon); Gonal F ™;Fertility AgentsFor treatment of female infertility78296Gonal-F ™FumagillinGalsulfaseNaglazyme ™; Naglazyme ™Enzyme ReplacementFor the treatment of adults and47047(BioMarin Pharmaceuticals)Agentschildren with MucopolysaccharidosisVI.GefitinibTyrosine Kinase Inhibitors447GemtuzumabMylotarg ™, Mylotarg ™ (Wyeth)Antineoplastic AgentsFor treatment of acute myeloid39826ozogamicinleukemiaGlatiramer AcetateCopaxone ™Adjuvants, Immunologic;For reduction of the frequency of29914Immunosuppressiverelapses in patients with Relapsing-AgentsRemitting Multiple Sclerosis.GlucagonGlucaGen ™ (Novo Nordisk);Antihypoglycemic AgentsFor treatment of severe54009recombinantGlucagon ™ (Eli Lilly)hypoglycemia, also used ingastrointestinal imagingGoserelinZoladex ™Antineoplastic Agents;Breast cancer; Prostate carcinoma;78617Antineoplastic Agents,EndometriosisHormonalHuman SerumAlbutein ™ (Alpha Therapeutic Corp)Serum substitutesFor treatment of severe blood loss,39000Albuminhypervolemia, hypoproteinemiaHyaluronidaseVitragan ™; Vitrase ™; Vitrase ™ (IstaAnesthetic Adjuvants;For increase of absorption and69367Pharma)Permeabilizing Agentsdistribution of other injected drugsand for rehydrationIbritumomabZevalin ™ (IDEC Pharmaceuticals)Antineoplastic AgentsFor treatment of non-Hodgkin’s33078lymphomaIdursulfaseBlaprase ™ (Shire Pharmaceuticals)Enzyme ReplacementFor the treatment of Hunter syndrome47047Agentsin adults and children ages 5 andolder.ImatinibTyrosine Kinase InhibitorsAMD, DME494Immune globulinCivacir ™; Flebogamma ™ (InstituteAnti-Infectives;For treatment of immunodeficiencies,42632Grifols SA); Gamunex ™ (TalecrisImmunomodulatory Agentsthrombocytopenic purpura, KawasakiBiotherapeutics)disease, gammablobulinemia,leukemia, bone transplantInfliximabRemicade ™ (Cenocor Inc)ImmunomodulatoryUveitis, AMD25645Agents;ImmunosuppressiveAgentsInsulin GlargineLantus ™Hypoglycemic AgentsFor treatment of diabetes (type I and156308recombinantII)Insulin LysproHumalog ™ (Eli Lil); Insulin LisproHypoglycemic AgentsFor treatment of diabetes (type I and154795recombinant(Eli Lily)II)Insulin recombinantNovolin R ™ (Nove Nordisk)Hypoglycemic AgentsFor treatment of diabetes (type I and156308II)Insulin, porcineIletin II ™Hypoglycemic AgentsFor the treatment of diabetes (type I156308and II)InterferonInterferon Alfa-2a,Roferon A ™ (Hoffmann-La RocheAntineoplastic Agents;For treatment of chronic hepatitis C,57759RecombinantInc); Veldona ™ (AmarilloAntiviral Agentshairy cell leukemia, AIDS-relatedBiosciences)Kaposi’s sarcoma, and chronicmyelogenous leukemia. Also for thetreatment of oral warts arising fromHIV infection.Interferon Alfa-2b,Intron A ™ (Schering Corp)Antineoplastic Agents;For the treatment of hairy cell57759RecombinantAntiviral Agents;leukemia, malignant melanoma, andImmunomodulatory AgentsAIDS-related Kaposi’s sarcoma.Interferon alfacon-1Advaferon ™; Infergen ™ (InterMuneAntineoplastic Agents;For treatment of hairy cell leukemia,57759Inc)Antiviral Agents;malignant melanoma, and AIDS-Immunomodulatory Agentsrelated Kaposi’s sarcomaInterferon alfa-n1Wellferon ™ (GlaxoSmithKline)Antiviral Agents;For treatment of venereal or genital57759Immunomodulatory Agentswarts caused by the HumanPapiloma VirusInterferon alfa-n3Alferon ™ (Interferon Sciences Inc.);Antineoplastic Agents;For the intralesional treatment of57759Alferon LDO ™; Alferon N Injection ™Antiviral Agents;refractory or recurring externalImmunomodulatory Agentscondylomata 13cuminate.Interferon beta-1bBetaseron™ (Chiron Corp)Antiviral Agents;For treatment of relapsing/remitting57759Immunomodulatory Agentsmultiple sclerosisInterferon gamma-1bActimmune ™; Actimmune ™Antiviral Agents;For treatment of Chronic37835(InterMune Inc)Immunomodulatory Agentsgranulomatous disease,OsteopetrosisLapatinibTyrosine Kinase Inhibitors581LepirudinRefludan ™Anticoagulants;For the treatment of heparin-induced70037Antithrombotic Agents;thrombocytopeniaFibrinolytic AgentsLestaurtinibTyrosine Kinase Inhibitors439LeuprolideEligard ™ (Atrix Labs/QLT Inc)Anti-Estrogen Agents;For treatment of prostate cancer,37731Antineoplastic Agentsendometriosis, uterine fibroids andpremature pubertyLutropin alfaLuveris ™ (Serono)Fertility AgentsFor treatment of female infertility78617MecaserminIncrelex ™; Increlex ™ (Tercica); IplexFor the long-term treatment of growth154795failure in pediatric patients withPrimary IGFD or with GH genedeletion who have developedneutralizng antibodies to GH. It is notindicatec to treat Secondary IGFDresulting from GH deficiency,malnutriton, hypothMenotropinsRepronex ™Fertility AgentsFor treatment of female infertility78617MethotrexateImmunomodulatoryUveitis, DMEmTOR inhibitorsMuromonabOrthoclone DKT3 ™ (Ortho Biotech)ImmunomodulatoryFor treatment of organ transplant23148Agents;recipients, prevention of organImmunosuppressiverejectionAgentsNatalizumabTysabri ™Immunomodulatory AgentsFor treatment of multiple sclerosis.115334NepafenacCyclooxygenase InhibitorsNesiritideNatrecor ™Cardiac drugsFor the intravenous treatment of118921patients with acutely decompensatedcongestive heart failure who havedyspnea at rest or with minimalactivity.NilotinibTyrosine Kinase Inhibitors530NS398Cyclooxygenase InhibitorsOctreotideAtrigel ™, Longastatin ™;Anabolic Agents;For treatment of acromegaly and42687Sandostatin ™, Sandostatin LAR ™;Antineoplastic Agents,reduction of side effects from cancerSandostatin LAR ™ (Novartis)Hormonal; GastrointestinalchemotherapyAgents; HormoneReplacement AgentsOmalizumabXolair ™ (Genentezh Inc)Anti-Asthmatic Agents;For treatment of asthma caused by29596Immunomodulatory AgentsallergiesOprelvekinNeumega ™; Neumega ™ (GeneticsCoagulants; ThromboticsIncreases reduced platelet levels due45223Institute Inc)to chemotherapyOspA lipoproteinLYMErix ™ (SmithKline Beecham)VaccinesFor prophylactic treatment of Lyme95348DiseaseOT-551(Othera)Anti-oxidant eyedropAMDOxytocinOxytocin ™ (BAM Biotech); Pitocin ™Anti-tocolytic Agents; LaborTo assist in labor, elective labor12722(Parke-Davis) Syrtocinon ™Induction Agents;induction uterine contraction(Sandoz)OxytocicsinductionPaliferminKepivance ™ (Amgen Inc)Antimucositis AgentsFor treatment of mucositis (mouth138885sores)PalivizumabSynagis ™Antiviral AgentsFor treatment of respiratory diseases63689casued by respiratory syncytial virusPanitumumabVectibix ™; Vectibix ™ (Amgen)Antineoplastic AgentsFor the treatment of EGFR-134279expressing, metastatic colorectalcarcinoma with disease progressionon or following fluoropyrimidine-,oxaliplatir-, and irinotecan- containingchemotherapy regimens.PDGF inhibitor(Jerini Ophthalmic); (Ophthotech)Inhibitors of PDGFAMDPEDF (pigmentepithelium derivedfactor)Pegademase bovineAdagen ™ (Enzon Inc.)Enzyme ReplacementFor treatment of adenosine36512Agentsdeaminase deficiencyPegaptanibMacugen ™OligonucleotideFor the treatment of neovascular103121(wet) age-related maculardegeneration.PegaspargaseOncaspar ™ (Enzen Inc)Antineoplastic AgentsFor treatment of acute lymphoblastic132.118leukemiaPegfilgrastimNeulasta ™ (Amgen Inc.)Anti-Infective Agents;Increases leukocyte production, for28518Antineutropenic Agents;treatment in non-myeloid cancer,Immunomodulatory Agentsneutropenia and bone marrowtransplantPeginterferon alfa-2aPegasys ™ (Hoffman-La Roche Inc)Antineoplastic Agents;For treatment of hairy cell leukemia,57759Antiviral Agents;malignant melanoma, and AIDS-Immunomodulatory Agentsrelated Kaposi's sarcoma.Peginterferon alfa-2bPEG-Intron (Scher ng Corp); UnitronAntineoplastic Agents;For the treatment of chronic hepatitis57759PEG ™Antiviral Agents;C in patients not previously treatedImmunomodulatory Agentswith interferon alpha who havecompensated liver disease and are atleast 18 years of age.PegvisomantSomavert ™ (Pfizer Inc)Anabolic Agents; HormoneFor treatment of acromegaly71500Replacement AgentsPentoxifyllinePerindozrilACE InhibitorsPimecrolimusLimus ImmunophilinBinding CompoundsPKC (protein kinaseC) inhibitorsPOT-4Potencia/AlconComplement CascadeAMDInhibitor (Factor C3)PramlintideSymlin ™; Symlin ™ (AmylinFor the mealtime treatment of Type 116988Pharmaceuticals)and Type II diabetes in combinationwith standard insulin therapy, inpatients who have failed to achieveadequate glucose control on insulinmonotherapy.Proteosome inhibitorsVelcade ™Proteosone inhibitorsPyrrolidineQuinoprilACE InhibitorsRanibizumabLucentis ™For the treatment of patients with27043neovascular (wet) age-relatedmacular degeneration.Rapamycin(MacuSight)Limus ImmunophilinAMD(siroliums)Binding CompoundsRasburicaseElitek ™; Elitek ™ (Sanofi-SynthelaboAntihyperuricemic AgentsFor treatment of hyperuricemia,168.11Inc); Fasturtec ™reduces elevated plasma uric acidlevels (from chemotherapy)ReteplaseRetavase ™ (Centocor); Retavase ™Thrombolytic AgentsFor lysis of acute pulmonary emboli,54732(Roche)intracoronary emboli andmanagement of myocardial infarctionRetinal stimulantNeurosolve ™ (VitreoretinalRetinal stimulantsAMDTechnologies)Retinoid(s)RituximabMabThera ™, Rituxan ™Antineoplastic AgentsFor treatment of B-cell non-Hodgkins33078lymphoma (CD20 positive)RNAI (RNAinterference ofangiogenic factors)RofecoxibVioxx ™; Ceoxx ™; Ceeoxx ™ (MerckCyclooxygenase Inhibitors& Co.)RosiglitazoneThiazolidinedionesRuboxistaurinEli LillyProtein Kinase C (PKC)-bDME, diabetic peripheral retinopathy469InhibitorSalmon CalcitoninCalcimar ™, Miacalcin ™ (Novartis)Antihypocalcemic Agents;For the treatment of post-menopausal57304Antiosteporotic Agents;osteoporosisBone Density ConservationAgentsSargramostimImmunex ™; Leucomax ™ (Novartis);Anti-Infective Agents;For the treatment of cancer and bone46207Leukine ™; Leukine ™ (BerlexAntineoplastic Agents;marrow transplantLaboratories Inc)Immunomodulatory AgentsSAR 1118SARCodeImmunomodulatory AgentDry eye, DME, conjunctivitisSDZ-RADLimus ImmunophilinBinding CompoundsSecretinSecreFlo ™, Secremax ™,Diagnostic AgentsFor diagrosis of pancreatic exocrine50207SecreFlo ™ (Repligen Corp)dysfunction and gastrinomaSelective inhibitor ofthe factor 3complement cascadeSelective inhibitor ofthe factor 5complement cascadeSemaxanibTyrosine Kinase Inhibitors238SermorelinGeref ™ (Serono Pharma)Anabolic Agents; HormoneFor the treatment of dwarfism,47402Replacement Agentsprevention of HIV-induced weight lossSerum albuminMegatope ™ (IsoTex Diagnostics)Imaging AgentsFor determination of total blood and39000iodinatedplasma volumesSF1126SemaforeFI3k/mTOR InhibitionAMD, DIVESirolimus(MacuSight)Limus ImmunophilinAMDreformulationBinding Compounds(rapamycin)siRNA molecule(Quark Pharmaceuticals)siRNA molecule syntheticAMDsynthetic, FTP-801i-14SomatropinBioTropin ™ (Biotech General);Anabolic Agents; HormoneFor treatment of dwarfism,71500recombinantGenotropin ™ (Pfizer); Humatrope ™Replacement Agentsacromegaly and prevention of HIV-(Eli Lilly); Norditroin ™ (Novoinduced weight lossNordisk); Nutropin ™ (GenentechInc.); NutropinAQ ™ (GenentechInc.); Protropin ™ (Genentech Inc.);Saizen ™ (Serono SA); Serostim ™;Serostim ™ (Seroro SA); Tev-Tropin ™ (GATE)SqualamineStreptokinaseStreptase ™ (Aventis BehringerThrombolytic AgentsFor the treatment of acute evolving90569GmbH)transmural myocardial infarction,pulmonary embolism, deep veinthrombosis, arterial thrombosis orembolism and occlusion ofarteriovenous cannulaeSunitinibTyrosine Kinase Inhibitors398TA106TaligenComplement CascadeAMDInhibitor (Factor B)TacrolimusLimus ImmunophilinFinding CompoundsTenecteplaseTNKase ™ (Genentech Inc)Thrombolytic AgentsFor treatment of myocardial infarction54732and lysis of intracoronary emboliTeriparatideApthela ™, Forsteo ™, Forteo ™,Bone Density ConservationFor the treatment of osteoporosis in66361Fortessa ™; Opthia ™; Optia ™;Agentsmen anc postmenopausal womenOptian ™; Zalectra ™; Zelletra ™who are at high risk for having afracture. Also used to increase bonemass in men with primary orhypogonadal osteoporosis who are athigh risk for fracture.TetrathiomolybdateThalidomideCelgeneAnti-inflammatory, Anti-UveitisproliferativeThyrotropin AlfaThyrogen ™ (Genzyme Inc)Diagnostic AgentsFor detection of residueal or recurrent86831thyroid cancerTie-1 and Tie-2kinase inhibitorsToceranibTyrosine Kinase Inhibitors396TositumomabBexxa ™ (Corixa Corp)Antineoplastic AgentsFor treatment of non-Hodgkin’s33078lymphoma (CD20 positive, follicular)TPN 470 analogueTrastuzumabHerceptin ™ (Gerentech)Antineoplastic AgentsFor treatment of HER2-positive137912pulmonary breast cancerTriamcinoloneTriesence ™GlucocorticoidDME, For treatment of inflammation435acetonideof the retinaTroglitazoneThiazolidinedionesTumistatinUrofollitropinFertinex ™ (Seron S.A.)Fertility AgentsFor treatment of female infertility78296UrokinaseAbbokinase ™, Abbokinase ™Thrombolytic AgentsFor the treatment of 22ulmonary90569(Abbott Laboratores)embolism, coronary artery thrombosisand IV catheter clearanceVandetanibTyrosine Kinase Inhibitors475VasopressinPitressin ™; Pressyn ™Antidiuretics; Oxytocics;For the treatment of enuresis,46800Vasoconstrictor Agentspolyuria, diabetes insipidus,polydipsia and oesophageal variceswith bleedingVatalanibTyrosine Kinase Inhibitors347VEGF receptorkinase inhibitorVEGF TrapAflibercept ™ (RegneronGenetically EngineeredDME, cancer, retinal vein occlusion,96600Pharmaceuticals, Bayer HealthcareAntibodieschoroidal neovascularization, delayAG)wound healing, cancer treatmentVisual Cycle(Acucela)Visual Cycle ModulatorAMDModulator ACU-4229Vitamin(s)Vitronectin receptorantagonistsVolociximabOphthotechalpha5beta1 IntegrinAMDInhibitorXL765Exelix’s/Sanofi-AventisPI3k/mTOR InhibitionAMD, DME