Patent Grant
11813196
The present disclosure is generally directed to diagnosis and treatment of disease such as disease of the eye.
Prior methods and apparatus for treating tissue of the eye can be less than ideal in at least some instances. Although examination of the tissues of the eye can provide an indication of the condition of the eye, in at least some instances the tissue of the eye may indicate disease progression later than would be ideal. In at least some instances, it may be beneficial to treat the eye or modify treatment before tissue of the eye is altered by a disease of the eye. In at least some instances, the tissue of the eye can be damaged with progression of an eye disease and treatment of the eye may not occur until at least some damage to tissue has occurred.
At least some of the current methods to access the vitreous humor of the eye can be more invasive than would be ideal. Intravitreal taps and microdialysis can rely on insertion of a needle into the vitreous humor of the eye, and may not be well suited to diagnose the condition of the eye of a patient in at least some instances.
In light of the above, it would be desirable to provide improved diagnosis and treatment of diseases such as diseases of the eye. Ideally, these treatments would decrease at least some of the deficiencies of the prior art, and provide diagnosis and treatment.
Some embodiments described herein provide improved methods and apparatus to treat diseases such as diseases of the eye. In many embodiments, a fluid of a device implanted in the eye is received in a container, and one or more components of the fluid of the implanted device identified to treat the eye. The components of the fluid of the implanted device may comprise one or more components of the eye or one or more components of a formulation placed in the device implanted in the eye. The components of the eye identified from the liquid of the implanted device can be used in many ways to treat the eye, and may comprise one or more components of the aqueous humor or the vitreous humor of the eye. In many embodiments, the eye can be treated based on one or more markers of a disease of the eye, such that the eye can be treated based on the markers prior to substantial damage to tissue of the eye. The marker may comprise one or more of a genetic marker, a genomic marker, or a protein marker. In many embodiments, the marker comprises a protein corresponding to one or more of a genetic marker or a protein marker. In many embodiments, the device implanted in the eye comprises a reservoir chamber to store a therapeutic agent and a porous structure coupled to the reservoir chamber to release the therapeutic agent into the vitreous humor or the aqueous humor of the eye. The volume of the chamber and the release rate of the porous structure can be tuned to an amount of therapeutic agent injected into the device. The amount of therapeutic agent in the reservoir chamber and the amount of the component in the eye can be related to the volume of the reservoir chamber and the release rate of the porous structure.
The components of the fluid of the implanted device may comprise one or more of a pathogen of the eye, an autogenic component of the eye, or a component placed in the implanted device such as a therapeutic agent or a stabilizer such as a surfactant, or combinations thereof. The eye can be diagnosed based on one or more of the pathogen, the autogenic component, or the component placed in the implanted device, or combinations thereof. In many embodiments, the treatment of the eye can be determined based on an autogenic component of the eye such as a growth factor. The therapeutic agent may interact with the autogenic component, and the amount of an autogenic component can be determined based on one or more of the amount of autogenic component, the amount of therapeutic agent, or an amount of therapeutic agent bound to the autogenic component. The autogenic component may comprise a growth factor such as vascular endothelial growth factor (hereinafter “VEGF”), and the therapeutic agent may comprise an antibody fragment such as ranibizumab to bind to the growth factor.
In many embodiments, the component placed in the implanted device comprises one or more components of a formulation placed in the implanted device, for example placed in the implanted device with injection. The injected formulation may comprise a therapeutic fluid comprising the therapeutic agent and a stabilizer. The amount of therapeutic agent and the amount of stabilizer in the fluid received from the implanted device can be measured and used to determine one or more of an amount of mixing of the therapeutic fluid with the implantable device fluid during placement, an amount of therapeutic agent in the implanted device prior to placement of the therapeutic fluid, rate of release of the therapeutic agent from the implant, or an amount of therapeutic fluid placed in the device and an amount of implantable device fluid remaining in the implanted device. In many embodiments, the amount of time since the prior injection of therapeutic fluid and the ratio of therapeutic agent and stabilizer can be used to determine the rate of release of the therapeutic agent from the implant.
The components of the eye identified from the liquid of the implanted device may comprise a plurality of markers. The plurality of markers may comprise a first plurality of markers from a first sample and a second plurality of markers from a second sample, and the first plurality of markers may comprise a first marker profile of the eye measured at a first time, and the second plurality of markers may comprise a second marker profile of the eye measured at a second time. The first marker profile can be compared to the second marker profile to one or more of diagnose or treat the patient.
Embodiments as described herein can be combined in many ways to treat one or more of many diseases such as diseases of the eye. The embodiments can be beneficially combined with many known diagnostics, medicines and procedures, for example combined with known methods of diagnosing and treating the eye with a device implanted in the eye, and combinations thereof. Examples of implantable devices suitable for combination in accordance with embodiments of the present disclosure are described in U.S. patent application Ser. No. 12/696,678, filed 29 Jan. 2010, entitled “Posterior Segment Drug Delivery”, published as U.S. Pub. No. 2010/0255061 on Oct. 7, 2010, the full disclosure of which is incorporated herein by reference.
Although specific reference is made to the delivery of macromolecules comprising antibodies or antibody fragments to the posterior segment of the eye, embodiments can be used to diagnose the patient and to deliver many therapeutic agents to one or more of many tissues of the body. For example, embodiments can be used to diagnose the patient based on a sample from an implantable device and to deliver therapeutic agent for an extended period to one or more of the following tissues: intravascular, intra articular, intrathecal, pericardial, intraluminal and gut.
Embodiments provide sampling of a component of the eye from a device implanted in the eye and sustained release of a therapeutic agent to the posterior segment of the eye or the anterior segment of the eye, or combinations thereof. Therapeutic amounts of a therapeutic agent can be released into the vitreous humor of the eye, such that the therapeutic agent can be transported by at least one of diffusion or convection to the retina or other ocular tissue, such as the choroid or ciliary body, for therapeutic effect.
The diagnostic methods and apparatus as described herein can be used in many ways to one or more of treat or diagnose the patient, and can be combined in many ways with known treatments. In many embodiments, a diagnostic sample can be measured at a plurality of time points, such as when the therapeutic device is implanted, and one or more samples at a plurality of time points from the therapeutic device. A baseline sample can be measured from the patient when the device is implanted, for example prior to implantation with removal of a portion of the vitreous humor similar to a vitreal tap. When the device has been implanted, the fluid of the therapeutic device can be exchanged with a therapeutic fluid and analyzed, for example every 3-8 months.
As used herein the release rate index (PA/FL) encompasses where P comprises the porosity, A comprises an effective area, F comprises a curve fit parameter corresponding to an effective length, and L comprises a length or thickness of the porous structure. The units of the release rate index (RRI) comprise units of mm unless indicated otherwise and can be determined by a person of ordinary skill in the art in accordance with the teachings described herein.
As used herein, sustained release encompasses the release of therapeutic amounts of an active ingredient of a therapeutic agent for an extended period of time. The sustained release may encompass a 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.
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 tradename, the active ingredient of the commercially available formulation, the generic name of the active ingredient, or the molecule comprising the active ingredient. In addition, as used herein, similar numerals indicate similar structures and/or similar steps.
As used herein, terms of sequence such as first, second, and third can be used to illustrate combinations in accordance with embodiments merely by way of non-limiting example. Although terms of sequence may be used in accordance with one or more embodiments, a person of ordinary skill in the art will recognize many adaptations and variations based on the teachings described herein. For example, the order can be changed or one or more terms of sequence removed, or combinations thereof.
Measurement of One or More Ocular Components to Diagnose and Treat the Eye
Based on diagnostic tests of samples from a reservoir container of the device, the therapeutic treatment can be adjusted accordingly. For example, the patient may be diagnosed as a non-responder and the therapeutic agent changed, or the time interval at which the therapeutic agent is exchanged can be adjusted. For example, the exchange of the therapeutic fluid may be sooner e.g. every 3 months, or later, e.g. every 8 months, based on the components of the sample from the therapeutic device and patient response.
The components of the eye from the device may correspond to one or more pathways. For example, based on the diagnostic tests as described herein, amounts of pro-inflammatory cytokines that may upregulate VEGF can be measured and compared to one or more markers as described herein, such as VEGF. The embodiments as described herein can be well suited to determine one or more of a genotype of a patient, a phenotype of a patient, or combinations thereof, that can be used to diagnose and treat the patient. The sample may be combined with genetic testing to evaluate genes and phenotypes associated with a disease. For example, the sample may be combined with a DNA sample, such as from a swab of the sample used to determine a genotype of the patient, such as complement factor H-genotype. A patient having the compliment factor H genotype can be identified as more likely to get AMD, and the treatment and marker data interpreted based on one or more of the genotype of the phenotype of the patient. The one or more markers may comprise markers capable of binding to each other, such as complement factor H and c-reactive protein.
The marker measured from the implantable device sample may comprise one or more proteins having a substantial fluctuation in amount in response to the therapeutic agent. For example intra-vitreal amounts of the markers IL6 and GCSF can each have high ratios of mean pre-treatment to mean post treatment, such that these markers can be well suited to diagnose and treat the eye. The marker from the vitreous may correspond to a component of blood, such as serum amyloid, and may comprise a component of blood plasma. The marker may comprise one or more of the markers of Table I, herein below. The marker may comprise a protein, or alternatively a non-protein such as a carbohydrate, for example glucose or lactose, for example.
The marker can be a marker corresponding to a diagnosed condition of the patient. For example, insulin may be measured from the sample of the implantable device for patients having diabetic retinopathy, for example. Alternatively or in combination, the marker may comprise a marker corresponding to a target of the therapeutic agent, such as VEGF, and amounts of the marker bound to the therapeutic agent may be measured. For example, the therapeutic agent and marker can be bound when diffusing into the reservoir chamber of the device so as to decrease the rate of diffusion into the reservoir chamber, and the patient can be one or more of diagnosed or treated based on amounts of the therapeutic agent bound to the target and corresponding rates of diffusion of the bound components through the porous structure of the implantable device. For example, Ranibizumab when bound to VEGF can have a molecular weight of about 93 kilo Daltons (hereinafter “kDa”) and diffuse about 20% slower than unbound VEGF.
The plurality of markers measured from the implanted device as described herein can be combined with statistical analysis from a population of patients to one or more of diagnose or treat the patient. The sample from the implanted device can be measured so as to provide a marker profile of the plurality of components that can be compared with marker profiles determined from a variety of patients. For example, data from a population of patients can provide correlations, statistical metrics, and statistical significance to the amounts of markers of the profile. The marker profile may comprise a plurality of markers from the implantable device, at least about 10 markers, or 20 or more markers measured from the implantable device, for example.
Table 1 (see Appendix I) shows examples of markers that can be received from the implanted device and used to diagnose the eye or treat the eye, or both. The markers can be used to determine a course of treatment for the patient, and may be combined in many ways with the therapeutic agent as described herein. In many embodiments, the marker comprises a molecule that is a component of the eye which can diffuse through the porous structure into the reservoir structure. In many embodiments, the marker comprises a large molecule that can diffuse through the porous structure of the implanted device into the reservoir chamber. The therapeutic agent may comprise a large molecule or a small molecule that can diffuse through the porous structure, or combinations of large and small molecules. Work in relation to embodiments indicate that marker molecules having a lower molecular weight may accumulate in the implanted device more rapidly than larger molecular weight marker molecules, and that marker molecules having a molecular weight of no more than about 500 kDa can be used in many embodiments. In many embodiments the molecular weight can be smaller than 500 kDa, for example 100 kDa or less, so that the accumulation rate is increased. The molecular weight values of Table 1 can be combined in many ways to provide ranges of molecular weights of the measured marker. Alternatively or in combination, a plurality of markers of different molecular weight can be used to diagnose and treat the patient. Examples of markers and amounts similar to Table 1 can be used and are shown in Molecular Vision (Mol Vis. 2010; 16: 2175-2184, Published online 2010 Oct. 27) available on the world wide web (at the address http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994336/table/t1/)
A ratio of pre-treatment mean concentration to post-treatment mean concentration is shown for the markers of Table 1. This ratio can be used to determine markers suitable to indicate efficacy of treatment and markers suitable for use as housekeeping genes. The markers having a ratio above about 1.2, for example, can be suitable for use as housekeeping markers. Markers having a ratio above about 1.2 may be suitable for use as efficacy markers. In many embodiments, the one or more markers from the therapeutic device correspond to a pre/post ratio above of about 1.5, for example. Alternatively or in combination, the pre/post ratio can be less than 0.8, for example, and the marker risk may correspond to under-expression of protective factors, for example. The marker profile to diagnose the patient from a sample of the implanted device may comprise a plurality of up-regulation of pathogenic factor markers corresponding to a ratio above about 1.2 and a plurality of under-expression of protective factor markers corresponding to a ratio below about 0.8, for example.
A list of known Hugo symbols is provided in Appendix II of this disclosure, and can be used to determine genetic markers and corresponding genetic mapping in accordance with embodiments. This appendix includes genes and codenames for genes whose expression may change upon VEGF treatment of the eye.
The markers of Table 1 and the therapeutic agent of Table 1A (see Appendix I) can be combined in many ways to treat the eye. For example, one or more of the markers of Table 1 can be combined with one or more therapeutic agents of Table 1A to treat the eye. The efficacy of a treatment with the therapeutic agent can be evaluated based on the marker, and the therapeutic agent can be changed or the amount of therapeutic agent adjusted based on one or more of the presence or amount of the marker. The many combinations corresponding to each marker of Table 1 with one or more therapeutic agents of Table 1A provide many embodiments. A person of ordinary skill in the art can conduct experiments to determine empirically which of the one or more markers can be combined with which of the one or more therapeutic agents to beneficially treat the patient or the eye, or both. Further, one or more marker may be combined with a plurality of therapeutic agents, in accordance with embodiments. Alternatively, a plurality of markers may be combined with one or more therapeutic agents, in accordance with many embodiments. A person of ordinary skill in the art will recognize many embodiments in accordance with the teachings and embodiments described herein.
The molecular weights of the markers of Table 1 can be used to determine the rate of diffusion of the marker through the porous structure in accordance with the teachings described herein. The rate of accumulation of the marker can be determined based on the RRI and volume of the reservoir chamber of the device implanted in the eye. For example, markers having low molecular weight may accumulate in the reservoir chamber more rapidly than molecules with high molecular weight, and the time for the marker to accumulate in the reservoir chamber can be used to diagnose the eye and determine the effectiveness of the treatment. The molecular weights of the markers of Table 1 range from about 2.5 kDa for Endothelium-1 to about 540 kDa for fibrinogen, for example. The lower end of the range may comprise a low molecular weight cytokine, for example a MIP-1 alpha or MIP-1 beta. Alternatively or in combination, the lower end of the range may correspond to Endothelium-1. Based on the values of Table 1, the range of the molecular weight of the marker can be within a range from about 1 kDa to about 540 kDa, for example within a range from about 2.5 kDa to about 540 kDa.
The marker may comprise a molecular weight corresponding to a molecular weight of the therapeutic agent. For example, the molecular weight of the marker may correspond to a diffusion coefficient of at least about half of the diffusion coefficient of the therapeutic agent. For example, with Lucentis™ the molecular weight is about 48 kDa and a marker having a molecular weight of about 500 kDa can have a diffusion coefficient and corresponding accumulation rate that is about half of Lucentis™. In many embodiments, the molecular weight of the marker comprises no more than the molecular weight of the therapeutic agent, for example no more than about half of the molecular weight of the therapeutic agent.
For some entries in the table, ranges are shown that represent variations that may be due to glycosylation, subunits vs. association into soluble aggregates, and binding to other molecules. Hence, these are representative values that may be adjusted to account for the actual size of the moiety diffusing into the device during use.
The therapeutic agent may be contained within a chamber of a container, for example within a reservoir comprising the container and chamber. The therapeutic agent may comprise a formulation such as solution of therapeutic agent, a suspension of a therapeutic agent or a dispersion of a therapeutic agent, for example. Examples of therapeutic agents suitable for use in accordance with embodiments of the therapeutic device are described herein, for example with reference to Table 1A below and elsewhere.
The therapeutic agent may comprise a macromolecule, for example an antibody or antibody fragment. The therapeutic macromolecule may comprise 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 may comprise small molecules such as of a corticosteroid and analogues thereof. For example, the therapeutic corticosteroid may comprise one or more of trimacinalone, trimacinalone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, or analogues thereof. Alternatively or in combination, he small molecules of therapeutic agent may comprise 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 may comprise 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 may comprise 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 may comprise a therapeutic agent suitable for treatment of wet AMD (age-related macular degeneration) such as one or more of REDD14NP (Quark), Sirolimus™ (Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor (POT-4).
The therapeutic agent may comprise 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), sorafenib (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/VEGFR2, small molecule commercially available from Esai, Co.)
The amount of therapeutic agent within the therapeutic device may comprise from about 0.01 mg to about 1 mg, for example Lucentis™, so as to provide therapeutic amounts of the therapeutic agent for the extended time, for example at least 30 days. The extended time may comprise at least 90 days or more, for example at least 180 days or for example at least 1 year, at least 2 years or at least 3 years or more. The target threshold therapeutic concentration of a therapeutic agent such as Lucentis™ in the vitreous may comprise at least a therapeutic concentration of 0.1 ug/mL. For example the target threshold concentration may comprise from about 0.1 ug/mL to about 5 ug/mL for the extended time, where the upper value is based upon calculations shown in Example 9 of in U.S. patent application Ser. No. 12/696,678, filed 29 Jan. 2010, entitled “Posterior Segment Drug Delivery”, published as U.S. Pub. No. 2010/0255061 on Oct. 7, 2010, the full disclosure of which has been previously incorporated herein by reference. The target threshold concentration is drug dependent and thus may vary for other therapeutic agents.
The delivery profile may be configured in many ways to obtain a therapeutic benefit from the sustained release device. For example, an amount of the therapeutic agent may be inserted into the container at monthly intervals so as to ensure that the concentration of therapeutic device is above a safety protocol or an efficacy protocol for the therapeutic agent, for example with monthly or less frequent injections into the container. The sustained release can result in an improved delivery profile and may result in improved results. For example, the concentration of therapeutic agent may remain consistently above a threshold amount, for example 0.1 ug/mL, for the extended time.
The insertion method may comprise inserting a dose into the container of the therapeutic device. For example, a single injection of Lucentis™ may be injected into the therapeutic device.
The duration of sustained delivery of the therapeutic agent may extend for twelve weeks or more, for example four to six months from a single insertion of therapeutic agent into the device when the device is inserted into the eye of the patient.
The therapeutic agent may be delivered in many ways so as to provide a sustained release for the extended time. For example, the therapeutic device may comprise a therapeutic agent and a binding agent. The binding agent may comprise small particles configured to couple releasably or reversibly to the therapeutic agent, such that the therapeutic agent is released for the extended time after injection into the vitreous humor. The particles can be sized such that the particles remain in the vitreous humor of the eye for the extended time.
The therapeutic agent may be delivered with a device implanted in the eye. For example, the drug delivery device can be implanted at least partially within the sclera of the eye, so as to couple the drug delivery device to the sclera of the eye for an extended period of time. The therapeutic device may comprise a drug and a binding agent. The drug and binding agent can be configured to provide the sustained release for the extended time. A membrane or other diffusion barrier or mechanism may be a component of the therapeutic device to release the drug for the extended time.
The lifetime of the therapeutic device and number of injections can be optimized for patient treatment. For example, the device may remain in place for a lifetime of 30 years, for example with AMD patients from about 10 to 15 years. For example, the device may be configured for an implantation duration of at least two years, with 8 injections (once every three months) for sustained release of the therapeutic agent over the two year duration. The device may be configured for implantation of at least 10 years with 40 injections (once every three months) for sustained release of the therapeutic agent.
The therapeutic device can be refilled in many ways. For example, the therapeutic agent can be refilled into the device in the physician's office.
The therapeutic device may comprise many configurations and physical attributes, for example the physical characteristics of the therapeutic device may comprise at least one of a drug delivery device with a suture, positioning and sizing such that vision is not impaired, and biocompatible material. The device may comprise a reservoir capacity from about 0.005 cc to about 0.2 cc, for example from about 0.01 cc to about 0.1 cc, and a device volume of no more than about 2 cc. A vitrectomy may be performed for device volumes larger than 0.1 cc. The length of the device may not interfere with the patient's vision and can be dependent on the shape of the device, as well as the location of the implanted device with respect to the eye. The length of the device may also depend on the angle in which the device is inserted. For example, a length of the device may comprise from about 4 to 6 mm. Since the diameter of the eye is about 24 mm, a device extending no more than about 6 mm from the sclera into the vitreous may have a minimal effect on patient vision.
Embodiments may comprise many combinations of implanted drug delivery devices. The therapeutic device may comprise a drug and binding agent. The device may also comprise at least one of a membrane, an opening, a diffusion barrier, and a diffusion mechanism so as to release therapeutic amounts of therapeutic agent for the extended time.
Measurements to Determine Implantable Device Performance and Exchange Efficiency
As described herein, the amount of therapeutic agent in the exchanged implantable device fluid can be measured to evaluate the release of the therapeutic agent from the device and to determine the amount of therapeutic fluid placed in the device. In many embodiments, the therapeutic fluid placed in the eye comprises one or more components of a formulation of the therapeutic agent. The components of the formulation of the therapeutic fluid can be measured to determine the amount of therapeutic agent present in the implantable device fluid and the efficiency of placement of the therapeutic fluid in the implantable device. In many embodiments, a non-pharmacologic component of the implantable device fluid can be measured to determine one or more of the following; the amount of therapeutic agent released since a previous placement of a therapeutic fluid in the device; performance of the porous structure to release the therapeutic agent; leakage of the therapeutic agent from the reservoir chamber away from the porous structure; the efficiency of placement of the therapeutic fluid within the implantable device; or the amount of implantable fluid displaced with the therapeutic agent. For example, the ratio of a component of the formulation to the amount of therapeutic agent can be determined.
The measured component of the formulation may comprise a stabilizer, and a ratio of the stabilizer to the therapeutic agent can be measured, for example. The measured component comprises a diffusion coefficient and a molecular weight proportional to the therapeutic agent, such that the ratio of the therapeutic agent to the component in the implantable device fluid can be compared to determine the amount of therapeutic agent release since a prior placement of therapeutic fluid.
In many embodiments, the stabilizer increases an amount of time the therapeutic agent has a therapeutic effect when placed in a therapeutic device placed in a patient. The stabilizer may comprise one or more of the following; a buffer to maintain a pH of the formulation, hydrophilic functional groups; a hydrophilic functional group to provide a co-solvent stabilization; a charged functional group to provide charge interaction; or a functional group to form a complex with the therapeutic agent, so as to increase one or more of physical stability or chemical stability of the therapeutic agent and maintain biological activity of the therapeutic agent. The stabilizer can be soluble and may comprise one or more of a sugar, an alcohol, a polyol, or a carbohydrate and the functional group may comprise a hydroxyl group.
In some embodiments, the stabilizer comprises a molecular weight of at least about 3 k Daltons. The stabilizer may comprise a molecular weight of at least about 5 k Daltons, and may comprise a molecular weight of at least about 10 k Daltons, for example at least about 25 k Daltons.
In many embodiments, the stabilizer comprises a molecular weight of at least about 25% of a molecular weight of the therapeutic agent. The stabilizer and the therapeutic agent may each comprise a half-life when placed, for example injected, into a therapeutic device, and the half-life of the stabilizer may comprise at least about 25% of the half-life of the therapeutic agent. The half-life of the stabilizer may be comprised of at least about 50% of the half-life of the therapeutic agent.
In many embodiments, the therapeutic agent may comprise ranibizumab. The therapeutic agent may comprise ranibizumab and degradation products of ranibizumab, and the degradation products may comprise one or more of deamidized ranibizumab or oxidized ranibizumab.
In many embodiments, the stabilizer comprising the molecular weight comprises one or more of: HA (hyaluronic acid) having the molecular weight of at least 2 kDa, histidine polymer buffer having the molecular weight of at least 2 kDa, sugar having the molecular weight of at least 2 kDa, polysaccharides having the molecular weight of at least 2 kDa, carbohydrate having the molecular weight of at least 2 kDa, starch having the molecular weight of at least 2 kDa, alcohol having the molecular weight of at least 2 kDa, polyol having the molecular weight of at least 2 kDa, or polyethylene oxide having the molecular weight of at least 2 kDa, so as to stabilize the therapeutic agent and decrease release of the therapeutic agent when placed in a therapeutic device.
In some embodiments, the stabilizer comprising the molecular weight comprises one or more of: a phenol, a protein, or a charged stabilizers such as a metal comprising one or more of zinc ion, calcium ion, or iron ion, so as to form a reversible complex with the therapeutic agent.
In some embodiments, the stabilizer comprises a plurality of micelles and wherein the molecular weight of the stabilizer corresponds to a weight of each micelle of the plurality such that diffusion of the plurality of micelles corresponds to the weight of said each micelle. The plurality of micelles may comprise a reservoir of the stabilizer. The stabilizer may comprise a surfactant, and a concentration of surfactant may comprise at least about two times a critical micelle concentration of the surfactant. The concentration of surfactant may comprise at least about two times the critical micelle concentration, and may comprise at least about four times the critical micelle concentration.
In some embodiments, a stabilizer, may comprise a polysorbate.
In some embodiments, an amount of the stabilizer may correspond to at least about 0.05% by weight of a formulation when injected into the eye.
Ocular Anatomy, Therapeutic Devices and Placement
While the implant 100 can be positioned in the eye 10 in many ways, placement in the pars plana region 25 can release therapeutic agent 110 into the vitreous to treat the retina 26, for example therapeutic agent 110 comprising an active ingredient composed of large molecules.
Therapeutic agents 110 suitable for use with device 100 may include a variety of therapeutic agents 110, for example as listed in Table 1A, herein below. The therapeutic agent 110 of device 100 may comprise one or more of the following; an active ingredient of the therapeutic agent 110; a formulation of the therapeutic agent; a commercially available formulation of the therapeutic agent; a physician prepared formulation of therapeutic agent; a pharmacist prepared formulation of the therapeutic agent; or a commercially available formulation of therapeutic agent having an excipient. The therapeutic agent 110 may be referred to with a generic name or a trade name, for example as shown in Table 1A.
The therapeutic device 100 can be implanted in the eye 10 to treat the eye 10 for as long as is helpful and beneficial to the patient. For example the device 100 can be implanted for at least about 5 years, such as permanently for the life of the patient. Alternatively or in combination, the device 100 can be removed when no longer helpful or beneficial for treatment of the patient.
The non-permeable membrane 162 may comprise an opening 166 sized to release therapeutic amounts of the therapeutic agent 110 for an extended time. The porous structure 150 may comprise a thickness 150T and pore sizes configured in conjunction with the opening 166 so as to release therapeutic amounts of the therapeutic agent 110 for the extended time. The container 130 may comprise the reservoir 140 having a chamber 132 with a volume 142 sized to contain a therapeutic quantity of the therapeutic agent 110 for release over the extended time. The device 100 may comprise a needle stop 170. Proteins in the vitreous humor 30 may enter the device 100 and compete for adsorption sites on the porous structure and thereby may contribute to the release of therapeutic agent 110. The therapeutic agent 110 contained in the reservoir 140 can equilibrate with proteins in the vitreous humor 30, such that the system is driven towards equilibrium and the therapeutic agent 110 is released in therapeutic amounts.
The non-permeable membrane 162, the porous material 152, the reservoir 140, and the retention structure 120, may comprise many configurations to deliver the therapeutic agent 110. The non-permeable membrane 162 may comprise an annular tube joined by a disc having at least one opening formed thereon, such as opening 166, to release the therapeutic agent 110. The porous material 152 may comprise an annular porous glass frit 154 and a circular end disposed thereon. The reservoir 140 may be shape-changing for ease of insertion, i.e., it may assume a thin elongated shape during insertion through the sclera 24 and then assume an extended, ballooned shape, once it is filled with therapeutic agent 110.
The porous structure 150 can be configured in many ways to release the therapeutic agent 110 in accordance with an intended release profile. For example, the porous structure may comprise a porous structure 150 having a plurality of openings on a first side facing the reservoir 140 and a plurality of openings on a second side facing the vitreous humor 30, with a plurality of interconnecting channels disposed therebetween so as to couple the openings of the first side with the openings of the second side, for example a sintered rigid material. The porous structure 150 may comprise 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 retention structure 120 may comprise a flange 122 shaped to extend along a surface of the sclera 24 beneath the conjunctiva 16. The implantable device 100 may be retained without sutures. Alternatively, device 100 may comprise a suture tab 124 to couple to a suture 126 to retain the device 100.
The tube 168 and retention structure 120 may be configured to receive a glass rod, which may be surface treated, and the glass rod can be injected with therapeutic agent 110. When the therapeutic agent 110 has finished elution for the extended time, the rod can be replaced with a new rod.
The device 100 may comprise therapeutic agent 110 and a carrier, for example a binding medium 192 comprising a binding agent to deliver the therapeutic agent 110. The therapeutic agent 110 can be surrounded with a column comprising a solid support that is eroded away.
For example, in the United States of America, Lucentis™ (active ingredient ranibizumab) is supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL Lucentis™ aqueous solution with 10 mM histidine HCl, 10% α, α-trehalose dihydrate, 0.01% polysorbate 20, at pH 5.5. In Europe, the Lucentis™ formulation can be substantially similar to the formulation of the United States.
For example, the sustained release formulation of Lucentis™ developed by Genentech and/or Novartis, may comprise the therapeutic agent 110 injected into the device 100. The sustained release formulation may comprise particles comprising active ingredient.
For example, in the United States, Avastin™ (bevacizumab) is approved as an anticancer drug and in clinical trials are ongoing for AMD. For cancer, the commercial solution is a pH 6.2 solution for intravenous infusion. Avastin™ may be supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Avastin™ (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP. The commercial formulations are diluted in 100 mL of 0.9% sodium chloride before administration and the amount of the commercial formulation used varies by patient and indication. Based on the teachings described herein, a person of ordinary skill in the art can determine formulations of Avastin™ to inject into therapeutic device 100. In Europe, the Avastin™ formulation can be substantially similar to the formulation of the United States.
For example, in the United States, there may be two forms of Triamcinolone used in injectable solutions, the acetonide and the hexacetonide. The acetamide may be approved for intravitreal injections in the U.S. The acetamide is the active ingredient in TRIVARIS (Allergan), 8 mg triamcinolone acetonide in 0.1 mL (8% suspension) in a vehicle containing w/w percent of 2.3% sodium hyaluronate; 0.63% sodium chloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate, monobasic; and water, pH 7.0 to 7.4 for injection. The acetamide is also the active ingredient in Triesence™ (Alcon), a 40 mg/ml suspension.
A person of ordinary skill in the art can determine the osmolarity for these formulations. The degree of dissociation of the active ingredient in solution can be determined and used to determine differences of osmolarity from the molarity in these formulations. For example, considering at least some of the formulations may be concentrated (or suspensions), the molarity can differ from the osmolarity.
The formulation of therapeutic agent 110 may be injected into therapeutic device 100 and may comprise many known formulations of therapeutic agents, and the formulation therapeutic agent 110 may comprise an osmolarity suitable for release for an extended time from device 100. Table 1B shows examples of osmolarity (Osm) of saline and some of the commercially formulations of Table 1A.
The vitreous humor 30 of the eye 10 may comprises an osmolarity of about 290 mOsm to about 320 mOsm. Formulations of therapeutic agent 110 having an osmolarity from about 280 mOsm to about 340 mOsm are substantially isotonic and substantially iso-osmotic with respect to the vitreous humor 30 of the eye 10. Although the formulations listed in Table 1B are substantially iso-osmotic and isotonic with respect to the vitreous of the eye 10 and suitable for injection into the therapeutic device, the formulation of the therapeutic agent 110 injected into the therapeutic device can be hypertonic (hyper-osmotic) or hypotonic (hypo-osmotic) with respect to the tonicity and osmolarity of the vitreous. Work in relation to embodiments suggests that a hyper-osmotic formulation may release the active ingredient of the therapeutic agent 110 into the vitreous somewhat faster initially when the solutes of the injected formulation equilibrate with the osmolarity of the vitreous, and that a hypo-osmotic formulation such as Avastin™ may release the active ingredient of the therapeutic agent 110 into the vitreous somewhat slower initially when the solutes of the injected formulation equilibrate with the eye 10. A person of ordinary skill in the art can conduct experiments based on the teachings described herein to determine empirically the appropriate reservoir 140 chamber 132 volume and porous structure 150 for a formulation of therapeutic agent 110 disposed in the reservoir 140 chamber 132, so as to release therapeutic amounts of the therapeutic agent 110 for an extended time and to provide therapeutic concentrations of therapeutic agent 110 in the vitreous within a range of therapeutic concentrations that is above a minimum inhibitory concentration for the extended time.
Additional chambers and openings can be disposed on the device in order to linearize the delivery of the drug or therapeutic agent 110. For example, a third chamber 132C can be disposed distally to the second chamber 132B. The second opening can couple the second chamber 132B to the third chamber 132C. For example, a fourth chamber 132D can be disposed distally to the third chamber 132C, and a third opening can connect the third chamber 132C and the fourth chamber 132D.
Additionally or in the alternative, the therapeutic device may comprise at least one gate to provide for sustained drug delivery. The gate can be moved from “closed” to “open” position using magnetism or by applying electrical current. For example the gates can slide or twist. The gates can be spring-loaded, and may comprise a pump that can be re-loaded. The gates may comprise an osmotic pump.
As shown in
When protective membranes have pores of 0.2 μm diameter, they can be 20 or more times larger than the proteins of interest, which may comprise a model for delivery of the therapeutic agent 110. For example, molecular weights and diameters of models of proteins of therapeutic interest may include the following:
Therefore, solutions of therapeutic compounds in the size range of IgG and BSA can flow relatively easily through 0.2 μm pore size protective membranes which may be used to stop passage of bacterial and other cells.
Binding materials/agents may comprise at least one of a chemical binding material/agent, a structural binding agent or material, or an electrostatic binding agent or material. The types of binding agent may comprise a classification composed of non-biodegradable material, for example glass beads, glass wool or a glass rod. A surface can be derivatized with at least one functional group so as to impart the binding agent or material with the potential for at least one of ionic, hydrophobic, or bioaffinity binding to at least one therapeutic compound.
The binding agent may comprise a biodegradable material. For example, the biodegradation, binding, or any combination of the previous processes may control the diffusion rate.
The binding agent may comprise ion exchange, and the ion exchange may comprise at least one of a functional group, a pH sensitive binding or a positive or negative charge. For example, ion exchange may occur with at least one of diethylaminoethyl or carboxymethyl functional groups. Additionally, the ion exchange may comprise positive or negative ion exchange.
The binding agent may comprise a pH sensitive binding agent. For example the binding agent can be configured to elute therapeutic agent 110 at a pH of 7, and to bind the therapeutic agent 110 at a pH from about 4 to about 6.5. A cation exchange binding agent can be configured, for example, such that at a pH of 7, the net negative charge of the binding agent decreases causing a decrease in binding of the positively charged drug and release of the therapeutic agent 110. A target buffer can be provided with the binding agent to reversibly couple the binding agent to the therapeutic agent 110. The rate of release can be controlled, for example slowed down, by using insolubility of the buffer in the vitreous. Alternatively or in combination the elution can be limited by using a porous membrane or a physical property such as a size of an opening.
Furthermore, the binding agent may comprise hydrophobic interaction. For example, the binding agent may comprise at least one binding to hydrophobic pockets, for example at least one of methyl, ethyl, propyl, butyl, t-butyl or phenyl functional groups.
The binding agent may comprise affinity, for example at least one of a macromolecular affinity or a metal chelation affinity. Examples can include a hydroxyapatite, or chelated metal, for example zinc. Iminodiacetic acid can be chelated with zinc.
The binding agent may comprise at least one of the following functions: charging, recharging or elution. The charging may comprise a porous material injected therein so as to release the active ingredient. The porous matter may have an extremely large inert surface area, in which the surface area can be available for binding. The recharging may comprise removing carrier+therapeutic agent; and adding freshly “charged” carrier+therapeutic agent.
The elution may comprise a byproduct, for example unbound binding agent that can be removed. For example, diffusion (plug flow) of vitreous to change conditions, e.g. pH to reduce interaction of therapeutic agent+carriers.
Additionally or in the alternative, a sustained drug delivery system of the therapeutic agent 110 may comprise drug delivery packets, e.g. microspheres, that are activated. The packets can be activated with at least one of photochemical activation, thermal activation or biodegradation.
The therapeutic device 100 may comprise at least one structure configured to provide safety precautions. The device may comprise at least one structure to prevent at least one of macrophage or other immune cell within the reservoir body; bacterial penetration; or retinal detachment.
The therapeutic device 100 may be configured for other applications in the body. Other routes of administration of drugs may include at least one of intraocular, oral, subcutaneous, intramuscular, intraperitoneal, intranasal, dermal, intrathecal, intravascular, intra articular, pericardial, intraluminal in organs and gut, or the like.
Conditions that may be treated and/or prevented using any drug delivery device and method described herein may include at least one of the following: hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary diseases such as cerebrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves 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.
Examples of therapeutic agents 110 that may be delivered by the therapeutic device 100 are described in Table 1A and may include Triamcinolone acetonide, Bimatoprost (Lumigan), Ranibizumab (Lucentis™), Travoprost (Travatan, Alcon), Timolol (Timoptic, Merck), Levobunalol (Betagan, Allergan), Brimonidine (Alphagan, Allergan), Dorzolamide (Trusopt, Merck), Brinzolamide (Azopt, Alcon). Additional examples of therapeutic agents 110 that may be delivered by the therapeutic device 100 include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin and penicillin; antifungals such as amphotericin B and miconazole; anti-bacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals such as idoxuridine, trifluorotymidine, acyclovir, ganciclovir and interferon; antiallergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, and triamcinolone; non-steroidal anti-inflammatories such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such as phenylephrine, naphazoline and tetrahydrozoline; miotics and anticholinesterases such as pilocarpine, salicylate, acetylcholine chloride, physostigmine, eserine, carbachol, diisopropyl fluorophosphate, phospholine iodide and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such as epinephrine; antineoplastics such as carmustine, cisplatin and fluorouracil; immunological drugs such as vaccines and immune stimulants; hormonal agents such as estrogens, estradiol, progestational, progesterone, insulin, calcitonin, parathyroid hormone and peptide and vasopressin hypothalamus releasing factor; beta adrenergic blockers such as timolol maleate, levobunolol Hcl and betaxolol Hcl; growth factors such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotropin and fibronectin; carbonic anhydrase inhibitors such as dichlorophenamide, acetazolamide and methazolamide and other drugs such as prostaglandins, antiprostaglandins and prostaglandin precursors. Other therapeutic agents known to those skilled in the art which are capable of controlled, sustained release into the eye 10 in the manner described herein are also suitable for use in accordance with embodiments.
The therapeutic agent 110 may comprise one or more of the following: Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin, Alefacept, Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase, Anakinra, Anistreplase, Antihemophilic Factor, Antithymocyte globulin, Aprotinin, Arcitumomab, Asparaginase, Basiliximab, Becaplermin, Bevacizumab, Bivalirudin, Botulinum Toxin Type A, Botulinum Toxin Type B, Capromab, Cetrorelix, Cetuximab, Choriogonadotropin alfa, Coagulation Factor IX, Coagulation factor VIIa, Collagenase, Corticotropin, Cosyntropin, Cyclosporine, Daclizumab, Darbepoetin alfa, Defibrotide, Denileukin diftitox, Desmopressin, Dornase Alfa, Drotrecogin alfa, Eculizumab, Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept, Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase, Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant, Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab, Idursulfase, Immune globulin, Infliximab, Insulin Glargine recombinant, Insulin Lyspro recombinant, Insulin recombinant, Insulin, porcine, Interferon Alfa-2a, Recombinant, Interferon Alfa-2b, Recombinant, Interferon alfacon-1, Interferonalfa-n1, Interferon alfa-n3, Interferon beta-1b, Interferon gamma-1b, Lepirudin, Leuprolide, Lutropin alfa, Mecasermin, Menotropins, Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab, Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab, Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, Pramlintide, Ranibizumab, Rasburicase, Reteplase, Rituximab, Salmon Calcitonin, Sargramostim, Secretin, Sermorelin, Serum albumin iodonated, Somatropin recombinant, Streptokinase, Tenecteplase, Teriparatide, Thyrotropin Alfa, Tositumomab, Trastuzumab, Urofollitropin, Urokinase, or Vasopressin. The molecular weights of the molecules and indications of these therapeutic agents are set forth below in Table 1A.
The therapeutic agent 110 may comprise one or more compounds that act by binding members of the immunophilin family of cellular proteins. Such compounds are known as “immunophilin binding compounds” Immunophilin binding compounds include but are not limited to the “limus” family of compounds. Examples of limus compounds that may be used include but are not limited to cyclophilins and FK506-binding proteins (FKBPs), including sirolimus (rapamycin) and its water soluble analog SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad), and ABT-578 (Abbott Laboratories).
The limus family of compounds may be used in the compositions, devices and methods for the treatment, prevention, inhibition, delaying the onset of, or causing the regression of angiogenesis-mediated diseases and conditions of the eye 10, including choroidal neovascularization. The limus family of compounds may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD. Rapamycin may be used to prevent, treat, inhibit, delay the onset of, or cause regression of angiogenesis-mediated diseases and conditions of the eye, including choroidal neovascularization. Rapamycin may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD.
The therapeutic agent 110 may comprise one or more of: pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitors such as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) and other antibodies directed to the same target; pegaptanib (Macugen™); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; Accutane™ (13-cis retinoic acid); ACE inhibitors, including but not limited to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGF trap molecules; apoptosis inhibiting agents; Visudyne™, snET2 and other photo sensitizers, which may be used with photodynamic therapy (PDT); inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4).
The therapeutic agent 110 may comprise a combination with other therapeutic agents and therapies, including but not limited to agents and therapies useful for the treatment of angiogenesis or neovascularization, particularly CNV. Non-limiting examples of such additional agents and therapies include pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitors such as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) and other antibodies directed to the same target; pegaptanib (Macugen™); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; Accutane™ (13-cis retinoic acid); ACE inhibitors, including but not limited to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGF trap molecules; inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosis inhibiting agents; Visudyne™, snET2 and other photo sensitizers with photodynamic therapy (PDT); and laser photocoagulation.
The therapeutic agents may be used in conjunction with a pharmaceutically acceptable carrier such as, for example, solids such as starch, gelatin, sugars, natural gums such as acacia, sodium alginate and carboxymethyl cellulose; polymers such as silicone rubber; liquids such as sterile water, saline, dextrose, dextrose in water or saline; condensation products of castor oil and ethylene oxide, liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil, peanut oil, sesame oil, castor oil, and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide such as lecithin, polysorbate 80, and the like; glycols and polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, poly(vinyl pyrrolidone) and similar compounds, either alone, or with suitable dispensing agents such as lecithin, polyoxyethylene stearate and the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying agents or other related materials.
The therapeutic device 100 may comprise a container configured to hold at least one therapeutic agent 110, the container comprising a chamber 132 to hold the at least one therapeutic agent 110 with at least one opening to release the at least one therapeutic agent 110 to the vitreous humor 30 and porous structure 150 placed within the at least one opening. The porous structure 150 may comprise 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 110 to the vitreous humor 30. The rigid porous structures can provide certain advantages over capillary tubes, erodible polymers and membranes as a mechanism for controlling the release of a therapeutic agent 110 or agents from the therapeutic device 100. These advantages include the ability of the rigid porous structure to comprise a needle stop 170, simpler and more cost effective manufacture, flushability for cleaning or de-clogging either prior to or after implantation, high efficiency depth filtration of microorganisms provided by the labyrinths of irregular paths within the structure and greater robustness due to greater hardness and thickness of the structure compared to a membrane or erodible polymer matrix. Additionally, when the rigid porous structure is manufactured from a sintered metal, ceramic, glass or certain plastics, it can be subjected to sterilization and cleaning procedures, such as heat or radiation based sterilization and depyrogenation that might damage polymer and other membranes. In certain embodiments, as illustrated in Example 9 of in U.S. patent application Ser. No. 12/696,678, filed 29 Jan. 2010, entitled “Posterior Segment Drug Delivery”, published as U.S. Pub. No. 2010/0255061 on Oct. 7, 2010, the full disclosure of which has been previously incorporated herein by reference, the rigid porous structure may be configured to provide a therapeutically effective concentration of the therapeutic agent 110 in the vitreous for at least 6 months. This release profile provided by certain configurations of the rigid porous structures enables a smaller device which is preferred in a small organ such as the eye 10 where larger devices may alter or impair vision.
The porous structure 150 may comprise a first side 150S1 coupled to the reservoir 140 and a second side 150S2 to couple to the vitreous. The first side 150S1 may comprise a first area 150A1 and the second side 150S2 may comprise a second area 150A2. The porous structure 150 may comprise a thickness 150T. The porous structure 150 many comprise a diameter 150D.
The volume of the reservoir 140 may comprise from about 5 uL to about 2000 uL of therapeutic agent 110, or for example from about 10 uL to about 200 uL of therapeutic agent 110.
The therapeutic agent 110 stored in the reservoir 140 of the container 130 comprises at least one of a solid comprising the therapeutic agent 110, a solution comprising the therapeutic agent 110, a suspension comprising the therapeutic agent 110, particles comprising the therapeutic agent 110 adsorbed thereon, or particles reversibly bound to the therapeutic agent 110. For example, reservoir 140 may comprise a suspension of a cortico-steroid such as triamcinolone acetonide to treat inflammation of the retina 26. The reservoir 140 may comprise a buffer and a suspension of a therapeutic agent 110 comprising solubility within a range from about 1 μg/mL to about 100 μg/mL, such as from about 1 μg/mL to about 40 μg/mL. For example, the therapeutic agent 110 may comprise a suspension of triamcinolone acetonide having a solubility of approximately 19 μg/mL in the buffer at 37° C. when implanted.
The release rate index may comprise many values, and the release rate index with the suspension may be somewhat higher than for a solution in many embodiments, for example. The release rate index may be no more than about 5, and can be no more than about 2.0, for example no more than about 1.5, and in many embodiments may be no more than about 1.2, so as to release the therapeutic agent 110 with therapeutic amounts for the extended time.
The therapeutic device 100, including for example, the retention structure 120 and the porous structure 150, may be sized to pass through a lumen of a catheter.
The porous structure 150 may comprise a needle stop 170 that limits penetration of the needle 189. The porous structure 150 may comprise a plurality of channels configured for the extended release of the therapeutic agent 110. The porous structure 150 may comprise a rigid sintered material having characteristics suitable for the sustained release of the material.
The rigid porous structure 150 can be configured for injection of the therapeutic agent 110 into the container 130 in many ways. The channels 156 of the rigid porous structure 150 may comprise substantially fixed channels 156 when the therapeutic agent 110 is injected into the reservoir 140 with pressure. The rigid porous structure 150 comprises a hardness parameter within a range from about 160 Vickers to about 500 Vickers. In some embodiments the rigid porous structure 150 is formed from sintered stainless steel and comprises a hardness parameter within a range from about 200 Vickers to about 240 Vickers. In some embodiments it is preferred to inhibit ejection of the therapeutic agent 110 through the porous structure 150 during filling or refilling the reservoir 140 of the therapeutic device 100 with a fluid. In these embodiments the channels 156 of the rigid porous structure 150 comprise a resistance to flow of an injected solution or suspension through a thirty gauge needle such that ejection of said solution or suspension through the rigid porous structure 150 is substantially inhibited when said solution or suspension is injected into the reservoir 140 of the therapeutic device 100. Additionally, these embodiments may optionally comprise an evacuation vent or an evacuation reservoir 140 under vacuum or both to facilitate filling or refilling of the reservoir 140.
The reservoir 140 and the porous structure 150 can be configured to release therapeutic amounts of the therapeutic agent 110 in many ways. The reservoir 140 and the porous structure 150 can be configured to release therapeutic amounts of the therapeutic agent 110 corresponding to a concentration of at least about 0.1 μg per ml of vitreous humor 30 for an extended period of at least about three months. The reservoir 140 and the porous structure 150 can be configured to release therapeutic amounts of the therapeutic agent 110 corresponding to a concentration of at least about 0.1 μg per ml of vitreous humor 30 and no more than about 10 μg per ml for an extended period of at least about three months. The therapeutic agent 110 may comprise at least a fragment of an antibody and a molecular weight of at least about 10 kDa. For example, the therapeutic agent 110 may comprise one or more of ranibizumab or bevacizumab. Alternatively or in combination, the therapeutic agent 110 may comprise a small molecule drug suitable for sustained release. The reservoir 140 and the porous structure 150 may be configured to release therapeutic amounts of the therapeutic agent 110 corresponding to a concentration of at least about 0.1 ug per ml of vitreous humor 30 and no more than about 10 ug per ml for an extended period of at least about 3 months or at least about 6 months. The reservoir 140 and the porous structure 150 can be configured to release therapeutic amounts of the therapeutic agent corresponding to a concentration of at least about 0.1 ug per ml of vitreous humor 30 and no more than about 10 ug per ml for an extended period of at least about twelve months or at least about two years or at least about three years. The reservoir 140 and the porous structure 150 may also be configured to release therapeutic amounts of the therapeutic agent 110 corresponding to a concentration of at least about 0.01 ug per ml of vitreous humor 30 and no more than about 300 ug per ml for an extended period of at least about 3 months or 6 months or 12 months or 24 months.
The channels 156 of the rigid porous structure 150 comprise a hydrogel configured to limit a size of molecules passed through the channels 156 of the rigid porous structure 150. For example, the hydrogel can be formed within the channels 156 and may comprise an acrylamide gel. The hydrogel comprises a water content of at least about 70%. For example, the hydrogel may comprise a water content of no more than about 90% to limit molecular weight of the therapeutic agent 110 to about 30 kDa. The hydrogel comprises a water content of no more than about 95% to limit molecular weight of the therapeutic agent 110 to about 100 kDa. The hydrogel may comprise a water content within a range from about 90% to about 95% such that the channels 156 of the porous material are configured to pass Lucentis™ and substantially not pass Avastin™.
The rigid porous structure 150 may comprise a composite porous material that can readily be formed in or into a wide range of different shapes and configurations. For example, the porous material can be a composite of a metal, aerogel or ceramic foam (i.e., a reticulated inter-cellular structure in which the interior cells are interconnected to provide a multiplicity of pores passing through the volume of the structure, the walls of the cells themselves being substantially continuous and non-porous, and the volume of the cells relative to that of the material forming the cell walls being such that the overall density of the intercellular structure is less than about 30 percent theoretical density) the through pores of which are impregnated with a sintered powder or aerogel. The thickness, density, porosity and porous characteristics of the final composite porous material can be varied to conform with the desired release of the therapeutic agent 110.
Embodiments comprise a method of making an integral (i.e., single-component) porous structure 150. The method may comprise introducing particles into a mold having a desired shape for the porous structure 150. The shape may include a proximal end defining a plurality of proximal porous channel openings to couple to the reservoir 140, a distal end defining a plurality of outlet channel openings to couple to the vitreous humor 30 of the eye 10, a plurality of blind inlet cavities extending into the filter from the proximal openings, and a plurality of blind outlet cavities extending into the porous structure 150 from the outlet channel openings. The method further includes applying pressure to the mold, thereby causing the particles to cohere and form a single component, and sintering the component to form the porous structure 150. The particles can be pressed and cohere to form the component without the use of a polymeric binder, and the porous structure 150 can be formed substantially without machining.
The mold can be oriented vertically with the open other end disposed upwardly, and metal powder having a particle size of less than 20 micrometers can be introduced into the cavity through the open end of the mold while vibrating the mold to achieve substantially uniform packing of the metal powder in the cavity. A cap can be placed on the open other end of the mold, and pressure is applied to the mold and thereby to the metal powder in the cavity to cause the metal powder to cohere and form a cup-shaped powdered metal structure having a shape corresponding to the mold. The shaped powdered metal structure can be removed from the mold, and sintered to obtain a porous sintered metal porous structure 150.
The metal porous structure 150 can be incorporated into the device by a press fit into an impermeable structure with an opening configured to provide a tight fit with the porous structure 150. Other means, such as welding, known to those skilled in the art can be used to incorporate the porous structure 150 into the device. Alternatively, or in combination, the powdered metal structure can be formed in a mold where a portion of the mold remains with the shaped powdered metal structure and becomes part of the device. This may be advantageous in achieving a good seal between the porous structure 150 and the device.
The release rate of therapeutic agent 110 through a porous body, such as a sintered porous metal structure or a porous glass structure, may be described by diffusion of the therapeutic agent 110 within the porous structure 150 with the channel parameter, and with an effective diffusion coefficient equal to the diffusion coefficient of the therapeutic agent 110 in the liquid that fills the reservoir multiplied by the Porosity and a Channel Parameter of the porous body:
Release Rate=(DP/F)A(cR−cV)/L, where:
The release rate index can (hereinafter RRI) be used to determine release of the therapeutic agent 110. The RRI may be defined as (PA/FL), and the RRI values herein will have units of mm unless otherwise indicated. Many of the porous structures used in the therapeutic delivery devices described here have an RRI of no more than about 5.0, often no more than about 2.0, and can be no more than about 1.2 mm.
The channel parameter can correspond to an elongation of the path of the therapeutic agent 110 released through the porous structure 150. The porous structure 150 may comprise many interconnecting channels 156, and the channel parameter can correspond to an effective length that the therapeutic agent 110 travels along the interconnecting channels 156 of the porous structure 150 from the reservoir side to the vitreous side when released. The channel parameter multiplied by the thickness (length) of the porous structure 150 can determine the effective length that the therapeutic agent 110 travels along the interconnecting channels 156 from the reservoir side to the vitreous side. For example, the channel parameter (F) of about 1.5 corresponds to interconnecting channels 156 that provide an effective increase in length traveled by the therapeutic agent 110 of about 50%, and for a 1 mm thick porous structure 150 the effective length that the therapeutic agent 110 travels along the interconnecting channels 156 from the reservoir side to the vitreous side corresponds to about 1.5 mm. The channel parameter (F) of at least about 2 corresponds to interconnecting channels 156 that provide an effective increase in length traveled by the therapeutic agent 110 of about 100%, and for a 1 mm thick porous structure 150 the effective length that the therapeutic agent 110 travels along the interconnecting channels 156 from the reservoir side to the vitreous side corresponds to at least about 2.0 mm. As the porous structure 150 comprises many interconnecting channels 156 that provide many alternative paths for release of the therapeutic agent 110, blockage of some of the channels 156 provides no substantial change in the effective path length through the porous structure 150 as the alternative interconnecting channels 156 are available, such that the rate of diffusion through the porous structure 150 and the release of the therapeutic agent 110 are substantially maintained when some of the channels 156 are blocked.
If the reservoir solution is aqueous or has a viscosity similar to water, the value for the diffusion coefficient of the therapeutic agent (TA) in water at the temperature of interest may be used. The following equation can be used to estimate the diffusion coefficient at 37° C. from the measured value of DBSA,20C=6.1 e-7 cm2/s for bovine serum albumin in water at 20° C. (Molokhia et al, Exp Eye Res 2008):
DTA,37C=DBSA,20C(η20C/η37C)(MWBSA/MWTA)1/3 where
MW refers to the molecular weight of either BSA or the test compound and η is the viscosity of water. The following table lists diffusion coefficients of proteins of interest.
Small molecules have a diffusion coefficient similar to fluorescein (MW=330, D=4.8 to 6 e-6 cm2/s from Stay, M S et al., Pharm Res 2003, 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 structure 150 comprises a porosity, a thickness, a channel parameter and a surface area configured to release therapeutic amounts for the extended period. The porous material may comprise a porosity corresponding to the fraction of void space of the channels 156 extending within the material. The porosity may comprise a value within a range from about 3% to about 70%. In other embodiments, the porosity may comprise a value with 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
The porous structure 150 may comprise a plurality of porous structures, and the area used in the above equation may comprise the combined area of the plurality of porous structures.
The channel parameter may comprise a fit parameter corresponding to the tortuosity of the channels 156. For a known porosity, surface area and thickness of the surface parameter, the curve fit parameter F, which may correspond to tortuosity of the channels 156 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 110 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 150 releases the therapeutic agent 110 for the extended period. For example, the ratio of the porosity to the channel parameter is less than about 0.1 or for example less than about 0.2 such that the porous structure 150 releases the therapeutic agent 110 for the extended period. The channel parameter may comprise a value of at least about 1, such as at least about 1.2. For example, the value of the channel parameter may comprise at least about 1.5, for example at least about 2, and may comprise at least about 5. The channel parameter can be within a range from about 1.1 to about 10, for example within a range from about 1.2 to about 5. A person of ordinary skill in the art can conduct experiments based on the teachings described herein to determine empirically the channel parameter to release the therapeutic agent 110 for an intended release rate profile.
The area 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 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 body in the shape of a truncated cone, the effective area is a value in between the area where therapeutic agent 110 enters the porous body and the area where therapeutic agent 110 exits the porous body.
A model can be derived to describe the release rate as a function of time by relating the change of concentration in the reservoir 140 to the release rate described above. This model assumes a solution of therapeutic agent 110 where the concentration in the reservoir 140 is uniform. In addition, the concentration in the receiving fluid or vitreous 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 110 from a solution in a reservoir though a porous structure 150.
cR=cR0 exp((−DPA/FLVR)t)
and Cumulative Release=1−cR/cR0
When the reservoir 140 contains a suspension, the concentration in reservoir, cR, is the dissolved concentration in equilibrium with the solid (i.e., the solubility of the therapeutic agent). In this case, the concentration in the reservoir is constant with time, the release rate is zero order, and the cumulative release increases linearly with time until the time when the solid is exhausted.
Therapeutic concentrations for many ophthalmic therapeutic agents may be determined experimentally by measuring concentrations in the vitreous humor 30 that elicit a therapeutic effect. Therefore, there is value in extending predictions of release rates to predictions of concentrations in the vitreous. A one-compartment model may be used to describe elimination of therapeutic agent from eye tissue.
Current intravitreal administration of therapeutic agents such as Lucentis™ involves a bolus injection. A bolus injection into the vitreous may be modeled as a single exponential with rate constant, k=0.693/half-life and a cmax=dose/Vv where Vv is the vitreous volume. As an example, the half-life for ranibizumab is approximately 3 days in the rabbit and the monkey (Gaudreault et al) and 9 days in humans (Lucentis™ package insert). The vitreous volume is approximately 1.5 mL for the rabbit and monkey and 4.5 mL for the human eye. The model predicts an initial concentration of 333 ug/mL for a bolus injection of 0.5 mg Lucentis™ into the eye of a monkey. This concentration decays to a vitreous concentration of 0.1 ug/mL after about a month.
For devices with extended release, the concentration in the vitreous changes slowly with time. In this embodiment, a model can be derived from a mass balance equating the release rate from the device (described by equations above) with the elimination rate from the eye, k cv Vv. Rearrangement yields the following equation for the concentration in the vitreous:
cv=Release rate from device/kVv.
Since the release rate from a device with a solution of therapeutic agent 110 decreases exponentially with time, the concentration in the vitreous decreases exponentially with the same rate constant. In other words, vitreous concentration decreases with a rate constant equal to D PA/FL VR and, hence, is dependent on the properties of the porous structure 150 and the volume of the reservoir.
Since the release rate is zero order from a device with a suspension of therapeutic agent 110, the vitreous concentration will also be time-independent. The release rate will depend on the properties of the porous structure 150 via the ratio, PA/FL, but will be independent of the volume of the reservoir until the time at which the drug is exhausted.
Exemplary Porous Structures for Release of Therapeutic Agents
Although the porous structure 150 may comprise one or more of many structures as described herein to release the therapeutic agent 110, in many embodiments the porous structure 150 comprises a rigid porous structure 150. The channels 156 of the rigid porous structure 150 can be sized in many ways to release the intended therapeutic agent 110. For example, the channels 156 of the rigid porous structure 150 can be sized to pass therapeutic agent 110 comprising molecules having a molecular weight of at least about 100 Da or for example, at least about 50 kDa. The channels 156 of the rigid porous structure 150 can be sized to pass therapeutic agent 110 comprising molecules comprising a cross-sectional size of no more than about 10 nm. The channels 156 of the rigid porous structure 150 comprise interconnecting channels 156 configured to pass the therapeutic agent 110 among the interconnecting channels 156. The rigid porous structure 150 comprises grains of rigid material and wherein the interconnecting channels 156 extend at least partially around the grains of rigid material to pass the therapeutic agent 110 through the porous material. The grains of rigid material can be coupled together at a loci of attachment and wherein the interconnecting channels 156 extend at least partially around the loci of attachment.
The porous structure 150 and reservoir 140 may be configured to release the glucocorticoid for an extended time of at least about six months with a therapeutic amount of glucocorticoid of corresponding to an in situ concentration within a range from about 0.05 μg/mL to about 4 μg/mL, for example from 0.1 μg/mL to about 4 μg/mL, so as to suppress inflammation in the retina-choroid.
The porous structure 150 can be comprised of a sintered material. The sintered material may comprise grains of material 155 in which the grains comprise an average size of no more than about 20 μm. For example, the sintered material may comprise grains of material 155 in which the grains comprise an average size of no more than about 10 μm, an average size of no more than about 5 μm, or an average size of no more than about 1 μm. The channels 156 are sized to pass therapeutic quantities of the therapeutic agent 110 through the sintered material for the extended time based on the grain size of the sintered material and processing parameters such as compaction force and time and temperature in the furnace. The channels 156 can be sized to inhibit penetration of microbes including bacterial and fungal spores through the sintered material.
The sintered material can be comprised of a wettable material to inhibit bubbles within the channels 156 of the material.
The sintered material can be comprised of at least one of a metal, a ceramic, a glass or a plastic. The sintered material may comprise a sintered composite material, and the composite material can comprise two or more of the metal, the ceramic, the glass or the plastic. The metal can comprise at least one of Ni, Ti, nitinol, stainless steel including alloys such as 304, 304L, 316 or 316L, cobalt chrome, elgiloy, hastealloy, c-276 alloy or Nickel 200 alloy. The sintered material may comprise a ceramic. The sintered material may comprise a glass. The plastic may comprise a wettable coating to inhibit bubble formation in the channels, and the plastic may comprise at least one of polyether ether ketone (PEEK), polyethylene, polypropylene, polyimide, polystyrene, polycarbonate, polyacrylate, polymethacrylate, or polyamide.
The rigid porous structure 150 may comprise a plurality of rigid porous structures coupled to the reservoir and configured to release the therapeutic agent 110 for the extended period. For example, additional rigid porous structure 150 can be disposed along the container 130, for example the end of the container 130 may comprise the porous structure 150, and an additional porous structure 150 can be disposed along a distal portion of the container 130, for example along a tubular sidewall of the container 130.
The therapeutic device 100 can be tuned to release therapeutic amounts of the therapeutic agent 110 above the minimum inhibitory concentration for an extended time based on bolus injections of the therapeutic agent 110. For example, the volume of the chamber 132 of the reservoir 140 can be sized with the release rate of the porous structure 150 based on the volume of the bolus injection. A formulation of a therapeutic agent 110 can be provided, for example a known intravitreal injection formulation. The therapeutic agent 110 can be capable of treating the eye 10 with bolus injections, such that the formulation has a corresponding period between each of the bolus injections to treat the eye 10. For example the bolus injections may comprise monthly injections. Each of the bolus injections comprises a volume of the formulation, for example 50 μL. Each of the bolus injections of the therapeutic agent 110 may correspond to a range of therapeutic concentrations of the therapeutic agent 110 within the vitreous humor 30 over the time course between injections, and the device can be tuned so as to release therapeutic amounts of the therapeutic agent 110 such that the vitreous concentrations of the released therapeutic agent 110 from the device are within the range of therapeutic concentrations of the corresponding bolus injections. For example, the therapeutic agent 110 may comprise a minimum inhibitory concentration to treat the eye 10, for example at least about 3 μg/mL, and the values of the range of therapeutic concentrations can be at least about 3 μg/mL. The therapeutic device 100 can be configured to treat the eye 10 with an injection of the monthly volume of the formulation into the device, for example through the penetrable barrier 184. The reservoir 140 of the container 130 has a chamber 132 to contain a volume of the therapeutic agent 110, for example 35 μL, and a mechanism to release the therapeutic agent 110 from the chamber 132 to the vitreous humor 30.
The volume of the container 130 and the release mechanism can be tuned to treat the eye 10 with the therapeutic agent 110 with vitreous concentrations within the therapeutic range for an extended time with each injection of the quantity corresponding to the bolus injection, such that the concentration of the therapeutic agent 110 within the vitreous humor 30 remains within the range of therapeutic concentrations and comprises at least the minimum inhibitory concentration. The extended time may comprise at least about twice the corresponding period of the bolus injections. The release mechanism comprises one or more of a porous frit, a sintered porous frit, a permeable membrane, a semi-permeable membrane, a capillary tube or a tortuous channel, nano-structures, nano-channels or sintered nano-particles. For example, the porous frit may comprise a porosity, cross-sectional area, and a thickness to release the therapeutic agent 110 for the extended time. The volume of the container 130 reservoir 140 can be sized in many ways in relation to the volume of the injected formulation and can be larger than the volume of injected formulation, smaller than the volume of injected formulation, or substantially the same as the volume of injected formulation. For example, the volume of the container 130 may comprise no more than the volume of the formulation, such that at least a portion of the formulation injected into the reservoir passes through the reservoir and comprises a bolus injection to treat the patient immediately. As the volume of the reservoir is increased, the amount of formulation released to the eye 10 through the porous structure 150 upon injection can decrease along with the concentration of active ingredient of the therapeutic agent 110 within the reservoir 140, and the release rate index can be increased appropriately so as to provide therapeutic amounts of therapeutic agent 110 for the extended time. For example, the volume of the reservoir 140 of the container 130 can be greater than the volume corresponding to the bolus injection, so as to provide therapeutic amounts for at least about five months, for example 6 months, with an injection volume corresponding to a monthly injection of Lucentis™. For example, the formulation may comprise commercially available Lucentis™, 50 μL, and the reservoir may comprise a volume of about 100 μL and provide therapeutic vitreous concentrations of at least about 3 μg/mL for six months with 50 μL of Lucentis™ injected into the reservoir.
The chamber may comprise a substantially fixed volume and the release rate mechanism can be comprised of a substantially rigid structure to maintain release of the therapeutic agent 110 above the minimum inhibitory concentration for the extended time with each injection of a plurality of injections.
A first portion of the injection may pass through the release mechanism and treat the patient when the formulation is injected, and a second portion of the formulation can be contained in the chamber when the formulation is injected.
The channel parameter and effective length from the first side 150S1 to the second side 150S2 can be configured in many ways. The channel parameter can be greater than 1 and within a range from about 1.2 to about 5.0, such that the effective length is within a range about 1.2 to 5.0 times the thickness 150T, although the channel parameter may be greater than 5, for example within a range from about 1.2 to 10. For example, the channel parameter can be from about 1.3 to about 2.0, such that the effective length is about 1.3 to 2.0 times the thickness 150T. For example, experimental testing has shown the channel parameter can be from about 1.4 to about 1.8, such that the effective length is about 1.4 to 1.8 times the thickness 150T, for example about 1.6 times the thickness. These values correspond to the paths of the channels 156 around the sintered grains of material 155 and may correspond, for example, to the paths of channels 156 around packed beads of material.
The rigid porous structure 150 can be shaped and molded in many ways, for example with tubular shapes, conical shapes, discs and hemispherical shapes. The rigid porous structure 150 may comprise a molded rigid porous structure 150. The molded rigid porous structure 150 may comprises at least one of a disk, a helix or a tube coupled to the reservoir and configured to release the therapeutic agent 110 for the extended period.
The injector 701 may comprise a first container 702C to contain a formulation of therapeutic agent 702 and a second container 703C to receive the spent media 703. Work in relation to embodiments suggests that the removal of spent media 703 comprising material from the container reservoir of the therapeutic device 100 can remove particulate from the therapeutic device 100, for example particles comprised of aggregated therapeutic agent such as protein. The needle 189 may comprise a double lumen needle with a first lumen coupled to the first container 702C and a second lumen coupled to the second container 703C, such that spent media 703 passes from the container reservoir of device 100 to the injector. A valve 703V, for example a vent, can be disposed between the second lumen and the second container 703C. When the valve 703V is open and therapeutic agent 702 is injected, spent media 703 from the container reservoir of the therapeutic device 100 passes to the second container 703C of the injector 701, such that at least a portion of the spent media 703 within the therapeutic device 100 is exchanged with the formulation. When the valve 703V is closed and the therapeutic agent is injected, a portion of the therapeutic agent passes from the reservoir of the therapeutic device 100 into the eye 10. For example, a first portion of formulation of therapeutic agent 702 can be injected into therapeutic device 100 when the valve is open such that the first portion of the formulation is exchanged with material disposed within the reservoir; the valve is then closed and a second portion of the formulation is injected into therapeutic device 100 such that at least a portion of the first portion passes through the porous structure 150 into the eye 10. Alternatively or in combination, a portion of the second portion of injected formulation may pass through the porous structure 150 when the second portion is injected into the eye 10. The second portion of formulation injected when the valve 703V is closed may correspond to a volume of formulation that passes through the porous structure 150 into the vitreous humor 30 to treat the patient immediately. In addition, the needle 189 may comprise a dual lumen needle, for example as described with reference to
Work in relation to the injector embodiments indicates that a filling efficiency of at least about 80%, for example 90% or more can be achieved with injector apparatus and needles as described above.
The visual indicator 189DS may comprise a bright color and may comprise a soft deformable material such as silicone, and may have a Shore A hardness from about 5 to about 30, for example. The stop 189S may comprise a dark color, such that the deformable indicator becomes visible when coupled to tissue. Prior to contact with the tissue, the deformable indicator 189DS can have a first width 189DSW1.
The moving component of the valve 703V may comprise one or more of many components such as a ball valve, a sleeve, a gasket, a piston having holes, or a one way pressure valve, a solenoid, or a servo, for example.
The injector 701 can comprise a mechanism to maintain the rate of flow into the device and limit a maximum amount of flow, for example with a spring 701SP. The mechanism may comprise one or more of a mechanical mechanism, an electrical mechanism, a pneumatic mechanism, a hydraulic mechanism, or combinations thereof. Although a mechanical mechanism is shown, the above described mechanisms can provide similar results.
The visible indicator 189DS can be used to indicate to the operator that injector 701 is coupled to the therapeutic device 100 implanted in the eye 10 at a depth for injection. The operator can then depress the plunger.
The plunger 701PL can comprise a telescopic joint 701TJ and a spring 701SP, such that the joint 701TJ can be slid together such that the plunger 701PL is urged downward to contact the stop. When the plunger is urged downward, the spring may be compressed when the ends of the telescopic joint come together. The compressed spring can urge the piston toward the therapeutic device 100 such that the formulation of therapeutic agent may be injected into the therapeutic device 100 with the force of the spring. The valve 703V can close as described above (see
The retention structure 120 can comprise a narrow section 120N having a short distance 120NS and a long distance 120NL so as to fit in an elongate incision along, for example, the pars plana of the eye 10. The retention structure 120 may be comprised of an extension 120E. The extension of the retention structure 120E can comprise a short distance across 122S and a long distance across 122L, aligned with the short distance 120NS and long distance 120NL of the narrow portion 120N of the retention structure 120. The narrow portion 120N may comprise an indentation 1201 sized to receive the sclera 24 (see
The elongate cross-section 120NE of the narrow portion 120N can be sized in many ways to fit the incision. The elongate cross-section 120NE may comprise a first dimension longer than a second dimension and may comprise one or more of many shapes such as dilated slot, dilated slit, lentoid, oval, ovoid, or elliptical. The dilated slit shape and dilated slot shape may correspond to the shape sclera 24 tissue assumes when cut and dilated. The lentoid shape may correspond to a biconvex lens shape. The elongate cross-section of the narrow portion may comprise a first curve along a first axis and a second curve along a second axis different than the first curve.
Similar to the narrow portion 120N of the retention structure, the container reservoir may comprise a cross-sectional profile. The barrier 160 can have as a perimeter circumference 160P.
The retention structure 120 may comprise structures corresponding to a structure of the cross-sectional area. For example, the flange 122 may comprise a first distance across and a second distance across, with the first distance across greater than the second distance across. The extension may comprise many shapes, such as rectangular, oval, or elliptical, and the long distance across can correspond to the long distance of the reservoir and barrier. The retention structure 120 may comprise the narrow portion 120N having an indentation 1201 (see
The penetrable barrier 184, for example the septum, can be inserted into the access port 180. The penetrable barrier 184 may comprise an elastic material sized such that the penetrable barrier 184 can be inserted into the access port 180. The penetrable barrier 184 may comprise one or more elastic materials, such as siloxane or rubber. The penetrable barrier 184 may comprise tabs 184T to retain the penetrable barrier 184 in the access port. The penetrable barrier 184 may comprise a beveled upper rim 184R sized to seal the access port 180. The access port 180 of the reservoir container 130 may comprise a beveled upper surface to engage the beveled rim and seal the penetrable barrier 184 against the access port 180 when the tabs 184T engage an inner annular or elongate channel of the access port 180. The penetrable barrier 184 may comprise an opaque material, for example a grey material, for example silicone, such that the penetrable barrier 184 can be visualized by the patient and treating physician.
The reservoir container 130 of the device may comprise a rigid biocompatible material that extends at least from the retention structure to the rigid porous structure 150, such that the reservoir comprises a substantially constant volume when the therapeutic agent is released with the rigid porous structure 150 so as to maintain a stable release rate profile, for example when the patient moves. Alternatively or in combination, the reservoir container 130 may comprise an optically transmissive material such that the reservoir container 130 can be translucent, for example transparent, such that the reservoir chamber 140 can be visualized when the device is loaded with therapeutic agent outside the patient prior to implantation, for example when injected with a formulation of therapeutic agent prior to implantation in the physician's office. This visualization of the reservoir chamber 140 can be helpful to ensure that the reservoir chamber 140 is properly filled with therapeutic agent by the treating physician or assistant prior to implantation. The reservoir container 130 may comprise one or more of many biocompatible 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 or PTFE. The biocompatible material of the reservoir container may comprise an optically transmissive material such as one or more of acrylate, polyacrylate, methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate or siloxane. The reservoir container 130 can be machined from a piece of material, or injection molded, so as to form the retention structure 120 comprising flange 122 and the elongate narrow portion 120NE. The flange 122 may comprise a translucent material such that the physician can visualize tissue under the flange to assess the patient and to decrease appearance of the device 100 when implanted. The reservoir container 130 may comprise a channel extending along axis 100A from the access port 180 to porous structure 150, such that formulation injected into device 100 can be released in accordance with the volume of the reservoir and release rate of the porous structure 150 as described herein. The porous structure 150 can be affixed to the distal end of therapeutic device 100, for example with glue. Alternatively or in combination, the distal end of the reservoir container 130 may comprise an inner diameter sized to receive the porous structure 150, and the reservoir container 130 may comprise a stop to position the porous structure 150 at a predetermined location on the distal end so as to define a predetermined size of reservoir chamber 140.
The support 160S of the barrier 160 can provide a substantially constant volume of the reservoir in the expanded configuration. The substantially constant volume, for example +/−25%, can be combined with the release rate index of the porous structure 150 so as to tune the expanded reservoir and porous structure 150 to the volume of therapeutic agent to be injected into the therapeutic device, as described herein. The barrier 160 may comprise a thin compliant material, for example a membrane, and the support 160S can urge the barrier 160 to an expanded configuration so as to define the reservoir chamber having the substantially constant volume.
The therapeutic device 100 can be sized such that porous structure 150 is positioned along a flow path extending toward a target location of the retina 26. The therapeutic agent can be released along the flow path, such that the flow of vitreous humor 30 transports the therapeutic agent to the retina 26. The porous structure can be disposed on a distal portion of the therapeutic device 100, for example on a distal end, and the reservoir 130 can be sized for delivery for the extended time. The therapeutic device 100 can be sized such that the porous structure 150 is positioned such that it may correspond to the target region. The surgeon may identify a target region 798 of the retina 26, for example corresponding to a lesion, and the therapeutic device 100 can be positioned along the pars plana or other location such that the therapeutic agent is released to the target region.
Tuning of Therapeutic Device for Sustained Release Based on an Injection of a Formulation
The therapeutic device 100 can be tuned to deliver a target therapeutic concentration profile based on the volume of formulation injected into the device. The injected volume may comprise a substantially fixed volume, for example within about +/−30% of an intended pre-determined target volume. The volume of the reservoir can be sized with the release rate index so as to release the therapeutic agent for an extended time substantially greater than the treatment time of a corresponding bolus injection. The device can also be tuned to release the therapeutic agent based on the half-life of the therapeutic agent in the eye 10. The device volume and release rate index may comprise parameters that can be tuned together based on the volume of formulation injected and a half-life of the therapeutic agent in the eye 10. The following equations can be used to determine therapeutic device 100 parameters suitable for tuning the device.
Rate=Vr(dCr/dt)=−D(PA/TL)Cr
where Rate=Rate of release of therapeutic agent from device
Cr=concentration of therapeutic agent in reservoir
Vr=volume of reservoir
D=Diffusion constant
PA/TL=RRI
P=porosity
A=area
T=tortuosity=F=channel parameter.
For a substantially fixed volume injection,
Cr0=(Injection Volume)(Concentration of Formulation)/Vr
Where Cr0=initial concentration in reservoir following injection of formulation For Injection Volume=50 uL
Cr0=(0.05 mL)(10 mg/mL)/Vr(1000 ug/1 mg)=500 ug/Vr
Rate=x(500 ug)exp(−xt)
where t=time
x=(D/Vr)(PA/TL)
With a mass balance on the vitreous
Vv(dCv/dt)=Rate from device=kVvCv
where Vv=volume of vitreous (about 4.5 ml)
Cv=concentration of therapeutic agent in vitreous
k=rate of drug from vitreous (proportional to 1/half-life of drug in vitreous)
For the situation appropriate for the embodiments as described herein where Cv remains substantially constant and changes slowly with time (i.e., dCv/dt is approximately 0),
Cv=(Rate from device)/(kVv)
Since kVv is substantially constant, the max value of Cv will correspond to conditions that maximize the Rate from the device. At a given time since injection into the device (e.g., 180 days), the maximum Cv is found at the value of x that provides the maximum rate. The optimal value of x satisfies
d(Rate)/dx=0 at a given time.
Rate=500(x)exp(−xt)=f(x)g(x) where f(x)=500x and g(x)=exp(−xt)
d(Rate)/dx=f′(x)g(x)+f(x)g′(x)=500(1−xt)exp(−xt)
For a given time, t, d(Rate)/dx=0 when 1−xt=0 and xt=1
The rate is maximum when (D/Vr)(PA/TL)t=1.
For a given volume, optimal PA/TL=optimal RRI=Vr/(Dt)
Therefore the highest Cv at a given time, t, occurs for the optimal RRI=(PA/FL) for a given Vr.
Also, the ratio (Vr)/(RRI)=(Vr)/(PA/TL)=Dt will determine the optimal rate at the time.
The above equations can provide approximate optimized values that, when combined with numerical simulations, can provide optimal values of Vr and PA/TL. The final optimum value can depend on additional parameters, such as the filling efficiency.
The above parameters can be used to determine the optimal RRI, and the therapeutic device 100 can be tuned to the volume of formulation injected into the device with a device reservoir volume and release rate index within about +/−50% of the optimal values, for example +/−30% of the optimal values. For example, for an optimal release rate index of the porous structure 150 and an optimal reservoir volume sized to receive a predetermined quantity of therapeutic agent, e.g. 50 uL, so as to achieve therapeutic concentrations above a minimum inhibitory concentration for a predetermined extended time, such as 90 days, the maximum volume of the reservoir can be limited to no more than about twice the optimal volume. This tuning of the reservoir volume and the porous structure 150 to the injected volume of the commercially available formulation can increase the time of release of therapeutic amounts from the device as compared to a much larger reservoir volume that receives the same volume of commercially available injectable formulation. Although many examples as described herein show a porous frit structure and reservoir volume tuned together to receive a quantity of formulation and provide release for an extended time, the porous structure 150 tuned with the reservoir may comprise one or more of a porous frit, a permeable membrane, a semi-permeable membrane, a capillary tube or a tortuous channel, nano-structures, nano-channels 156 NC or sintered nano-particles, and a person of ordinary skill in the art can determine the release rate characteristics, for example a release rate index, so as to tune the one or more porous structures and the volume to receive the quantity of the formulation and release therapeutic amounts for an extended time.
As an example, the optimal RRI at 180 days can be determined for a reservoir volume of about 125 uL. Based on the above equations (Vr/Dt)=optimal RRI, such that the optimal RRI at 180 days is about 0.085 for the 50 uL formulation volume injected into the device. The corresponding Cv is about 3.19 ug/mL at 180 days based on the Rate of drug released from the device at 180 days and the rate of the drug from the vitreous (k corresponding to a half-life of about nine days). A device with a container reservoir volume of 63 uL and RRI of 0.044 will also provide the optimal Cv at 180 days since the ratio of Vr to PA/TL is also optimal. Although an optimal value can be determined, the therapeutic device 100 can be tuned to provide therapeutic amounts of drug at a targeted time, for example 180 days, with many values of the reservoir volume and many values of the release rate index near the optimal values, for example within about +/−50% of the optimal values. Although the volume of the reservoir can be substantially fixed, the volume of the reservoir can vary, for example within about +/−50% as with an expandable reservoir such as a balloon reservoir.
The half-life of the drug in the vitreous humor 30 of the eye 10 can be determined based on the therapeutic agent and the type of eye, for example human, rabbit or monkey, such that the half-life may be determined based on the species of the eye, for example. With at least some animal models the half-life of the therapeutic agent in the vitreous humor 30 can be shorter than for human eyes, for example by a factor of about two in at least some instances. For example, the half-life of the therapeutic agent Lucentis™ (ranibizumab) can be about nine days in the human eye and about two to four days in the rabbit and monkey animal models. For small molecules, the half-life in the vitreous humor 30 of the human eye can be about two to three hours and can be about one hour in the monkey and rabbit animal models. The therapeutic device 100 can be tuned to receive the volume of formulation based on the half-life of the therapeutic agent in the human vitreous humor 30, or an animal vitreous humor, or combinations thereof. Based on the teachings described herein, a person of ordinary skill in the art can determine empirically the half-life of the therapeutic agent in the eye 10 based on the type of eye and the therapeutic agent, such that the reservoir and porous structure can be tuned together so as to receive the volume of formulation and provide therapeutic amounts for the extended time.
The rate of accumulation of a component of the vitreous humor 30 of the eye can be determined based on the molecular weight of the component and the tuning of the therapeutic device 100 such as the reservoir volume and release of porous structure 150, such as a release rate index.
The container may be coupled to elongate structure 172, and the elongate structure may have a length sized so as to extend from the conjunctiva 16 to the vitreous to release the therapeutic agent into the vitreous. The length can be sized within a range, for example within a range from about 2 to about 14 mm, for example within a range from about 4 to 10 mm and can be about 7 mm, for example. The penetrable barrier 184 may comprise a septum disposed on a proximal end of the container, in which the septum comprises a barrier that can be penetrated with a sharp object such as a needle for injection of the therapeutic agent. The porous structure 150 may comprise a cross-sectional area sized to release the therapeutic agent for the extended period. The elongate structure 172 can be located near a center of the container 130, or may be eccentric to the center. In addition, the elongate structure 172 can be inserted into the sclera 24 at the pars plana region as described herein.
The barrier 160 can have a shape profile for placement between the conjunctiva 16 and sclera 24. The lower surface can be shaped to contact the sclera 24 and may comprise a concave shape such as a concave spherical or toric surface. The upper surface can be shaped to contact the conjunctiva 16 and may comprise a convex shape, such as a convex spherical or toric surface. The barrier 160 may comprise an oval, an elliptical, or a circular shape when implanted and viewed from above, and the elongate structure 172 can be centered or eccentric to the ellipse. When implanted the long dimension of the oval can be aligned so as to extend along a circumference of the pars plana.
The cross-sectional diameter of the elongate structure 172 can be sized to decrease the invasiveness of device 100, and may comprise a diameter of no more than about 1 mm, for example no more than about 0.5 mm, for example no more than about 0.25 mm such that the penetrate sclera 24 seals substantially when elongate structure 172 is removed and the eye 10 can seal itself upon removal of elongate structure 172. The elongate structure 172 may comprise a needle, and channel 174 may comprise a lumen of the needle, for example a 30 Gauge needle.
The porous structure 150 may comprise a first side as described herein coupled to the reservoir and a second side to couple to the vitreous. The first side may comprise a first area as described herein and the second side may comprise a second area. The porous structure 150 may comprise a thickness as described herein. The porous structure 150 many comprise a diameter. The porous structure 150 may comprise a release rate index, and the chamber of container 130 that defines the volume of reservoir 140 can be sized such that the porous structure 150 and the volume are tuned to receive an amount of therapeutic agent injected with a volume of formulation of therapeutic agent and tuned to release therapeutic amounts for an extended time. Many release rate mechanisms as described herein can be used to tune the release rate and volume to the quantity of therapeutic agent injected as described herein. In addition, the volume of the reservoir 140 defined by the chamber of the container may comprise from about 5 μL to about 2000 μL of therapeutic agent, or for example from about 10 μL to about 200 μL of therapeutic agent.
The porous structure 150 may comprise a needle stop 170 that limits penetration of the needle. The porous structure 150 may comprise a plurality of channels configured for the extended release of the therapeutic agent. The porous structure may comprise a rigid sintered material having characteristics suitable for the sustained release of the material.
The injector 701 as described above (see
The cartridge 320 comprises a connector 322 to couple to a syringe. The connector 322 may comprise one or more standard connectors to couple to a syringe such as a Luer connector or a Hamilton connector. The cartridge 320 may comprise at least one needle such as a first needle 324 having a first lumen 324L and a second needle 326 having a second lumen 326L. The first needle and lumen are fluidically coupled to the connector 322. The second needle 326 and second lumen 326L are fluidically coupled to the container 328. The cartridge container 328 may comprise a window 328W to view the contents of container 328 and the container 328 may comprise an optically clear material. The at least one needle may comprise a double lumen needle as described herein. A valve 703V is coupled to the container 328, such that the valve 703V substantially closes when the volume of the container 328 is filled with sample fluid.
The valve 703V may comprise one or more of the valves as described herein. In many embodiments, the valve 703V may comprise a porous structure 150 having a resistance to flow of liquid greater than a resistance to a flow of air, such that the flow of liquid is substantially inhibited when liquid contacts the porous structure 150. The valve 703V may have a resistance to flow greater than porous structure 150, so as to drive liquid through porous structure 150 when liquid contact the porous structure 150 of valve 703V.
The packaging container 310 comprises a removable cover 314 and a housing 312. The housing 312 comprises a channel 316 to receive the at least one needle 324. The height of the housing 312 and channel 316 are sized to receive the cartridge 320 with the at least one needle extending along the channel 316 and the cover 314 placed on the housing 312.
The apparatus 300 comprises an identifier 350. The identifier 350 may comprise one or more of an optical bar code, a 2D bar code, a magnetic stripe, or an RFID device. The identifier 350 can be located on the housing 312. Alternatively, identifier 350 can be located on cartridge 320. The identifier 350 can be linked to a patient ID when the sample is taken to link the sample of the device to the patient.
Some embodiments suggests that the formulation of therapeutic 110 can be more dense than the fluid 400 of the device 100, and that it can be helpful to inject the formulation with the porous structure 150 below the penetrable barrier 184 of therapeutic device 100, such that the formulation of therapeutic agent 110 directed to a location of the reservoir chamber 140 is below the lumen 326L to receive fluid 400. The plunger of the syringe is depressed to urge the liquid into the device 100. When the level of fluid 400 rises to the valve 703V, the flow of liquid is substantially inhibited. The valve 703 comprising the porous structure 150 can provide a user perceptible resistance to air flow such that the formulation of agent 110 is directed to the porous structure with decreased flow that may increase gravity based separation of fluid 400 with the formulation.
In many embodiments, the cartridge 320 comprises a support component 320S comprising the at least one needle 189 and deformable stop 189DS, in which the support component 320S comprises the connector 322 to couple to the syringe and a connector 327 to couple to the sample container 328 when the at least one needle 189 is placed on the eye 10. The support component 320S may comprise the at least one needle 189 such as first needle 324 having a first lumen 324L and a second needle 326 having a second lumen 326L. The support 320S can be formed in many ways and may comprise injection molded plastic, for example. A first channel 324C can extend from a distal opening near a tip of the first needle 324 to a proximal opening near connector 322 such that the first channel 324C couples the syringe to the implantable device 100 when the deformable stop 189DS couples to the conjunctiva 16 of the eye 10. A second channel 326C can extend from a distal opening near a tip of the second needle 326 to a proximal opening near connector 327 such that the second channel 326C couples the container 328 to the reservoir chamber of the implantable device 100 when the deformable stop 189DS couples to the conjunctiva 16 of the eye 10.
The connector 327 can be configured to couple to the detachable container 328 in many ways. The connector 327 may comprise an opening sized to receive a neck of the container 328. The connector 327 may comprise a needle 327N having a tip 327T. Needle 327N can be sized to extend through a penetrable barrier 328PB of the container 328 when the neck of the container 328 is placed in the opening sized to receive the neck of the container. The first channel and the second channel can be spaced apart so as to separate the syringe from the container.
Release of Stabilizers and Therapeutic Agents
The therapeutic agent may comprise one or more of the therapeutic agents as described herein, and the amount of therapeutic agent can be compared to the amount of stabilizer displaced from the device implanted in the eye 10 to one or more of diagnose or treat the patient. Examples of stabilizers and therapeutic agents released from therapeutic devices are described in U.S. Prov. Pat. App. Ser. No. 61/415,674, filed Nov. 19, 2010, entitled “THERAPEUTIC AGENT FORMULATIONS FOR IMPLANTED DEVICES”; and PCT/US11/061535, filed on Nov. 18, 2011, entitled “THERAPEUTIC AGENT FORMULATIONS FOR IMPLANTED DEVICES”; the full disclosures of which and incorporated herein by reference and suitable for combination in accordance with embodiments described herein. The stabilizer may comprise one or more of an alcohol, a polyol, a phenol, a carbohydrate, a sugar (sucrose, lactose, and glucose), amino acids (glycine, alanine, and proline), or amines (betaine and trimethylamine N-oxide), for example. The stabilizer may comprise a molecular weight corresponding to the therapeutic agent, for example at least about 20% of the molecular weight of the therapeutic agent. The molecular weight can be sufficient such that a portion of the stabilizer remains in the device 100 when a portion of the therapeutic agent is released so as to stabilize a remaining portion of the therapeutic agent. The stabilizer may comprise a high molecular weight polymer, for example at least about 2 k Daltons. The stabilizer may comprise one or more forms of cellulose (e.g., carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), chitin (e.g., chitosan), other oligosaccharides and polysaccharides, or polymeric forms of amino acids.
The diffusion constant of the stabilizer can be determined, for example, based on an estimate of hydrodynamic radius corresponding to the cube root of the molecular weight as described herein.
Table 2 shows some possible diffusion coefficients and estimates of device half-life relative to Ranibizumab.
Table 2 shows that the molecular weight, diffusion co-efficient, equivalent diameter of ranibizumab can be about 48 k Daltons, 1.0E-6, and 5.3 nm, respectively.
The molecular weight of the stabilizer can be provided in 1 k Dalton increments from about 1 k Dalton to about 200 k Daltons and provide in a Table having about 200 rows similar to Table 2. The parameters of Table 2 determined such as the half-life in the device, the equivalent volume, the equivalent diameter, and % in the device at the half-life of the therapeutic agent 110. The table may comprise a row for each molecular weight in 1 k Dalton increments, and the % of stabilizer in the device compared with the therapeutic agent 110. The table may include columns for two half-lives of the therapeutic agent, three half-lives of the therapeutic agent, four half-lives of the therapeutic agent, and the corresponding percentage of stabilizer remaining in the device.
The percentage at 1, 2, 3, 4 5, and 6 half-lives can be determined.
The molecular weight, diffusion coefficient and equivalent diameter of trehalose can be about 0.4 k Daltons, 5.0E-6, and 1.1 nm, respectively. The relative molecular weight of trehalose to ranibizumab can be about 0.8%, and the relative half-life of trehalose in device 100 can be about 20% of ranibizumab. The relative amount of trehalose remaining in therapeutic device 100 at the half-life of ranibizumab can be about 3.1%. This decreased half-life of trehalose and amount in the device 100 relative to ranibizumab can be related to the decreased molecular weight of trehalose relative to ranibizumab.
A disaccharide such as trehalose can be combined with one or more of micelles or polymeric proteins as described herein, so as to associate with the one or more of the micelles or the polymeric proteins so as to decrease a rate of release of the disaccharide from the reservoir chamber.
The molecular weight, diffusion coefficient and equivalent diameter of polysorbate 20 can be about 1.2 k Daltons, 3.4E-6, and 1.6 nm, respectively. The relative molecular weight of polysorbate to ranibizumab is about 2.6%, and the relative half-life of polysorbate 20 in device 100 can be about 29% of ranibizumab. The relative amount of polysorbate 20 remaining in therapeutic device 100 at the half-life of ranibizumab can be about 9.5%. This decreased half-life of polysorbate and amount in the device 100 relative to ranibizumab is related to the decreased molecular weight of polysorbate relative to ranibizumab.
The diffusion coefficients of Table 2 can be determined based on weight for molecular weights up to about 2.5 M Daltons, and based on size above about 2.5 M Daltons.
The stabilizer may comprise a molecular weight that is at least about 10% of the molecular weight of the therapeutic agent; such that the half-life of the stabilizer corresponds to at least about 50% of the half-life of the therapeutic agent. For example, a stabilizer 192 with a molecular weight of about 5 k Daltons corresponding to about 10% of the molecular weight of ranibizumab, the relative half life of the stabilizer is about half (0.47) of the half life of ranibizumab. When the half-life of the stabilizer is about half that of the therapeutic agent, about ¼ of the stabilizer may remain in the therapeutic device 100 for an extended time corresponding to the half-life of the therapeutic agent. For example, when the half-life of the therapeutic agent ranibizumab in the device is about 100 days, about ¼ of a 5 k Dalton molecular weight stabilizer may remain in the therapeutic device 100.
The stabilizer may comprise a molecular weight that is at least about 20% of the molecular weight of the therapeutic agent, such that the half life of the stabilizer corresponds to at least about 50% of the half life of the therapeutic agent. At a time of two half lives post-placement in the therapeutic device 100, the relative proportion of stabilizer to therapeutic agent is about 1 to 4. This amount of stabilizer can be sufficient to stabilize the therapeutic agent in many embodiments.
When the formulation contains a component with a substantially faster or slower diffusion coefficient than the therapeutic agent, the concentration of the formulation component in the Exchange Fluid can be utilized to determine additional information from a therapeutic device 100 refill procedure. The diffusion coefficients may differ by a factor of 2, more preferably by a factor of 5 or more, for example.
After about 90 days of delivery, the Ranibizumab concentration in the implantable device can be about 50% of the original concentration while the concentration of Trehalose is less than 5% of the original concentration. The ratio of Trehalose to Ranibizumab in the implant can continue to decline with time.
The trehalose concentration in the implantable device after refill, CTI2, can be related to the trehalose concentration of the therapeutic fluid in the Refill Syringe, CTS, and the Trehalose concentration in the implantable device fluid just prior to refill, CTI1, via the following equation:
CTI2=XCTS+(1−X)CTI1
where X denotes the fraction of the concentration in the implanted device resulting from the syringe. When the implantable device is refilled using an exchange needle after 90 or more days of delivery, the trehalose concentration in the implant just prior to refill, CTI1, may be approximately zero and X=CTI2/CTS.
A mass balance can be performed on the trehalose in the system to yield:
VSCTS+VICTI1=VECTE+VICTI2
where VS=volume injected from syringe, VI=volume of implantable device, VE=volume of exchange fluid, and CTE=trehalose concentration in Exchange Fluid. This can be rearranged and simplified (CTI1, =0 and VS=VE) to yield a measure of the fraction resulting from the syringe calculated from known values (VS, VI, and CTS) and the trehalose concentration measured in the exchange fluid (CTE):
X=(VS/VI)(1−(CTE/CTS))
The ranibizumab found in the exchange fluid can be separated into ranibizumab that came from the syringe comprising the therapeutic fluid and the ranibizumab of the implantable device fluid that had been in the implant prior to refill. The ranibizumab from the syringe will have the 1:10 ratio of ranibizumab:trehalose corresponding to full strength Lucentis™. The ranibizumab from the implant will have essentially no trehalose associated with it. The fraction, X, that had been replaced by fresh solution in the implantable has been pushed into the receiver container comprising the collection chamber for the exchange fluid. The resulting mass balance can be:
CREVE=( 1/10)CTEVE+X CRi1VI
where CRE=ranibizumab concentration in the exchange fluid, CRI1=ranibizumab concentration in the implant just prior to refill. This equation can be rearranged to calculate the concentration in the implant just prior to refill using a known value (CTS) and the concentrations measured in the exchange fluid (CRE and CTE):
CRI1=(CRE−( 1/10)CTE)/(1−CTE/CTS)
The ranibizumab concentration in the implant just prior to refill that can be determined using the equation above can be compared to the diffusion model predicted value to determine if the implant is performing as expected, for example.
In addition, the concentration in the implant post refill can be calculated from the following equation using parameters obtained via the method described above:
CRI2=XCRS+(1−X)CRI1
In many embodiments, the delivery rate after refill can be proportional to the concentration in the implant post refill.
The examples described herein show measurement of the concentrations of two components in the Exchange Fluid to provide determination of the concentrations in the implant before and after the refill process, for example when the formulation component diffuses substantially faster than the therapeutic agent. Alternatively to trehalose or in combination with trehalose, other embodiments having fast diffusing formulation components include buffers such as histidine, acetate, and citrate, or other sugars such as sucrose.
The formulation component may comprise a molecular weight greater than the therapeutic agent such that the formulation component diffuse more slowly than the therapeutic agent, for example. In addition, the formulation placed in the therapeutic device 100 may comprise one or more marker components to measure device function. The one or more marker components of the formulation may comprise one or more molecules or substances that can be readily measured from the exchange sample by a person of ordinary skill in the art. The one or more marker components may comprise one or more of a therapeutic agent, a stabilizer, a second therapeutic agent, or another measurable substance provided with the formulation to determine the device function. For example, the marker may comprise one or more therapeutic agents as described herein, one or more stabilizers as described herein, a second therapeutic agent comprising a therapeutic agent as described herein, or another component such as a biocompatible dye, for example. The marker component may comprise a stabilizer added to the formulation that may not be necessary to stabilize the therapeutic agent. For example, a measurable buffer component or a measurable surfactant component can be provided in a formulation with a stable small molecule therapeutic agent, in which the small molecule therapeutic agent does not require the buffer for stabilization when placed in the therapeutic device 100. The marker component may comprise a measurable nutrient that can have therapeutic benefit, for example a vitamin.
The equations above can be applied to embodiments where the concentration of the formulation component in the implant just prior to refill was close to zero. A person of ordinary skill in the art can apply correction factors based upon the diffusion model described herein so as to allow the teachings described herein to apply to embodiments where the formulation component in the implant just prior to refill is higher than zero.
A person of ordinary skill in the art can also derive equations to extract similar information when the formulation component diffuses more slowly than the therapeutic agent based on the teachings and embodiments described herein. Examples of slowly diffusing formulation components can include carboxymethylcellulose sodium, and sodium hyaluronate, for example.
The evaluation of implanted device performance and the determination of the concentrations in the implant before and after the refill process as described herein, can be combined with the analysis of markers as described herein, to one or more of diagnose or treat the patient as described herein. For example, the measured concentrations of markers and the therapeutic agent from the sample can be adjusted based on measurements of the therapeutic agent and the stabilizer from the sample fluid collected in the receiver container as described herein.
Release of Formulation Components and Accumulation of Vitreous Components
The measurement of one or more formulation components released from the device can be combined with the measurement of one or more components of the vitreous humor 30 from the device to determine device function, diagnose the patient, or treat the patient, and combinations thereof, for example. For example, the measurement of two or more formulation components initially placed in the device and subsequently removed by exchange, such as the therapeutic agent and another component such as one or more of a stabilizer or a marker, can be combined with the measurement of one or more components of the vitreous obtained from the device, for example a bio marker and a house keeping marker as described herein. For example, the exchange fluid obtained from the device may comprise a plurality of formulation components and a plurality of vitreal components useful to determine device function, diagnose the patient, treat the patient, and combinations thereof.
The measurement of the formulation components can be used to determine the amount of one or more vitreal components in the implanted device. For example, the amount of therapeutic fluid present in the sample collected from the implanted that has mixed with the implantable device fluid during exchange can be determined and used to determine and quantify the amount of vitreal component in the therapeutic device 100 prior to exchange, for example with an adjustment to the measure amount of vitreal component.
The amount of component or therapeutic agent measured from the device may comprise an amount exchanged from the device. The determined amount may comprise a total mass exchanged from the device or a concentration, or both. The determined amount can be used to determine the amount of the component or agent in the reservoir chamber of the device.
The component of the eye 10 from the implanted device may comprise one or more markers corresponding to a condition of the eye 10. The component of the eye 10 from the implanted device may include an extracellular component, such as one or more of a molecule, a macromolecule, a protein, a carbohydrate, or a component of blood plasma, for example. The rate of accumulation of the marker can be related to the molecular weight of the marker and the tuning of the implanted device to release amounts of the therapeutic agent over an extended time based on a volume of the reservoir chamber and release structure, such as porous structure 150 (for example
The measured accumulation of the plurality of markers from the implantable device sample can be used in many ways to diagnose and treat the patient. The ratios of a plurality of markers to a housekeeping gene, and the ratio of markers having a substantial change in pre-treatment to post treatment amounts to each other can be used to one or more of diagnose or treat the patient. The measured markers may comprise a marker profile of the patient, for example from 10 or more markers, and the marker profile can be used to evaluate the patient or treatment or both. For example, the accumulation time of the marker can depend on when a gene switches off or on, and the measurement of the plurality of markers and corresponding ratios can be used to determine whether a therapeutic agent is appropriate for the patient, and whether an amount of the therapeutic agent should be increased or decreased or a new therapeutic agent used. The plurality of markers may correspond to intracellular RNA or DNA, or combinations thereof, for example.
The ratio of VEGF to another marker having a slower response to therapeutic agent below therapeutic amounts may be compared, for example. The proportional amounts of the markers may be used to one or more of diagnose or treat an eye 10 based on a plurality of ratios of a plurality of markers, such as ratios of VEGF to GADPH, IL-8 to GADPH and VEGF to IL-8, for example.
The accumulation of the plurality of markers as described herein can be used in many ways to diagnose and treat patient. For example, each sample of the device may comprise a plurality of markers, and the plurality of markers assayed for each sample. The assay for each sample may comprise a profile of the markers. The profiles from each of the samples can be combined so as to comprise an array of marker data for the patient. The profile of marker data from a sample can be compared with an array of marker data from the same patient or a population of patients, so as to diagnose the patient. For example, an array of marker data may comprise a profile of at least about 5 markers measured from a first measurement of sample of the device implanted in the patient and at least about 5 markers from a second profile based on a second sample of the device implanted in the patient at a subsequent time. Alternatively, an array from a patient may be compared with an array corresponding to a patient population, so as to one or more of diagnose or treat the patient.
Based on the teachings described herein, the accumulation of the marker in the therapeutic device 100 can be compared with amounts in the vitreous humor 30, for example with an area under the concentration curve and many known integration methods. The accumulated marker may be compared with a pre-implantation sample such as from a vitreal tap or a sample drawn through an incision formed to place the implant in the eye 10. The amount of marker in the vitreous humor 30 can be measured with dialysis and the vitreal concentration of the component compared with the amount accumulated in the device so as to determine the corresponding rate of accumulation in the device as compared with the vitreous humor 30. Examples of experimental methods and dialysis apparatus that may be modified so as to be suitable for incorporation in accordance with the embodiments described herein are described in “Microdialysis assessment of drug delivery systems for vitreoretinal targets”, Advanced Drug Delivery Reviews, 57(2005) 2080-2091, Sridhar Duvvuri A, Kay D. Rittenhouse B, Ashim K. Mitra, Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, 64110, USA, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA Received 12 Sep. 2005; accepted 13 Sep. 2005, available online 4 Nov. 2005, which is incorporated by reference herein in its entirety.
The accumulated sample fluid removed from the implanted device may comprise or correspond to one or more biological markers as described in U.S. patent application Ser. No. 12/856,394, published as US2011/0117083, entitled “Biological Markers for Monitoring Response to VEFG Agonists” in the name of Bais et al., the full disclosure of which is incorporated herein by reference, which patent application describes genes, assays and markers suitable for incorporation and combination in accordance with embodiments described herein. For example, the biomarker measured from the reservoir chamber may comprise a biomarker of the plasma of the patient and correspond to one or more of genes, RNA or DNA of the patient, for example. Tables X, Y, Z correspond to Tables I, II and III of the above referenced Ser. No. 12/856,394 patent application previously incorporated by reference, and may describe one or more biological markers capable of diffusing into a device implanted in the patient, for example the eye, and corresponding assays suitable for incorporation in accordance with embodiments described herein.
The molecular weight of the biomarker corresponding to the one or more markers of Tables X, Y, and Z can be used to determine the rate of accumulation, and the fold decrease in gene expression used to one or more of diagnose or treat the patient in accordance with accumulation of the one or more markers in the reservoir chamber of the implantable device as described herein.
The assay may comprise a known commercially available assay such as one or more of CFH, CFB & C2 for AMD diagnostic, commercially available from Sequenom or Ophtherion. In addition, the assay may comprise genomic profiling. The sample may be frozen in the container with the identifier and sent to a remote location for analysis.
Table 4 shows an example embodiment of steps of a method 600 for diagnosing and/or treating the patient based on the data of the fluid of the device implanted in the eye 10.
The processor system can determine changes in a marker amount over time in a patient. For example, the patient may return at approximately four month intervals for a device refill/exchange. The processor system may comprise instructions to determine and identify trends in a marker which have accumulated over that interval of time between visits. This trend analysis of marker change from baseline can provide increased sensitivity to changes in the individual patient. For example, a small and potentially relevant change can be detected within a broader band of what can be considered normal as defined by a broader patient population. For example, the normal baseline range for an amount of marker as determined with an assay of a patient population can be within a range from about 0.1 to about 1.0. The patient can present sequential values over a year's time of 0.2, 0.6, 0.9 at four months, eight months and twelve months, respectively. Although these values of the marker can be considered normal results based on comparison with the patient population, the trend can indicate early disease progression based on comparison of the values from baseline and the instructions of the processor system can be configured to identify the patient based on the trends of the marker and report the patient and the values corresponding to the trend to the health care provider, for example. The trend analysis and comparison from baseline can be performed for each of a plurality of markers as described herein at a plurality of times.
The method of Table 4 can be implemented with the processor system, and the steps shown in Table 4 may correspond to instructions of a computer program embodied on the computer readable memory of the processor system.
Although Table 4 shows a particular method in accordance with an embodiment, a person of ordinary skill in the art will recognize many adaptations and variations based on the teachings described herein. For example, the steps of the method can be removed, the order changed, or combinations thereof. Further, the steps may comprise subs-steps, and the steps may be repeated.
The embodiments as described herein can be combined in many ways including alternatively or in combination.
As used herein, like numerals and/or letters can denote like elements in the drawings as will be apparent to a person of ordinary skill in the art.
Based on the teachings described herein, a person of ordinary skill in the art can conduct experiments to determine empirically assays and accumulation rates of markers of the eye 10. The amount of a marker corresponding to a clinical effect can be determined empirically with assays developed for the fluid sample from the implanted device. The assay from the implanted device may comprise one or more components from known commercially available assays. Known commercially available assays include the known ELISA assay, fluorometric binding, array assays, beads with beads combined with antibodies such as the Bioplex™ system commercially available from BioRad. Alternatively or in combination, the accumulated sample fluid removed from the implanted device may be analyzed with known methods of assay analysis suitable for combination in accordance with embodiments. U.S. patent application Ser. No. 12/856,394, published as US2011/0117083, entitled “Biological Markers for Monitoring Response to VEFG Agonists” in the name of Bais et al., the full disclosure of which has been previously incorporated herein by reference, describes genes, assays and markers suitable for incorporation and combination in accordance with embodiments described herein. For example, the biomarker measured from the reservoir chamber may comprise a biomarker of the plasma of the patient and correspond to one or more of genes, RNA or DNA of the patient, for example. Pharmokinetic studies and assays suitable for incorporation in accordance with embodiments as described herein are noted in a publication entitled, “Preclinical Pharmokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration”, Investigative Ophthalmology & Visual Science, February 2005, Vol. 46, No. 2, for example, which is incorporated by reference in its entirety herein.
The amount of each marker can be determined empirically as part of assays developed to one or more of diagnose or treat the eye 10 based on the teachings described herein. The accumulation of the component of the vitreous can be assayed and measured in many ways, for example with assays of one or more marker components of the vitreous as described herein. For example, for each genetic marker evaluated having sensitivity to the disease of the eye 10, one could determine a corresponding comparison genetic marker that has a substantially decreased sensitivity to the therapeutic agent and also a substantially similar relative abundance so as to inhibit over amplification of one marker relative to the other marker. Alternatively or in combination, for each protein marker evaluated having sensitivity to the disease of the eye 10, one could determine a corresponding comparison protein marker that has a substantially decreased sensitivity to the therapeutic agent and also a substantially similar relative abundance. Based on the teachings described herein, one or more protein markers, genetic markers, or genomic markers can be assayed and compared to diagnose or treat the patient, or combinations thereof.
Experiments have been conducted to show displacement of fluid from an implantable device into an injector cartridge having a container to store fluid from the therapeutic device 100 suitable for analysis as described herein.
The implantable device may include an axis that extends at an angle about 60 to 70° down off the horizontal. Red solution may be contained inside the device which may have an approximate density of 1 g/ml, while clear refill solution may have an approximate density of 1 g/ml as well. The approximate refill rate can be 1.3 μl/sec. A total of 45 μl can be injected into a device. In addition, the device capacity may be 25 μl. This device configuration and refill condition may yield an approximate refill efficiency of 60-90%.
While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of ordinary skill in the art will recognize that a variety of modifications, adaptations, and changes may be employed. Hence, the scope of the present disclosure should be limited solely by the appended claims.
This application is a continuation of U.S. application Ser. No. 14/129,200, filed Apr. 10, 2014, which is a 371 Application of PCT Application Serial No. PCT/US2012/044695, filed Jun. 28, 2012, which claims priority to U.S. Provisional Application Ser. No. 61/502,157, filed Jun. 28, 2011; U.S. Provisional Application Ser. No. 61/503,492, filed Jun. 30, 2011; U.S. Provisional Application Ser. No. 61/538,736, filed Sep. 23, 2011; and U.S. Provisional Application Ser. No. 61/595,618, filed Feb. 6, 2012, the full disclosures of which are incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1747814 | Bradley | Feb 1930 | A |
| 2564977 | Hu et al. | Aug 1951 | A |
| 2585815 | McLintock | Feb 1952 | A |
| 2646042 | Hu | Jul 1953 | A |
| 2886497 | Butler | May 1959 | A |
| 3232117 | Gilmont | Feb 1966 | A |
| 3416530 | Ness | Dec 1968 | A |
| 3612089 | Beguiristain | Oct 1971 | A |
| 3618604 | Ness | Nov 1971 | A |
| 3641237 | Gould et al. | Feb 1972 | A |
| 3734095 | Santomieri | May 1973 | A |
| 3828777 | Ness | Aug 1974 | A |
| 3831583 | Edmunds, Jr. et al. | Aug 1974 | A |
| 3845201 | Haddad et al. | Oct 1974 | A |
| 3902495 | Weiss et al. | Sep 1975 | A |
| 3914402 | Shell | Oct 1975 | A |
| 3916899 | Theeuwes et al. | Nov 1975 | A |
| 3926188 | Baker et al. | Dec 1975 | A |
| 3949748 | Malmin | Apr 1976 | A |
| 3949750 | Freeman | Apr 1976 | A |
| 3961628 | Arnold | Jun 1976 | A |
| 3977404 | Theeuwes | Aug 1976 | A |
| 3995635 | Higuchi et al. | Dec 1976 | A |
| 4008719 | Theeuwes et al. | Feb 1977 | A |
| 4014333 | McIntyre | Mar 1977 | A |
| 4014334 | Theeuwes et al. | Mar 1977 | A |
| 4014335 | Arnold | Mar 1977 | A |
| 4034756 | Higuchi et al. | Jul 1977 | A |
| 4034758 | Theeuwes | Jul 1977 | A |
| 4077407 | Theeuwes et al. | Mar 1978 | A |
| 4111201 | Theeuwes | Sep 1978 | A |
| 4111203 | Theeuwes | Sep 1978 | A |
| 4135514 | Zaffaroni et al. | Jan 1979 | A |
| 4160452 | Theeuwes | Jul 1979 | A |
| 4164559 | Miyata et al. | Aug 1979 | A |
| 4179497 | Cohen et al. | Dec 1979 | A |
| 4186184 | Zaffaroni | Jan 1980 | A |
| 4200098 | Ayer et al. | Apr 1980 | A |
| 4220152 | Dresback | Sep 1980 | A |
| 4220153 | Dresback | Sep 1980 | A |
| 4256108 | Theeuwes | Mar 1981 | A |
| 4298000 | Thill et al. | Nov 1981 | A |
| 4300557 | Refojo et al. | Nov 1981 | A |
| 4309776 | Berguer | Jan 1982 | A |
| 4326525 | Swanson et al. | Apr 1982 | A |
| 4327725 | Cortese et al. | May 1982 | A |
| 4343787 | Katz | Aug 1982 | A |
| 4439196 | Higuchi | Mar 1984 | A |
| 4439198 | Brightman, II et al. | Mar 1984 | A |
| 4475916 | Himmelstein | Oct 1984 | A |
| 4484922 | Rosenwald | Nov 1984 | A |
| 4519801 | Edgren | May 1985 | A |
| 4609374 | Ayer | Sep 1986 | A |
| 4627850 | Deters et al. | Dec 1986 | A |
| 4634418 | Binder | Jan 1987 | A |
| 4634427 | Hannula et al. | Jan 1987 | A |
| 4673405 | Guittard et al. | Jun 1987 | A |
| 4693886 | Ayer | Sep 1987 | A |
| 4712550 | Sinnett | Dec 1987 | A |
| 4730013 | Bondi et al. | Mar 1988 | A |
| 4737150 | Baeumle et al. | Apr 1988 | A |
| 4774091 | Yamahira et al. | Sep 1988 | A |
| 4777049 | Magruder et al. | Oct 1988 | A |
| 4781675 | White | Nov 1988 | A |
| 4851228 | Zentner et al. | Jul 1989 | A |
| 4853229 | Theeuwes | Aug 1989 | A |
| 4863457 | Lee | Sep 1989 | A |
| 4865846 | Kaufman | Sep 1989 | A |
| 4883459 | Calderon | Nov 1989 | A |
| 4959217 | Sanders et al. | Sep 1990 | A |
| 4979938 | Stephen et al. | Dec 1990 | A |
| 5049142 | Herrick et al. | Sep 1991 | A |
| 5053030 | Herrick et al. | Oct 1991 | A |
| 5084021 | Baldwin | Jan 1992 | A |
| 5098443 | Parel et al. | Mar 1992 | A |
| 5128145 | Edgren et al. | Jul 1992 | A |
| 5141748 | Rizzo | Aug 1992 | A |
| 5147647 | Darougar | Sep 1992 | A |
| 5164188 | Wong | Nov 1992 | A |
| 5171270 | Herrick | Dec 1992 | A |
| 5174999 | Magruder et al. | Dec 1992 | A |
| 5238687 | Magruder et al. | Aug 1993 | A |
| 5273530 | del Cerro et al. | Dec 1993 | A |
| 5277912 | Lowe et al. | Jan 1994 | A |
| 5282829 | Hermes | Feb 1994 | A |
| 5300114 | Gwon et al. | Apr 1994 | A |
| 5322504 | Doherty et al. | Jun 1994 | A |
| 5322691 | Darougar et al. | Jun 1994 | A |
| 5324518 | Orth et al. | Jun 1994 | A |
| 5334189 | Wade | Aug 1994 | A |
| 5336175 | Mames | Aug 1994 | A |
| 5358473 | Mitchell | Oct 1994 | A |
| 5364343 | Apolet et al. | Nov 1994 | A |
| 5378475 | Smith et al. | Jan 1995 | A |
| 5413572 | Wong et al. | May 1995 | A |
| 5443505 | Wong et al. | Aug 1995 | A |
| 5466233 | Weiner et al. | Nov 1995 | A |
| 5476448 | Urich | Dec 1995 | A |
| 5476511 | Gwon et al. | Dec 1995 | A |
| 5554132 | Straits et al. | Sep 1996 | A |
| 5562915 | Lowe et al. | Oct 1996 | A |
| 5578042 | Cumming | Nov 1996 | A |
| 5674193 | Hayes | Oct 1997 | A |
| 5681572 | Seare, Jr. | Oct 1997 | A |
| 5725493 | Avery et al. | Mar 1998 | A |
| 5755684 | Chen | May 1998 | A |
| 5766242 | Wong et al. | Jun 1998 | A |
| 5770076 | Chu et al. | Jun 1998 | A |
| 5773019 | Ashton et al. | Jun 1998 | A |
| 5792099 | DeCamp et al. | Aug 1998 | A |
| 5797898 | Santini, Jr. et al. | Aug 1998 | A |
| 5807581 | Rosenblatt et al. | Sep 1998 | A |
| 5817075 | Giungo | Oct 1998 | A |
| 5824072 | Wong | Oct 1998 | A |
| 5830173 | Avery et al. | Nov 1998 | A |
| 5830546 | Ehret et al. | Nov 1998 | A |
| 5836935 | Ashton et al. | Nov 1998 | A |
| 5868697 | Richter et al. | Feb 1999 | A |
| 5902598 | Chen et al. | May 1999 | A |
| 5916584 | O'Donoghue et al. | Jun 1999 | A |
| 5928662 | Phillips | Jul 1999 | A |
| 5951512 | Dalton | Sep 1999 | A |
| 5968008 | Grams | Oct 1999 | A |
| 5972369 | Roorda et al. | Oct 1999 | A |
| 5985328 | Chu et al. | Nov 1999 | A |
| 6001386 | Ashton et al. | Dec 1999 | A |
| 6123861 | Santini, Jr. et al. | Sep 2000 | A |
| 6196993 | Cohan et al. | Mar 2001 | B1 |
| 6251090 | Avery et al. | Jun 2001 | B1 |
| 6303290 | Liu et al. | Oct 2001 | B1 |
| 6331313 | Wong et al. | Dec 2001 | B1 |
| 6331523 | Kljavin et al. | Dec 2001 | B1 |
| 6375972 | Guo et al. | Apr 2002 | B1 |
| 6395300 | Straub et al. | May 2002 | B1 |
| 6413540 | Yaacobi | Jul 2002 | B1 |
| 6416777 | Yaacobi | Jul 2002 | B1 |
| 6420399 | Graff et al. | Jul 2002 | B1 |
| 6468264 | Gillis et al. | Oct 2002 | B1 |
| 6472162 | Coelho et al. | Oct 2002 | B1 |
| 6605066 | Gravagna et al. | Aug 2003 | B1 |
| 6620139 | Plicchi et al. | Sep 2003 | B1 |
| 6663668 | Chaouk et al. | Dec 2003 | B1 |
| 6669950 | Yaacobi | Dec 2003 | B2 |
| 6685940 | Andya et al. | Feb 2004 | B2 |
| 6695821 | Sjaarda | Feb 2004 | B1 |
| 6713081 | Robinson et al. | Mar 2004 | B2 |
| 6719750 | Varner et al. | Apr 2004 | B2 |
| 6740077 | Brandau et al. | May 2004 | B1 |
| 6756049 | Brubaker et al. | Jun 2004 | B2 |
| 6756058 | Brubaker et al. | Jun 2004 | B2 |
| 6869412 | Ross | Mar 2005 | B2 |
| 6932983 | Straub et al. | Aug 2005 | B1 |
| 6976982 | Santini, Jr. et al. | Dec 2005 | B2 |
| 6986900 | Yaacobi | Jan 2006 | B2 |
| 7026329 | Crain et al. | Apr 2006 | B2 |
| 7074426 | Kochinke | Jul 2006 | B2 |
| 7077848 | de Juan, Jr. et al. | Jul 2006 | B1 |
| 7090681 | Weber et al. | Aug 2006 | B2 |
| 7094222 | Siekas et al. | Aug 2006 | B1 |
| 7094226 | Yaacobi | Aug 2006 | B2 |
| 7117870 | Prescott | Oct 2006 | B2 |
| 7141023 | Diermann et al. | Nov 2006 | B2 |
| 7141152 | Le Febre | Nov 2006 | B2 |
| 7181287 | Greenberg | Feb 2007 | B2 |
| 7195774 | Carvalho et al. | Mar 2007 | B2 |
| 7195778 | Fleshner-Barak et al. | Mar 2007 | B2 |
| 7211272 | Renner et al. | May 2007 | B2 |
| 7276050 | Franklin | Oct 2007 | B2 |
| 7468065 | Weber et al. | Dec 2008 | B2 |
| 7476510 | Kapur et al. | Jan 2009 | B2 |
| 7585517 | Cooper et al. | Sep 2009 | B2 |
| 7615141 | Schwartz et al. | Nov 2009 | B2 |
| 7621907 | Rodstrom | Nov 2009 | B2 |
| 7625927 | Klimko et al. | Dec 2009 | B2 |
| 7678078 | Peyman et al. | Mar 2010 | B1 |
| 7686016 | Wharton et al. | Mar 2010 | B2 |
| 7699820 | French | Apr 2010 | B1 |
| 7709049 | Chappa | May 2010 | B2 |
| 7883717 | Varner et al. | Feb 2011 | B2 |
| 7893040 | Loftsson et al. | Feb 2011 | B2 |
| 7906136 | Wong et al. | Mar 2011 | B2 |
| 7909800 | Cazzini | Mar 2011 | B2 |
| 7914442 | Gazdzinski | Mar 2011 | B1 |
| 7939094 | Schwarz et al. | May 2011 | B2 |
| 7973068 | Demopulos et al. | Jul 2011 | B2 |
| 8795712 | de Juan, Jr. et al. | Aug 2014 | B2 |
| 8808727 | de Juan, Jr. et al. | Aug 2014 | B2 |
| 8905963 | de Juan, Jr. et al. | Dec 2014 | B2 |
| 9066779 | de Juan, Jr. et al. | Jun 2015 | B2 |
| 9861521 | de Juan, Jr. et al. | Jan 2018 | B2 |
| 9883968 | Doud et al. | Feb 2018 | B2 |
| 10398592 | Erickson | Sep 2019 | B2 |
| 20020026176 | Varner et al. | Feb 2002 | A1 |
| 20020049389 | Abreu | Apr 2002 | A1 |
| 20020086051 | Viscasillas | Jul 2002 | A1 |
| 20020106395 | Brubaker | Aug 2002 | A1 |
| 20020110591 | Brubaker et al. | Aug 2002 | A1 |
| 20020110592 | Brubaker et al. | Aug 2002 | A1 |
| 20020110635 | Brubaker et al. | Aug 2002 | A1 |
| 20020188244 | Smith | Dec 2002 | A1 |
| 20030003129 | Yaacobi | Jan 2003 | A1 |
| 20030005945 | Onishi et al. | Jan 2003 | A1 |
| 20030014036 | Varner et al. | Jan 2003 | A1 |
| 20030047011 | Diermann et al. | Mar 2003 | A1 |
| 20030118649 | Gao et al. | Jun 2003 | A1 |
| 20030119177 | Gruber et al. | Jun 2003 | A1 |
| 20030120217 | Abergel | Jun 2003 | A1 |
| 20030176854 | Rodstrom | Sep 2003 | A1 |
| 20030185872 | Kochinke | Oct 2003 | A1 |
| 20030212383 | Cote et al. | Nov 2003 | A1 |
| 20030233067 | McIntosh et al. | Dec 2003 | A1 |
| 20030235603 | Schwarz et al. | Dec 2003 | A1 |
| 20040011651 | Becker et al. | Jan 2004 | A1 |
| 20040019325 | Shekalim | Jan 2004 | A1 |
| 20040024371 | Plicchi et al. | Feb 2004 | A1 |
| 20040029832 | Zeldis | Feb 2004 | A1 |
| 20040092911 | Yaacobi | May 2004 | A1 |
| 20040106906 | Yaacobi | Jun 2004 | A1 |
| 20040131654 | Yaacobi | Jul 2004 | A1 |
| 20040131655 | Yaacobi | Jul 2004 | A1 |
| 20040171997 | Wilson et al. | Sep 2004 | A1 |
| 20040209359 | Yayon et al. | Oct 2004 | A1 |
| 20040230183 | Breegi | Nov 2004 | A1 |
| 20040247487 | Commercon et al. | Dec 2004 | A1 |
| 20040260240 | Beyerlein | Dec 2004 | A1 |
| 20040260380 | Marco et al. | Dec 2004 | A1 |
| 20040260381 | Marco et al. | Dec 2004 | A1 |
| 20050064010 | Cooper et al. | Mar 2005 | A1 |
| 20050074497 | Schultz | Apr 2005 | A1 |
| 20050112175 | Yaacobi | May 2005 | A1 |
| 20050112759 | Radisic et al. | May 2005 | A1 |
| 20050113806 | De Carvalho et al. | May 2005 | A1 |
| 20050119737 | Bene et al. | Jun 2005 | A1 |
| 20050143363 | De Juan et al. | Jun 2005 | A1 |
| 20050154399 | Weber et al. | Jul 2005 | A1 |
| 20050163711 | Nycz et al. | Jul 2005 | A1 |
| 20050171491 | Minh Miner | Aug 2005 | A1 |
| 20050181018 | Peyman | Aug 2005 | A1 |
| 20050244467 | Nivaggioli et al. | Nov 2005 | A1 |
| 20050244469 | Whitcup et al. | Nov 2005 | A1 |
| 20050255144 | Schultz | Nov 2005 | A1 |
| 20050256499 | Pettis et al. | Nov 2005 | A1 |
| 20050271703 | Anderson et al. | Dec 2005 | A1 |
| 20050271706 | Anderson et al. | Dec 2005 | A1 |
| 20050276837 | Anderson et al. | Dec 2005 | A1 |
| 20050277802 | Larsen et al. | Dec 2005 | A1 |
| 20050281861 | Hughes et al. | Dec 2005 | A1 |
| 20050281863 | Anderson et al. | Dec 2005 | A1 |
| 20050287188 | Anderson et al. | Dec 2005 | A1 |
| 20060013835 | Anderson et al. | Jan 2006 | A1 |
| 20060039952 | Yaacobi | Feb 2006 | A1 |
| 20060052754 | Fields | Mar 2006 | A1 |
| 20060057277 | Chappa | Mar 2006 | A1 |
| 20060073182 | Wong et al. | Apr 2006 | A1 |
| 20060104969 | Oray et al. | May 2006 | A1 |
| 20060110428 | deJuan et al. | May 2006 | A1 |
| 20060129215 | Helmus et al. | Jun 2006 | A1 |
| 20060154981 | Klimko et al. | Jul 2006 | A1 |
| 20060172941 | Rastelli et al. | Aug 2006 | A1 |
| 20060182783 | Hughes et al. | Aug 2006 | A1 |
| 20060200097 | Humayun et al. | Sep 2006 | A1 |
| 20060233858 | Tzekov et al. | Oct 2006 | A1 |
| 20060246112 | Snyder et al. | Nov 2006 | A1 |
| 20060257450 | Mudumba et al. | Nov 2006 | A1 |
| 20060258000 | Allen et al. | Nov 2006 | A1 |
| 20060258994 | Avery | Nov 2006 | A1 |
| 20070020336 | Loftsson et al. | Jan 2007 | A1 |
| 20070021357 | Tobia et al. | Jan 2007 | A1 |
| 20070026037 | Kloke et al. | Feb 2007 | A1 |
| 20070059336 | Hughes et al. | Mar 2007 | A1 |
| 20070071756 | Peyman | Mar 2007 | A1 |
| 20070072933 | Peyman | Mar 2007 | A1 |
| 20070077270 | Wen | Apr 2007 | A1 |
| 20070078359 | Luloh et al. | Apr 2007 | A1 |
| 20070083155 | Muller | Apr 2007 | A1 |
| 20070088414 | Campbell et al. | Apr 2007 | A1 |
| 20070119450 | Wharton et al. | May 2007 | A1 |
| 20070128644 | Munenaka | Jun 2007 | A1 |
| 20070131610 | Peng et al. | Jun 2007 | A1 |
| 20070131611 | Peng et al. | Jun 2007 | A1 |
| 20070134305 | Zilberman | Jun 2007 | A1 |
| 20070141111 | Suokas et al. | Jun 2007 | A1 |
| 20070191863 | De Juan et al. | Aug 2007 | A1 |
| 20070197491 | Robin et al. | Aug 2007 | A1 |
| 20070203174 | Klimko et al. | Aug 2007 | A1 |
| 20070212388 | Patravale et al. | Sep 2007 | A1 |
| 20070212397 | Roth | Sep 2007 | A1 |
| 20070233037 | Gifford, et al. | Oct 2007 | A1 |
| 20070235331 | Simpson et al. | Oct 2007 | A1 |
| 20070243230 | de Juan et al. | Oct 2007 | A1 |
| 20070260201 | Prausnitz et al. | Nov 2007 | A1 |
| 20070265599 | Castillejos | Nov 2007 | A1 |
| 20070269487 | de Juan et al. | Nov 2007 | A1 |
| 20080003219 | Peyman | Jan 2008 | A1 |
| 20080004329 | Jamieson et al. | Jan 2008 | A1 |
| 20080015545 | Sanchez et al. | Jan 2008 | A1 |
| 20080020045 | Chappa et al. | Jan 2008 | A1 |
| 20080038316 | Wong et al. | Feb 2008 | A1 |
| 20080057561 | Takahashi et al. | Mar 2008 | A1 |
| 20080066739 | LeMahieu et al. | Mar 2008 | A1 |
| 20080066741 | LeMahieu et al. | Mar 2008 | A1 |
| 20080069854 | Xiao et al. | Mar 2008 | A1 |
| 20080089923 | Burkstrand et al. | Apr 2008 | A1 |
| 20080108954 | Mathias et al. | May 2008 | A1 |
| 20080111282 | Xie et al. | May 2008 | A1 |
| 20080124372 | Hossainy et al. | May 2008 | A1 |
| 20080139674 | Archambeau et al. | Jun 2008 | A1 |
| 20080145406 | Asgharian et al. | Jun 2008 | A1 |
| 20080146679 | Archambeau et al. | Jun 2008 | A1 |
| 20080147021 | Jani | Jun 2008 | A1 |
| 20080152694 | Lobl et al. | Jun 2008 | A1 |
| 20080154241 | Burkstrand et al. | Jun 2008 | A1 |
| 20080161741 | Bene et al. | Jul 2008 | A1 |
| 20080167600 | Peyman | Jul 2008 | A1 |
| 20080172014 | Whitcup et al. | Jul 2008 | A1 |
| 20080181930 | Rodstrom et al. | Jul 2008 | A1 |
| 20080195218 | Jones | Aug 2008 | A1 |
| 20080207502 | Rastelli et al. | Aug 2008 | A1 |
| 20080213611 | Asgari | Sep 2008 | A1 |
| 20080216736 | David | Sep 2008 | A1 |
| 20080228127 | Burns et al. | Sep 2008 | A1 |
| 20080233053 | Gross et al. | Sep 2008 | A1 |
| 20080233171 | Whitcup et al. | Sep 2008 | A1 |
| 20080233172 | Whitcup et al. | Sep 2008 | A1 |
| 20080233173 | Whitcup et al. | Sep 2008 | A1 |
| 20080241219 | Whitcup et al. | Oct 2008 | A1 |
| 20080241220 | Whitcup et al. | Oct 2008 | A1 |
| 20080241221 | Whitcup et al. | Oct 2008 | A1 |
| 20080241222 | Whitcup et al. | Oct 2008 | A1 |
| 20080241223 | Nivaggioli et al. | Oct 2008 | A1 |
| 20080249501 | Yamasaki | Oct 2008 | A1 |
| 20080286338 | Rosenthal et al. | Nov 2008 | A1 |
| 20080292679 | Lyons et al. | Nov 2008 | A1 |
| 20090005864 | Eggleston | Jan 2009 | A1 |
| 20090012485 | Michaels et al. | Jan 2009 | A1 |
| 20090036827 | Cazzini | Feb 2009 | A1 |
| 20090043253 | Podaima | Feb 2009 | A1 |
| 20090047335 | Rastelli et al. | Feb 2009 | A1 |
| 20090081271 | Clarke et al. | Mar 2009 | A1 |
| 20090081272 | Clarke et al. | Mar 2009 | A1 |
| 20090082631 | Cronin et al. | Mar 2009 | A1 |
| 20090087494 | Kompella et al. | Apr 2009 | A1 |
| 20090092654 | de Juan, Jr. et al. | Apr 2009 | A1 |
| 20090093752 | Richard et al. | Apr 2009 | A1 |
| 20090099626 | de Juan, Jr. et al. | Apr 2009 | A1 |
| 20090104243 | Utkhede et al. | Apr 2009 | A1 |
| 20090105749 | de Juan et al. | Apr 2009 | A1 |
| 20090124986 | Hayakawa | May 2009 | A1 |
| 20090124997 | Pettis et al. | May 2009 | A1 |
| 20090192493 | Meng et al. | Jul 2009 | A1 |
| 20090196903 | Kliman | Aug 2009 | A1 |
| 20090214601 | Chappa et al. | Aug 2009 | A1 |
| 20090220572 | Deschatelets et al. | Sep 2009 | A1 |
| 20090224064 | Brodbeck et al. | Sep 2009 | A1 |
| 20090234449 | De Juan, Jr. et al. | Sep 2009 | A1 |
| 20090240208 | Cowan | Sep 2009 | A1 |
| 20090240215 | Humayun et al. | Sep 2009 | A1 |
| 20090247458 | Watson et al. | Oct 2009 | A1 |
| 20090258069 | Burnier et al. | Oct 2009 | A1 |
| 20090259212 | Sabbah | Oct 2009 | A1 |
| 20090263346 | Taft et al. | Oct 2009 | A1 |
| 20090263495 | Watson et al. | Oct 2009 | A1 |
| 20090274730 | Watson et al. | Nov 2009 | A1 |
| 20090274771 | Watson et al. | Nov 2009 | A1 |
| 20090280470 | Fare et al. | Nov 2009 | A1 |
| 20090306025 | Lane | Dec 2009 | A1 |
| 20090306595 | Shih et al. | Dec 2009 | A1 |
| 20090318545 | Silver et al. | Dec 2009 | A1 |
| 20090324686 | Cooper et al. | Dec 2009 | A1 |
| 20090324687 | Cooper et al. | Dec 2009 | A1 |
| 20090324688 | Cooper et al. | Dec 2009 | A1 |
| 20090324689 | Cooper et al. | Dec 2009 | A1 |
| 20090324690 | Cooper et al. | Dec 2009 | A1 |
| 20090326448 | Huo et al. | Dec 2009 | A1 |
| 20090326489 | Kensy et al. | Dec 2009 | A1 |
| 20100003333 | Watson et al. | Jan 2010 | A1 |
| 20100004189 | Watson et al. | Jan 2010 | A1 |
| 20100008997 | Watson et al. | Jan 2010 | A1 |
| 20100009008 | Watson et al. | Jan 2010 | A1 |
| 20100010452 | Paques et al. | Jan 2010 | A1 |
| 20100011888 | Pawliszyn et al. | Jan 2010 | A1 |
| 20100015157 | Andya et al. | Jan 2010 | A1 |
| 20100015158 | Robinson et al. | Jan 2010 | A1 |
| 20100016786 | Drews et al. | Jan 2010 | A1 |
| 20100021464 | Archambeau et al. | Jan 2010 | A1 |
| 20100022943 | Mauch et al. | Jan 2010 | A1 |
| 20100022945 | Rodstrom | Jan 2010 | A1 |
| 20100023033 | Mauch et al. | Jan 2010 | A1 |
| 20100028442 | Archambeau et al. | Feb 2010 | A1 |
| 20100028443 | Watson et al. | Feb 2010 | A1 |
| 20100030136 | Dacquay et al. | Feb 2010 | A1 |
| 20100034870 | Sim et al. | Feb 2010 | A1 |
| 20100083963 | Wharton et al. | Apr 2010 | A1 |
| 20100100054 | Cormier et al. | Apr 2010 | A1 |
| 20100114017 | Lenker et al. | May 2010 | A1 |
| 20100114309 | de Juan, Jr. et al. | May 2010 | A1 |
| 20100158980 | Kopczynski et al. | Jun 2010 | A1 |
| 20100168535 | Robinson et al. | Jul 2010 | A1 |
| 20100174272 | Weiner | Jul 2010 | A1 |
| 20100185205 | Novakovic et al. | Jul 2010 | A1 |
| 20100189765 | Erickson et al. | Jul 2010 | A1 |
| 20100191176 | Ho et al. | Jul 2010 | A1 |
| 20100197512 | Trinkle et al. | Aug 2010 | A1 |
| 20100211041 | Omori et al. | Aug 2010 | A1 |
| 20100216702 | Szkudlinski et al. | Aug 2010 | A1 |
| 20100221309 | Myers et al. | Sep 2010 | A1 |
| 20100227904 | Kabra et al. | Sep 2010 | A1 |
| 20100255061 | de Juan, Jr. | Oct 2010 | A1 |
| 20100256597 | Prausnitz et al. | Oct 2010 | A1 |
| 20100266664 | Asgharian et al. | Oct 2010 | A1 |
| 20100286121 | Rohrs et al. | Nov 2010 | A1 |
| 20100286791 | Goldsmith | Nov 2010 | A1 |
| 20100297046 | Schwartz et al. | Nov 2010 | A1 |
| 20100297120 | Beliveau et al. | Nov 2010 | A1 |
| 20100297193 | Archambeau et al. | Nov 2010 | A1 |
| 20100303917 | Watson et al. | Dec 2010 | A1 |
| 20100303918 | Watson et al. | Dec 2010 | A1 |
| 20100310664 | Watson et al. | Dec 2010 | A1 |
| 20100310665 | Watson et al. | Dec 2010 | A1 |
| 20100316723 | Watson et al. | Dec 2010 | A1 |
| 20100330146 | Chauhan et al. | Dec 2010 | A1 |
| 20110009571 | Taft et al. | Jan 2011 | A1 |
| 20110014264 | Helmus et al. | Jan 2011 | A1 |
| 20110033933 | Gharib et al. | Feb 2011 | A1 |
| 20110034448 | Chang et al. | Feb 2011 | A1 |
| 20110081384 | Archambeau et al. | Apr 2011 | A1 |
| 20110098686 | Varner et al. | Apr 2011 | A1 |
| 20110104155 | Rekik | May 2011 | A1 |
| 20110108025 | Fink et al. | May 2011 | A1 |
| 20110111006 | Wong et al. | May 2011 | A1 |
| 20110112188 | Tobia et al. | May 2011 | A1 |
| 20110117083 | Bais et al. | May 2011 | A1 |
| 20110125178 | Drews et al. | May 2011 | A1 |
| 20110159073 | deJuan et al. | Jun 2011 | A1 |
| 20110190723 | Fangrow | Aug 2011 | A1 |
| 20110206646 | Alfonso et al. | Aug 2011 | A1 |
| 20120029445 | de Juan, Jr. et al. | Feb 2012 | A1 |
| 20120029470 | Juan, Jr. et al. | Feb 2012 | A1 |
| 20120095439 | de Juan, Jr. et al. | Apr 2012 | A1 |
| 20130165860 | Doud et al. | Jun 2013 | A1 |
| 20130218081 | Roth | Aug 2013 | A1 |
| 20130245544 | de Juan, Jr. et al. | Sep 2013 | A1 |
| 20130274691 | de Juan, Jr. et al. | Oct 2013 | A1 |
| 20130274692 | Alster et al. | Oct 2013 | A1 |
| 20130304031 | Varner et al. | Nov 2013 | A1 |
| 20130324918 | de Juan, Jr. et al. | Dec 2013 | A1 |
| 20130324942 | de Juan, Jr. et al. | Dec 2013 | A1 |
| 20140031769 | de Juan, Jr. et al. | Jan 2014 | A1 |
| 20140073714 | Reich et al. | Mar 2014 | A1 |
| 20140276482 | Astafieva et al. | Sep 2014 | A1 |
| 20140296800 | Erickson et al. | Oct 2014 | A1 |
| 20140358125 | de Juan, Jr. et al. | Dec 2014 | A1 |
| 20150080846 | de Juan, Jr. et al. | Mar 2015 | A1 |
| 20150297402 | de Juan, Jr. et al. | Oct 2015 | A1 |
| 20160101046 | Reich et al. | Apr 2016 | A1 |
| 20160184134 | Varner et al. | Jun 2016 | A1 |
| 20160258855 | Farinas et al. | Sep 2016 | A1 |
| 20160302965 | Erickson et al. | Oct 2016 | A1 |
| 20170165110 | Erickson et al. | Jun 2017 | A1 |
| 20170172794 | Varner et al. | Jun 2017 | A1 |
| 20170258634 | de Juan, Jr. et al. | Sep 2017 | A1 |
| 20180161202 | de Juan, Jr. et al. | Jun 2018 | A1 |
| 20180243130 | Doud et al. | Aug 2018 | A1 |
| 20180243131 | Erickson et al. | Aug 2018 | A1 |
| 20180289542 | de Juan, Jr. et al. | Oct 2018 | A1 |
| 20180292403 | de Juan, Jr. et al. | Oct 2018 | A1 |
| 20190336335 | de Juan, Jr. et al. | Nov 2019 | A1 |
| Number | Date | Country |
|---|---|---|
| 101505683 | Aug 2009 | CN |
| 0033042 | Aug 1984 | EP |
| 0 228 185 | Nov 1986 | EP |
| 0498471 | Aug 1992 | EP |
| 0500143 | Aug 1992 | EP |
| 0671165 | Sep 1995 | EP |
| 0295248 | Apr 1999 | EP |
| 0944658 | Jun 2003 | EP |
| 1671624 | Jun 2006 | EP |
| 1385452 | Sep 2006 | EP |
| 1409065 | Jan 2007 | EP |
| 1337284 | Dec 2007 | EP |
| 1911481 | Apr 2008 | EP |
| 1521572 | Mar 2009 | EP |
| 01-149716 | Jun 1989 | JP |
| 01-197429 | Aug 1989 | JP |
| 08509636 | Oct 1996 | JP |
| WO-8804573 | Jun 1988 | WO |
| WO-9007545 | Jul 1990 | WO |
| WO-9424969 | Nov 1994 | WO |
| WO-9528984 | Nov 1995 | WO |
| WO-9729850 | Aug 1997 | WO |
| WO-9825982 | Jun 1998 | WO |
| WO-9911244 | Mar 1999 | WO |
| WO-0048660 | Aug 2000 | WO |
| WO-0126714 | Apr 2001 | WO |
| WO-0150943 | Jul 2001 | WO |
| WO-0168016 | Sep 2001 | WO |
| WO-02100318 | Dec 2002 | WO |
| WO-03028765 | Apr 2003 | WO |
| WO-03077972 | Sep 2003 | WO |
| WO-03082188 | Oct 2003 | WO |
| WO-2004000267 | Dec 2003 | WO |
| WO-2004112653 | Dec 2004 | WO |
| WO-2005016401 | Feb 2005 | WO |
| WO-2005025413 | Mar 2005 | WO |
| WO-2005027906 | Mar 2005 | WO |
| WO-2005028006 | Mar 2005 | WO |
| WO-2005091922 | Oct 2005 | WO |
| WO-2005107705 | Nov 2005 | WO |
| WO-2005110362 | Nov 2005 | WO |
| WO-2005110436 | Nov 2005 | WO |
| WO-2005110473 | Nov 2005 | WO |
| WO-2005117780 | Dec 2005 | WO |
| WO-2006014484 | Feb 2006 | WO |
| WO-2006015385 | Feb 2006 | WO |
| WO-2006023530 | Mar 2006 | WO |
| WO-2006031358 | Mar 2006 | WO |
| WO-2006031388 | Mar 2006 | WO |
| WO-2006044614 | Apr 2006 | WO |
| WO-2006050221 | May 2006 | WO |
| WO-2006068838 | Jun 2006 | WO |
| WO-2006071554 | Jul 2006 | WO |
| WO-2006082588 | Aug 2006 | WO |
| WO-2006108054 | Oct 2006 | WO |
| WO-2006127962 | Nov 2006 | WO |
| WO-2006138609 | Dec 2006 | WO |
| WO-2007012974 | Feb 2007 | WO |
| WO-2007035473 | Mar 2007 | WO |
| WO-2007035621 | Mar 2007 | WO |
| WO-2007038453 | Apr 2007 | WO |
| WO-2007044534 | Apr 2007 | WO |
| WO-2007047744 | Apr 2007 | WO |
| WO-2007066339 | Jun 2007 | WO |
| WO-2007084582 | Jul 2007 | WO |
| WO-2007084765 | Jul 2007 | WO |
| WO-2007101204 | Sep 2007 | WO |
| WO-2007115259 | Oct 2007 | WO |
| WO-2007117394 | Oct 2007 | WO |
| WO-2007131050 | Nov 2007 | WO |
| WO-2007133761 | Nov 2007 | WO |
| WO-2007133762 | Nov 2007 | WO |
| WO-2008003043 | Jan 2008 | WO |
| WO-2008005240 | Jan 2008 | WO |
| WO-2008011125 | Jan 2008 | WO |
| WO-2008019265 | Feb 2008 | WO |
| WO-2008033924 | Mar 2008 | WO |
| WO-2008040062 | Apr 2008 | WO |
| WO-2008045272 | Apr 2008 | WO |
| WO-2008061043 | May 2008 | WO |
| WO-2008052145 | May 2008 | WO |
| WO-2008060359 | May 2008 | WO |
| WO-2008076544 | Jun 2008 | WO |
| WO-2008094989 | Aug 2008 | WO |
| WO-2008115290 | Sep 2008 | WO |
| WO-2008116165 | Sep 2008 | WO |
| WO-2008144340 | Nov 2008 | WO |
| WO-2008144919 | Dec 2008 | WO |
| WO-2009012075 | Jan 2009 | WO |
| WO-2009023615 | Feb 2009 | WO |
| WO-2009046164 | Apr 2009 | WO |
| WO-2009055620 | Apr 2009 | WO |
| WO-2009055671 | Apr 2009 | WO |
| WO-2009055729 | Apr 2009 | WO |
| WO-2009055824 | Apr 2009 | WO |
| WO-2009061607 | May 2009 | WO |
| WO-2009073192 | Jun 2009 | WO |
| WO-2009086112 | Jul 2009 | WO |
| WO-2009089409 | Jul 2009 | WO |
| WO-2009094466 | Jul 2009 | WO |
| WO-2009112878 | Sep 2009 | WO |
| WO-2009117112 | Sep 2009 | WO |
| WO-2009124096 | Oct 2009 | WO |
| WO-2009128932 | Oct 2009 | WO |
| WO-2009134929 | Nov 2009 | WO |
| WO-2009137777 | Nov 2009 | WO |
| WO-2009137780 | Nov 2009 | WO |
| WO-2010008424 | Jan 2010 | WO |
| WO-2010021993 | Feb 2010 | WO |
| WO-2010047753 | Apr 2010 | WO |
| WO-2010062628 | Jun 2010 | WO |
| WO-2010066714 | Jun 2010 | WO |
| WO-2010075565 | Jul 2010 | WO |
| WO-2010078063 | Jul 2010 | WO |
| WO-2010088548 | Aug 2010 | WO |
| WO-2010093945 | Aug 2010 | WO |
| WO-2010095940 | Aug 2010 | WO |
| WO-2010125416 | Nov 2010 | WO |
| WO-2010126908 | Nov 2010 | WO |
| WO-2010135369 | Nov 2010 | WO |
| WO-2010141729 | Dec 2010 | WO |
| WO-2010147661 | Dec 2010 | WO |
| WO-2011008896 | Jan 2011 | WO |
| WO-2011008897 | Jan 2011 | WO |
| WO-2011028850 | Mar 2011 | WO |
| WO-2011034627 | Mar 2011 | WO |
| WO-2011079232 | Jun 2011 | WO |
| WO-2012019047 | Feb 2012 | WO |
| WO-2012019136 | Feb 2012 | WO |
| WO-2013003620 | Jan 2013 | WO |
| WO-2013022801 | Feb 2013 | WO |
| Entry |
|---|
| U.S. Appl. No. 13/814,466, filed Jun. 28, 2013, 2013/0274691. |
| U.S. Appl. No. 14/753,574, filed Jun. 29, 2015, 2015/0297402. |
| U.S. Appl. No. 14/937,754, filed Nov. 10, 2015, 2016/0128867. |
| U.S. Appl. No. 15/102,191, filed Jun. 6, 2016, 2016/0302965. |
| U.S. Appl. No. 15/606,647, filed May 26, 2017, 2017/0258634. |
| U.S. Appl. No. 15/730,537, filed Oct. 11, 2017, 2018/0243131. |
| U.S. Appl. No. 15/807,396, filed Nov. 8, 2017, 2018/0292403. |
| U.S. Appl. No. 15/877,146, filed Jan. 22, 2018, 2018/0243130. |
| U.S. Appl. No. 16/004,085, filed Jun. 8, 2018, 2018/0289542. |
| U.S. Appl. No. 16/091,493, filed Oct. 4, 2018, 2019/0117454. |
| U.S. Appl. No. 16/386,854, filed Apr. 17, 2019, 2019/0336335. |
| PCT/US2018/61262, Nov. 15, 2018, WO 2019/10396. |
| “Juvederm”, FDA, 2006, XP002670727, Retrieved from the Internet: URL:http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf [retrieved on Mar. 1, 2012] p. 1, last paragraph. |
| “MAbPac SCX-10 Column for Monoclonal Antibody Variant Analysis.” Dionex. Aug. 2010. [http://www.dionex.com/en-us/webdocs/87008-DS-MAbPac-SCX-10-Column-20Aug2010-LPN2567-03.pdf]. Web. Retrieved May 2012. 4 pages. |
| Andrews, “Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa,” Am J Physiol. Apr. 1994;266(4 Pt 1):G657-664. |
| Arvo, Agenda for the Summer Eye Research Conference, (Jul. 2009). 7 pages. |
| Avery et al., “Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy,” Ophthalmology. Oct. 2006, 113(10):1695-1705.e6. |
| Bakri et al., “The effect of intravitreal triamcinolone acetonide on intraocular pressure,” Ophthalmic Surgery, Lasers and Imaging, Sep./Oct. 2003; 34(5): 386-390. |
| Bird et al., Transport Phenomena, John Wiley & Sons, Inc., New York, 1960, pp. 196-201. |
| Block et al., “Solubility and dissolution of triamcinolone acetonide,” Journal of Pharmaceutical Sciences, Apr. 1973; 62(4):617-621. |
| Breslin, C.W., et al., “Chapter 7. Slow Release Artificial Tears”, Symposium on Ocular Therapy pp. 77-83, 1977. |
| Castro et al., “Effect of COX inhibitors on VEGF-induced retinal vascular leakage and experimental corneal and choroidal neovascularization,” Exp Eye Res. Aug. 2004;79(2):275-285. |
| Chirila et al., “The Vitreous Humor” in Handbook of Biomaterial Properties, eds. Black & Hastings. Chapman & Hall, London, 1998; pp. 125-131. |
| Cousins et al., “Program # 1251—Targeting Complement Factor 5 in Combination with Vascular Endothelial Growth Factor (VEGF) Inhibition for Neovascular Age Related Macular Degeneration (AMD): Results of a Phase 1 Study,” [Presentation Abstract], AMD Clinical Trials Session # 220, May 3, 2010. 2 pages. |
| Deissler et al., “VEGF-induced effects on proliferation, migration and tight junctions are restored by ranibizumab (Lucentis) in microvascular retinal endothelial cells,” Br J Ophthalmol 2008;92:839-843. |
| Del Amo, et al., Current & future ophthalmic drug delivery systems . . . , Drug Discovery Today, vol. 13, Nos. 3/4, Feb. 2008. pp. 135-143. |
| Donoso et al., “The role of inflammation in the pathogenesis of age-related macular degeneration,” Surv Ophthalmol. Mar.-Apr. 2006;51(2):137-52. |
| Duvvuri et al., Drug Delivery to the Retina: Challenges and Opportunities, Expert Opinion on Biological Therapy, 2003, vol. 3(1): 45-56. |
| Duvvuri, S. et al. “Microdialysis assessment of drug delivery systems for vitreoretinal targets.” Advanced Drug Delivery Reviews. 57(2005):2080-2091. |
| European Medicine Agency, Scientific Discussion; retrieved from the Internet; <http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf>, EMEA 2007, 54 pages total. 2007. |
| Funatsu et al. “Association of vitreous inflammatory factors with diabetic macular edema,” Ophthalmology 2009;116:73-79. |
| Gaudana et al., Recent Perspectives in Ocular Drug Delivery, Pharmaceutical Research, 2008. 20 pages. |
| Gaudreault et al., “Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration,” Investigative Ophthalmology and Visual Science. 2005;46:726-733. Retrieved from the Internet: <<http://www.iovs.org/cgi/reprint/46/2/726>>. |
| Gillies et al., “Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial,” Ophthalmology. Sep. 2006;113(9):1533-1538. |
| Haller, An Overview of Sustained-release Drug Implants, Retinal Physician, Jan. 2008. 4 pages. |
| Hastedt & Wright, “Diffusion in porous materials above the percolation threshold,” Pharm. Res. Sep. 1990; 7(9):893-901 (1990). |
| Heier et al, “Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema,” Ophthalmology. Nov. 2000;107(11):2034-2038;discussion 2039. |
| International Search Report dated Jan. 28, 2013, for PCT application No. PCT/US2012/044695. 4 pages. |
| Janoria et al., Novel Approaches to Retinal Drug Delivery, Expert Opinion Drug Delivery, 2007, 4 (4):371-388. |
| Jena et al., “A Novel Technique for Surface Area and Particle Size Determination of Components of Fuel Cells and Batteries,” Porous Materials, Inc., Dec. 2006, 3 pages total. Downloaded from the Internet: <<http://www.pmiapp.com/publications/docs/A_Novel_technique_for_surface_area.pdf>>. |
| Kang et al., “Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity,” Biol Pharm Bull. Jun. 2001;24(6):701-703. |
| Katz, I.M., et al., “A Soluble Sustained-Release Ophthalmic Delivery Unit”, 8:5 (May 1977) pp. 728-734. |
| Lamberts, D.W., M.D., et al., “A Clinical Study of Slow-Releasing Artificial Tears”, Ophthalmology 85 (1978) pp. 794-800. |
| Lee, D.A., et al., “Glaucoma Filtration Surgery in Rabbits Using Bioerodible Polymers and 5-Fluorouracil”, Ophthalmology 94:12 (1987) pp. 1523-1530. |
| Lee, D.A., et al., “The Use of Bioerodible Polymers and 5-Fluorouracil in Glaucoma Filtration Surgery”, Investigative Ophthalmology & Visual Science 29-11 (1988) pp. 1692-1697. |
| Li, et al., An electrochemical introculardrug delivery device, Science Direct, Sensors and Actuators, www.sciencedirect.com,Jul. 4, 2007. pp. 41-48. |
| Lopez-Armada et al., “Modulation of cell recruitment by anti-inflammatory agents in antigen-induced arthritis,” Ann Rheum Dis Nov. 2002;61(11):1027-1030. |
| Luncentis, INN-Ranibizumab, “Scientific Discussion,” European Medicines Agency; retrieved from the Internet:<http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000715/WC500101009.pdf>. Oct. 21, 2010. 32 pages. |
| Metal Powder Industries Federation, Porous Metal Design Guidebook, 2007, 24 pages total. Downloaded from the Internet: <<http://www.mpif.org/DesignCenter/porous.pdf>>. |
| Miller, DP, et al., Thermophysical Properties of Trehalose and Its Concentrated Aqueous Solutions,Pharmaceutical Research, vol. 14, No. 5, 1997, pp. 578-590. |
| Molokhia et al., “Transscleral iontophoretic and intravitreal delivery of a macromolecule: Study of ocular distribution in vivo and postmortem with MRI”, Experimental Eye Research 88 (2009) 418-425. |
| Moritera, T., et al., “Microspheres of Biodegradable Polymers as a Drug-Delivery System in the Vitreous”, Investigative Ophthalmology & Visual Science 32-6 (1991) pp. 1785-1790. |
| MOTT Corporation, “Sintered Metal Powder Media,” American Filtration & Separation Society 2007, 2 pages total. Downloaded from the Internet:<<http://www.afssociety.org/education/0907oneminute.htm>>. |
| Navarro, “The Optical Design of the Human Eye: a Critical Review,” J Optom, Jan.-Mar. 2009 2(1): 3-18. |
| Nutan, MTH, et al., General Principles of Suspensions, in Pharmaceutical Suspensions From Formulation Development to Manufacturing, editors AK Kulshreshtha, et al., Spinger, 2010. 29 pages. |
| Okabe et al., “Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device,” Investigative Ophthalmology and Visual Science. 2003;44:2702-2707. Downloaded from the Internet: <<http://www.iovs.org/cgi/reprint/44/6/2702>>. |
| Rosenfeld, “The Latest Research: Intravitreal Bevacizumab for Proliferative Diabetic Retinopathy,” Review of Ophthalmology's Retina Online, Feb. 2006. 2 pages. Retrieved from the Internet: http://www.revophth.com/archive/newsletter/0206_retina.htm. |
| SALINE (medicine)—Wikipedia, the free encyclopedia. http://web.archive.org/web/20110205192937/http://en.wikipedia.org/wiki/Saline_(medicine). Apr. 27, 2012. 4 pages. |
| Sanborn G.E., et al., Sustained-Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis, Use of an Intravitreal Device, Arch. Ophthalmol, vol. 110, 188-195 (Feb. 1992). |
| Sharma, Rajesh K., Anna T. Rogojina, and K.V. Chalam. “Bevacizumab Therapy Normalizes the Pathological Intraocular Environment beyond Neutralizing VEGF.” Molecular Vision 16 (2010): 2175-2184. Print. |
| Sheardown and Saltzman, Novel Drug Delivery Systems for Posterior Segment Ocular Disease, Opthalmology: Ocular Angiogenesis: Diseases, Mechanisms and Therapeutics, 2007, pp. 393-408. |
| Smith et al., “Spectrophotometric determination of pKa values for fluorescein using activity coefficient corrections,” WaterSA 2002; 28(4):395-402. |
| Smith, T.J., et al., “Intravitreal Sustained-Release Ganciclovir”, Arch. Ophthamol 110 (1992) pp. 255-258. |
| Soheilian et al., “Pilot Study of Intravitreal Injection of Diclofenac for Treatment of Macular Edema of Various Etiologies,” Retina, Mar. 2010; 30(3): 509-515. |
| Stay et al. Computer Simulation of Convective and Diffusive Transport of Controlled-Release Drugs in the vitreous Humor, Pharm Res 2003,20(1), pp. 96-102. |
| Theodossiadis et al., “Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration,” Am J Ophthalmol. May 2009;147(5):825-830. |
| Weiner, A.L., “Chapter 13: Polymeric Drug Delivery Systems for the Eye”, Polymeric Site—Specific Pharmacotherapy, pp. 315-346, Edited by A.J. Domb (1994) John Wiley & Sons Ltd. |
| Williams et al., “Treating Diabetic Macular Edema With Ocular NSAIDs,” Retinal Physician, Nov. 2007; retrieved from the Internet Nov. 11, 2007. http://www.retinalphysician.com/article.aspx?article=101096>, 5 pages total. |
| Wright, P., et al. “Slow-Release Artificial Tear Inserts in the Treatment of Dry Eyes Resulting from the Oculomucocutaneous Syndrome”, British Journal of Ophthalmology 67(1983) pp. 393-397. |
| Yao et al. (Prevention of Laser Photocoagulation Induced Choroidal Neovascularization Lesions by Intravitreal Doses of Ranibizumab in Cynomolgus Monkeys, ARVO 2009 abstract D906). 2 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20200030142 A1 | Jan 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61595618 | Feb 2012 | US | |
| 61538736 | Sep 2011 | US | |
| 61503492 | Jun 2011 | US | |
| 61502157 | Jun 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14129200 | US | |
| Child | 16540617 | US |
