Patent Grant
10166142
The present disclosure relates at least in part to the delivery of therapeutic agents to the eye, such as the posterior segment of the eye. Although specific reference is made to the delivery of macromolecules comprising antibodies or antibody fragments to the eye, such as the posterior segment of the eye, embodiments of the present disclosure can be used to deliver many therapeutic agents to many tissues of the body. For example, embodiments of the present disclosure can be used to deliver therapeutic agent to one or more of at least the following tissues: intravascular, intra-articular, intrathecal, pericardial, intraluminal and gut.
The eye is critical for vision. The eye has a cornea 12 and a lens that can form an image on the retina. The image formed on the retina is detected by rods and cones on the retina. The light detected by the rods and cones of the retina can be transmitted to the occipital cortex brain via the optic nerve, such that the individual can see the image formed on the retina. Visual acuity is related to the density of rods and cones on the retina. The retina comprises a macula that has a high density of cones, such that the user can perceive color images with high visual acuity.
Unfortunately, diseases can affect vision. In some instances the disease affecting vision can cause damage to the retina, even blindness in at least some instances. One example of a disease that can affect vision is age-related macular degeneration (AMD). Although therapeutic drugs are known that can be provided to minimize degradation of the retina, in at least some instances the delivery of these drugs can be less than ideal.
In some instances a drug is injected into the eye through the sclera. One promising class of drugs for the treatment of AMD is known as vascular endothelial growth factor VEGF inhibitors. Unfortunately, in at least some instances injection of drugs can be painful for the patient, involve at least some risk of infection and hemorrhage and retinal detachment, and can be time consuming for the physician and patient. Consequently, in at least some instances the drug may be delivered less often than would be ideal, such that at least some patients may receive fewer drugs than would be ideal in at least some instances.
Work in relation to embodiments of the present disclosure also suggests that an injection of the drug with a needle results in a bolus delivery of the drug, which may be less than ideal in at least some instances. For example, with a bolus injection of drug, the concentration of drug in the vitreous humor of the patient may peak at several times the required therapeutic amount, and then decrease to below the therapeutic amount before the next injection.
Although some implant devices have been proposed, many of the known devices can be deficient in at least some respects in at least some instances. At least some of the known implanted devices do not provide sustained release of a therapeutic drug for an extended period. For example, at least some of the known implanted devices may rely on polymer membranes or polymer matrices to control the rate of drug release, and many of the known membranes and matrices may be incompatible with at least some therapeutic agents such as ionic drugs and large molecular weight protein drugs in at least some instances. At least some of the known semi-permeable polymer membranes may have permeability that is less than ideal for the extended release of large molecular weight proteins such as antibodies or antibody fragments. Also, work in relation to embodiments of the present disclosure also suggests that at least some of the known semi-permeable membranes can have a permeability of large molecules that may vary over time and at least some of the known semi-permeable membranes can be somewhat fragile, such that drug release for extended periods can be less than ideal in at least some instances. Although capillary tubes have been suggested for drug release, work in relation to embodiments of the present disclosure suggests that flow through capillary tubes can be less than ideal in at least some instances, for example possibly due to bubble formation and partial clogging.
At least some of the known implantable devices can result in patient side effects in at least some instances when a sufficient amount of drug is delivered to treat a condition of the eye. For example, at least some of the commercially available small molecule drug delivery devices may result in patient side effects such as cataracts, elevated intraocular pressure, dizziness or blurred vision in at least some instances. Although corticosteroids and analogues thereof may be delivered with an implanted device to treat inflammation, the drug delivery profile can be less than ideal such that the patient may develop a cataract in at least some instances.
Although at least some of the proposed implanted devices may permit an injection into the device, one potential problem is that an injection into an implanted device can cause at least some risk of infection for the patient in at least some instances. Also, in at least some instances the drug release rate of an implanted device can change over time, such that the release rate of the drug can be less than ideal after injection in at least some instance. At least some of the proposed implanted devices may not be implanted so as to minimize the risk of infection to the patient. For example, at least some of the proposed devices that rely on pores and capillaries may allow microbes such as bacteria to pass through the capillary and/or pore, such that infection may be spread in at least some instances. Also, work in relation to embodiments of the present disclosure suggests that at least some of the proposed implanted devices do not provide adequate protection from the patient's immune system, such as from macrophages and antibodies, thereby limiting the therapeutic effect in at least some instances.
At least some of the prior injection devices may not be well suited to inject an intended amount of a therapeutic agent into a therapeutic device implanted in the eye in at least some instances. For example, in at least some instances, coupling of the injector to the therapeutic device implanted in the eye may be less than ideal. Also, the therapeutic device may provide resistance to flow such that injection can be difficult and may take more time than would be ideal or the flow into the therapeutic device can be somewhat irregular in at least some instances. The injector may decouple from the therapeutic device such that the amount of therapeutic agent delivered can be less than ideal in at least some instances. In at least some instances, the injected therapeutic agent may mix with a solution previously inside the therapeutic device such that the amount of therapeutic agent that remains in the device when the injection is complete can be more less than ideal in at least some instances.
In light of the above, it would be desirable to provide improved therapeutic devices and methods that overcome at least some of the above deficiencies of the known therapies, for example with improved drug release that can be maintained when implanted over an extended time.
Embodiments of the present disclosure can provide methods and apparatus of injecting a formulation therapeutic agent into the body, for example injection of the therapeutic agent into an implanted therapeutic device such that the therapeutic agent can be delivered from the therapeutic device in therapeutic amounts for an extended time, which can be at least about one month. The injector apparatus can accurately inject intended amounts of the therapeutic agent into the therapeutic device, such that the amount of therapeutic agent inside the chamber reservoir of the device and the amount released into the eye can correspond to substantially targeted amounts. The injector apparatus may comprise a coupling indicator to indicate when the injector apparatus is coupled to the therapeutic device and an injector apparatus extends a sufficient depth into the device for one or more of injection of the therapeutic agent or exchange of the therapeutic agent with material within the therapeutic device. The reservoir chamber of the therapeutic device can be implanted in the eye such that the reservoir chamber is located under the sclera, between the conjunctiva and the sclera, or under the sclera in the vitreous humor, or combinations thereof.
In many embodiments, the therapeutic device can be configured to provide continuous release of therapeutic quantities of at least one therapeutic agent for an extended time of at least 3 months, for example 6 months, such that the frequency of injections into the therapeutic device and risk of infection can be substantially decreased. In additional embodiments, the therapeutic device can be configured to provide continuous release of therapeutic quantities of at least one therapeutic agent for an extended time of at least 12 months, or at least 2 years or at least 3 years.
The therapeutic device can be configured in many ways to release the therapeutic agent for the extended time and may comprise at least one of an opening, an elongate structure, a porous structure, or a porous surface sized to release the therapeutic agent for the extended time. For example, the therapeutic device may comprise the porous structure to release the therapeutic agent through the porous structure for the extended period. The porous structure may comprise a sintered material having many channels, for example interconnecting channels, extending around many particles adhered to each other. The porous structure may comprise a first side comprising a first plurality of openings coupled to the reservoir and a second side comprising a second plurality of openings to couple to the vitreous humor. The interconnecting channels may extend between each of the first plurality of openings of the first side and each of the second plurality of openings of the second side so as to maintain release of the therapeutic agent through the porous structure, for example when at least some the openings are blocked. The porous structure can be rigid and maintain release of the therapeutic agent through the interconnecting channels when tissue or cells cover at least a portion of the openings, for example when the porous structure is implanted for an extended time and the drug reservoir refilled.
The therapeutic device may comprise a retention structure configured to couple to the sclera to position the container for delivery of the therapeutic agent into the vitreous humor of the eye, such that the conjunctiva may extend over the retention structure when the device is implanted so as to inhibit the risk of infection to the patient and allow access to the device with decreased risk of infection. For example, the retention structure may comprise a flange extending outward for placement between the conjunctiva and sclera and a narrow portion to fit within the incision through the sclera. The narrow portion to fit the incision may comprise an elongate cross sectional profile sized to fit the incision. The elongate cross-sectional profile sized to fit the incision can improve the fit of the implanted device to the scleral incision, and may seal the implant against the sclera along the incision. The elongate cross sectional profile of the narrow portion can be sized in many ways to fit the incision. For example, the elongate cross section may comprises a first dimension longer than a second dimension and may comprise one or more of many shapes such as dilated slit, dilated slot, lentoid, oval, ovoid, or elliptical. The dilated slit shape and dilated slot shape may correspond to the shape sclera 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.
In many embodiments, the reservoir of the therapeutic device is flushable and/or refillable. This can provide an added benefit that the physician may remove the therapeutic agent from the patient by flushing the agent from the reservoir of the therapeutic device rather than waiting for the therapeutic agent to be eliminated from the patient. This removal can be advantageous in cases where the patient has an adverse drug reaction or benefit from a pause in therapy sometimes referred to as a drug holiday. The volume of the reservoir and release rate of the porous structure can be tuned to receive a volume of a commercially available formulation, such that the therapeutic agent can be released for an extended time. For example, the volume of commercially available therapeutic agent may correspond to a bolus injection having a treatment duration, for example one month, and the reservoir volume and release rate tuned to receive the formulation volume can extend the treatment duration of the injected volume by a factor of at least about two, for example from one month to two or more months.
In a first aspect, embodiments can provide a method of treating an eye having a vitreous humor. At least about 3.5 mg of ranibizumab can be injected into a therapeutic device implanted in the eye, and the amount can be within a range from about 3.5 to about 5.5 mg, for example about 4.5 mg. The therapeutic device can have a chamber volume sized to store no more than about 1.5 mg of ranibizumab, for example no more than about 2.5 mg, such that at least about 2 mg of ranibizumab can be released from the therapeutic device to the vitreous humor of the eye as a bolus injection.
In many embodiments, at least about 4 mg of ranibizumab can be injected into the therapeutic device implanted in the eye, such that at least about 2 mg of ranibizumab can be released from the therapeutic device to the vitreous humor of the eye as a second bolus injection.
In another aspect, embodiments provide a method of treating an eye having a vitreous humor. A first amount of a therapeutic agent can be injected into a therapeutic device implanted in the eye. A second amount of the therapeutic agent can be injected into the therapeutic device implanted in the eye. The second amount can be less than the first amount based on a portion of the amount of therapeutic agent contained in the therapeutic device when the second amount is injected.
In at least some embodiments, the second amount can be less than the first amount based on a mixing ratio of the second amount with the portion. In at least some embodiments, the second amount can be injected at least about one month after the first amount is injected.
In another aspect, embodiments can provide methods of treating an eye having a vitreous humor. A first amount of a therapeutic agent can be injected into a therapeutic device implanted in the eye. The first amount can correspond to a first injection volume greater than a chamber volume of the therapeutic device, such that a first portion of the first amount can be passed through the chamber into the vitreous humor as a first bolus injection and a second contained portion can be contained in the chamber and released for an extended time. A second amount of the therapeutic agent can be injected into the therapeutic device implanted in the eye, and the second amount corresponds to a second injection volume greater than the chamber volume of the therapeutic device, such that a first portion of the second amount can be passed through the chamber into the vitreous humor as a second bolus injection and a second contained portion can be contained in the chamber and released for an extended time. The second amount can be less than the first amount such that the second bolus injection has no more therapeutic agent than the first bolus injection.
In another aspect, embodiments can provide a method of treating an eye having a vitreous humor. An amount of therapeutic agent can be injected into a reservoir of a therapeutic device. The reservoir can have a substantially fixed volume coupled to a porous structure. The amount may be greater than the substantially fixed volume, such that a first portion of the amount can be released into the vitreous humor of the eye as a bolus injection and a second portion of the amount can be retained in the reservoir. The second portion may be released from the porous structure at amounts lower than amounts of the first portion, such that the bolus injection corresponds to a maximum concentration of the therapeutic agent in the eye.
In at least some embodiments, the maximum concentration can comprise no more than a peak concentration corresponding to an amount of the bolus injection. In another aspect, some embodiments provide a method of treating an eye having a vitreous humor and an established safe bolus amount of a therapeutic agent. A first amount of a therapeutic agent can be injected into a therapeutic device implanted in the eye. A second amount of the therapeutic agent can be injected into the therapeutic device implanted in the eye. A portion of the first amount of therapeutic agent can be contained in the therapeutic device when the second amount is injected such that a second bolus is released from the therapeutic device to the vitreous humor, the second bolus comprising a second amount of the therapeutic agent greater than the established safe bolus amount.
In at least some embodiments, the second amount can comprise an incremental increase in exposure to the therapeutic agent. In at least some embodiments, further comprising injecting additional bolus amounts above the second amount to establish a second safe bolus amount. In at least some embodiments, further comprising removing the therapeutic agent from the therapeutic device based on a negative response to the second amount of the therapeutic agent, wherein the therapeutic agent is exchanged with a solution substantially lacking the therapeutic agent.
In another aspect, some embodiments can provide an apparatus to treat an eye an eye with a therapeutic agent having an established safe amount. An injector can have a volume of liquid comprising an amount of therapeutic agent. A therapeutic device can have a chamber volume sized smaller than the injector volume to release a bolus of the therapeutic agent.
In another aspect, some embodiments can provide a sustained drug delivery formulation comprising a therapeutic agent wherein the therapeutic agent can be contained in a reservoir of the device as described above, and the therapeutic agent has a half-life within the reservoir when implanted. The half life within the reservoir can be substantially greater than a corresponding half-life of the at least one of the therapeutic agent when injected directly into the vitreous of an eye.
In at least some embodiments, the device can be configured by selection of the reservoir volume and a porous structure with an appropriate rate release index to achieve the desired effective half-life. In at least some embodiments, the rate release index of the porous structure can be from about 0.001 to about 5, for example from about 0.002 to about 5, and can be from about 0.01 to about 5. In at least some embodiments, the first therapeutic agent can be a VEGF-inhibitor and the second therapeutic agent is an inflammatory response inhibitor.
In another aspect, some embodiments can provide sustained drug delivery formulation to treat a patient of a population. The formulation comprises a therapeutic agent, and the therapeutic agent has a half-life within the eye corresponding to a half life the therapeutic agent injected into a device implanted in the eye.
In another aspect, some embodiments can provide a method of treating an eye. An amount therapeutic agent can be injected into a therapeutic device, such as in the amount within a range from about 0.01 mg to about 50 mg, and the range can be from about 0.1 mg to about 30 mg.
In another aspect, some embodiments can provide an apparatus to treat an eye. The apparatus can comprise an amount of formulation corresponding to an amount of therapeutic agent, such as in which the amount within a range from about 0.01 mg to about 50 mg, and the range can be from about 0.1 to about 30 mg. A therapeutic device can have a reservoir chamber and porous structure tuned to receive the amount of formulation corresponding to the amount of therapeutic agent. For example, in some embodiments, the amount can be within a range from about 0.1 mg to about 30 mg.
In another aspect, some embodiments can provide an apparatus to treat an eye with a therapeutic agent. The apparatus can comprise an injector having a volume of fluid comprising an amount of therapeutic agent. A therapeutic device can comprise a reservoir chamber, and the reservoir chamber can have a volume sized to receive the amount of therapeutic agent. Additionally, the amount of therapeutic agent can be placed in the reservoir chamber.
In some embodiments, the fluid can comprise a concentration of ranibizumab within a range from about 40 mg/mL to about 200 mg/mL, for example within a range from about 40 mg/ml to about 100 mg/mL.
In some embodiments, the injector is configured to place the amount of therapeutic agent with no substantial bolus. In addition, some embodiments of the injector can be configured to place the amount of therapeutic agent with an exchange efficiency of at least about 80%.
In some embodiments, the injector can comprise an injection lumen to inject the therapeutic and a vent to receive fluid of the chamber, the therapeutic device can comprise a reservoir chamber to release the therapeutic agent. The vent may comprise a resistance to flow substantially lower than a resistance to flow of the porous structure of the therapeutic device so as to inhibit a bolus of the therapeutic agent through the porous structure.
In another aspect, some embodiments provide an apparatus to treat an eye with a therapeutic agent. A volume of a fluid comprising an amount of therapeutic agent can be injected into a therapeutic device comprising a reservoir chamber. The reservoir chamber can have a volume sized to receive the amount of therapeutic agent, and the amount of therapeutic agent can be placed in the reservoir chamber.
In some embodiments, the injector can be configured to place the amount with an exchange efficiency of at least about 80%. Additionally, in some embodiments, the amount is placed in the reservoir chamber with no substantial bolus of the fluid comprising the therapeutic agent through the porous structure.
In another aspect, some embodiments provide an expandable and collapsible therapeutic device having a substantially fixed volume. The therapeutic device may comprise a first narrow profile configuration for placement and a second expanded wide profile configuration to deliver the drug with the reservoir when positioned in the eye. The expanded device can have one or more support structures that can be collapsed, for example compressed or extended to decrease cross sectional size, such that the device can fit through the incision. For example, the therapeutic device may comprise a flexible barrier material coupled to a support, such that the barrier material and support can be expanded from a first narrow profile configuration to a second expanded profile configuration, and subsequently collapsed to the first narrow profile configuration for removal. The support can provide a substantially constant reservoir volume in the expanded configuration, such that the device can be tuned with the porous structure and expandable reservoir to receive the volume of therapeutic agent formulation and release therapeutic amounts for the extended time.
The therapeutic device may comprise a porous barrier extending around the container with channels sized to pass the therapeutic agent from the container therethrough and to inhibit migration of at least one of a bacterial cell out of the container or a macrophage or other immune cell into the container. To remove the therapeutic device having the flexible barrier coupled to the support, the support can be collapsed at least partially for removal, for example with elongation along an axis of the therapeutic device such that the cross sectional size of the support can be decreased for removal through the incision.
In some embodiments, a proximal end of the therapeutic device can be coupled to a removal apparatus, and an elongate structure may couple to a distal portion of the therapeutic device and extended along such that the distal portion may be urged distally and the cross sectional size of the support decreased for removal through the incision. The elongate structure may comprise one or more of a needle, a shaft, a mandrel or a wire, and the distal portion may comprise a stop coupled to the support, such as the porous structure or a portion of the support, such that the support is extended along the axis for removal when the elongate structure is advanced distally.
In some embodiments, a removal apparatus can comprise the elongate structure and jaws to couple to the retention structure and wherein the elongate structure can comprise one or more of a needle, a shaft, a mandrel or a wire.
In some embodiments, the porous structure can comprise a rigid porous structure affixed to a distal end of the support to release the therapeutic agent into a vitreous humor of the eye for an extended time. The flexible support and flexible barrier may comprise flexibility sufficient to increase the length increases from the second length to the first length when the elongate structure contacts the rigid porous structure.
In some embodiments, the support can comprise a plurality of flexible struts that extend axially from the retention structure to an annular flange sized to support the porous structure on the distal end of device, and wherein the flexible struts are space apart when the device comprises the second expanded profile configuration to define the chamber having the substantially constant volume.
Although specific reference is made to the delivery of macromolecules comprising antibodies or antibody fragments to the posterior segment of the eye, embodiments of the present disclosure can be used to deliver many therapeutic agents to many tissues of the body. For example, embodiments of the present disclosure can be used 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 of the present disclosure provide sustained release of a therapeutic agent at least 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.
As used herein, the release rate index encompasses (PA/FL) 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 determine by a person of ordinary skill in the art in accordance with the teachings described hereon.
As used herein, sustained release encompasses release of therapeutic amounts of an active ingredient of a therapeutic agent for an extended period of time. The sustained release may encompass first order release of the active ingredient, zero order release of the active ingredient, or other kinetics of release such as intermediate to zero order and first order, or combinations thereof.
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.
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 a 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, the 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. In addition, the therapeutic agent may comprise a therapeutic agent suitable for treatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™ (Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor (POT-4).
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.)
For example, the amount of therapeutic agent within the therapeutic device may comprise from about 0.01 mg to about 50 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 using published data. 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 the 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. Additionally, 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. In addition, 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, a diffusion mechanism so as to release therapeutic amounts of therapeutic agent for the extended time.
While the implant can be positioned in the eye 10 in many ways, one position includes, for example, placement in the pars plana 25 region such that therapeutic agent 110 can be released 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 includes many therapeutic agents, for example as listed in Table 1A, herein below. The therapeutic agent 110 of device 100 may comprise one or more of an active ingredient of the therapeutic agent, 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 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, 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 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 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 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 tube 168 and retention structure 120 may be configured to receive a glass rod (not shown), which can be surface treated, and the glass rod can be injected with therapeutic agent. 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 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.
The formulation 110F may comprise a commercially available formulation of therapeutic agent 110, for example therapeutic agents as described herein and with reference to Table 1A. Non-limiting examples of commercially available formulations that may be suitable for use in accordance with the embodiments described herein include Lucentis™ and Triamcinolone, for example. The formulation 110F may be a concentrated or diluted formulation of a commercially available therapeutic agent 110, for example Avastin™ The osmolarity and tonicity of the vitreous humor 30 can be within a range from about 290 to about 320. For example, a commercially available formulation of Avastin™ may be diluted so as to comprise a formulation having an osmolarity and tonicity substantially similar to the osmolarity and tonicity of the vitreous humor 30, for example within a range from about 280 to about 340, for example about 300 mOsm. While the therapeutic agent 110 may comprise an osmolarity and tonicity substantially similar to the vitreous humor 30, the therapeutic agent 110 may comprise a hyper osmotic solution relative to the vitreous humor 30 or a hypo osmotic solution relative to the vitreous humor 30. A person or ordinary skill in the art can conduct experiments based on the teachings described herein so as to determine empirically the formulation and osmolarity of the therapeutic agent 110 to provide release of therapeutic agent 110 for an extended time.
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™ in development by Genentech and/or Novartis, may comprise the therapeutic agent 110 injected into the device 100. The sustained release formulation may comprise particles comprising one or more active ingredients.
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™ is 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 are 2 forms of Triamcinolone used in injectable solutions, the acetonide and the hexacetonide. The acetamide is 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 percents 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 determined 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 injected into therapeutic device 100 may comprise many known formulations of therapeutic agents, and the formulation therapeutic agent comprises 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 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 100, the formulation of the therapeutic agent 110 injected into the therapeutic device 100 can be hypertonic (hyper-osmotic) or hypotonic (hypo-osmotic) with respect to the tonicity and osmolarity of the vitreous. Additionally, 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 teaching described herein to determine empirically the appropriate reservoir 140 chamber volume and porous structure for a formulation of therapeutic agent 110 disposed in the reservoir 140 chamber, 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 the minimum inhibitory concentration for the extended time.
The device 100 may include additional chambers and openings which can assist in linearizing the delivery of the one or more drugs. For example, a third chamber can be disposed distally to the second chamber. The second opening can couple the second chamber to the third chamber. For example, a fourth chamber can be disposed distally to the third chamber, a third opening can connect the third chamber and the fourth chamber.
Additionally or in the alternative, the therapeutic device 100 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. Additionally, the gates may comprise an osmotic pump.
As shown in
For example, when some protective membranes have pores of 0.2 um 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 can be:
Therefore, solutions of therapeutic compounds in the size range of IgG and BSA may flow relatively easily through 0.2 um pore size protective membranes used to stop passage of bacterial and other cells.
Binding Materials/Agents may comprise at least one of a chemical binding agent/material, 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 at 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 a 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 with at least one of diethylaminoethyl or carboxymethyl functional groups.
Additionally, 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 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 ion exchange may comprise positive or negative ion exchange.
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. Additionally, 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, which surface area is 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 100 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.
Furthermore, 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 the 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 100100 are described in Table 1A and may include at least 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 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.
The therapeutic agent 110 may comprise at least 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 for below in Table 1A, below.
The therapeutic agent 110 may comprise at least one or more of 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 10, 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 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 can include the ability of the rigid porous structure 150 to comprise a needle stop, simpler and more cost effective manufacture, flushability for cleaning or declogging 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 150 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, the rigid porous structure 150 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 can enable a smaller device to be used, which is preferred in a small organ such as the eye 10 where larger devices may alter or impair vision.
The container may comprise a tubular barrier 160 that defines at least a portion of the reservoir 140, and the container may comprise a width, for example a diameter 134. The diameter 134 can be sized within a range, for example within a range from about 0.5 to about 4 mm, for example within a range from about 1 to 3 mm and can be about 2 mm, for example. The container 130 may comprise a length 136 (see, for example,
The volume of the reservoir 140 may be substantially determined by an inner cross sectional area of the tubular structure and distance from the porous structure 150 to the penetrable barrier. The retention structure may comprise an annular extension having a retention structure diameter greater than a diameter of the container. The retention structure may comprise an indentation configured to receive the sclera when the extension extends between the sclera and the conjunctive. The penetrable barrier 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 110. The porous structure 150 may comprise a cross sectional area 150A sized to release the therapeutic agent 110 for the extended period.
The porous structure 150 may comprise a first side 150S1 coupled to the reservoir and a second side 150S2 to couple to the vitreous. The first side may comprise a first area 150A1 and the second side may comprise a second area 150A2. The porous structure 150 may comprise a thickness 105T. The porous structure 150 many comprise a diameter 150D. In addition, 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 can comprise 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 ug/mL to about 100 ug/mL, such as from about 1 ug/mL to about 40 ug/mL. For example, the therapeutic agent 110 may comprise a suspension of triamcinolone acetonide having a solubility of approximately 19 ug/mL in the buffer at 37C 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 some embodiments may be no more than about 1.2, so as to release the therapeutic agent 110 with therapeutic amounts for the extended time. In addition, the therapeutic device 100, including for example, the retention structure 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 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 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 158 can be configured for injection of the therapeutic agent 110 into the container in many ways. The channels of the rigid porous structure 158 may comprise substantially fixed channels when the therapeutic agent 110 is injected into the reservoir 140 with pressure. The rigid porous structure may comprise a hardness parameter within a range from about 160 Vickers to about 500 Vickers. In some embodiments the rigid porous structure can be formed from sintered stainless steel and comprised of 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 of the rigid porous structure 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 158 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 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 ug 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 ug per ml of vitreous humor 30 and no more than about 10 ug 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 k Daltons. 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 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 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 of the rigid porous structure 158 can comprise a hydrogel configured to limit a size of molecules passed through the channels of the rigid porous structure. For example, the hydrogel can be formed within the channels and may comprise an acrylamide gel. The hydrogel can have 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 k Daltons. The hydrogel may comprise a water content of no more than about 95% to limit molecular weight of the therapeutic agent 110 to about 100 k Daltons. The hydrogel may comprise a water content within a range from about 90% to about 95% such that the channels of the porous material are configured to pass Lucentis™ and substantially not pass Avastin™.
The rigid porous structure 158 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 to the desired release of the therapeutic agent 110.
Some 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 includes 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 may further include 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 can be 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, 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 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 (RRI) can be used to determine release of the therapeutic agent 110. The RRI may be defined as (PA/FL), and the RRI values herein can have units of mm unless otherwise indicated. Some of the porous structures used in the therapeutic delivery devices described herein 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, and the channel parameter can correspond to an effective length that the therapeutic agent 110 travels along the interconnecting channels 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 from the reservoir side to the vitreous side. For example, the channel parameter (F) of about 1.5 can correspond to interconnecting channels that can 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 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 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 from the reservoir side to the vitreous side corresponds to at least about 2.0 mm. The porous structure 150 many comprise interconnecting channels that provide many alternative paths for release of the therapeutic agent 110. Blockage of some of the channels may provide little to no substantial change in the effective path length through the porous structure 150 as the alternative interconnecting channels can be available. Therefore, the rate of diffusion through the porous structure 150 and the release of the therapeutic agent 110 can be substantially maintained when some of the channels 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 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 may comprise 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 extending within the material. The porosity can comprise a value within a range from about 3% to about 70%. In other embodiments, the porosity can 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. Additionally, 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. 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 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 can correspond 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 can be 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.
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 can assume 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 can be considered negligible (cv=0). Solving the differential equation and rearrangement yields the following equations describing the concentration in the reservoir 140 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=cR0exp((−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 140 can be constant with time, the release rate can be zero order, and the cumulative release can increase 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 110 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 may be approximately 3 days in rabbit and monkey (Gaudreault et al) and 9 days in humans (Lucentis™ package insert). The vitreous volume can be approximately 1.5 mL for the rabbit and monkey and 4.5 mL for the human eye 10. The model can predict an initial concentration of 333 ug/mL for a bolus injection of 0.5 mg Lucentis™ into the eye of a monkey. This concentration can decay 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 situation, 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 can yield the following equation for the concentration in the vitreous:
cv=Release rate from device/k Vv.
Since the release rate from a device with a solution of therapeutic agent 110 can decrease exponentially with time, the concentration in the vitreous can decrease exponentially with the same rate constant. In other words, vitreous concentration can decrease with a rate constant equal to D PA/FL VR and, hence, can be dependent on the properties of the porous structure 150 and the volume of the reservoir 140.
Since the release rate can be zero order from a device 100 with a suspension of therapeutic agent 110, the vitreous concentration can also be time-independent. The release rate can depend on the properties of the porous structure 150 via the ratio, PA/FL, but can be independent of the volume of the reservoir 140 until the time at which the drug is exhausted.
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 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 Daltons or for example, at least about 50 k Daltons. The channels 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 of the rigid porous structure 150 comprise interconnecting channels configured to pass the therapeutic agent 110 among the interconnecting channels. The rigid porous structure 150 can comprise grains of rigid material and wherein the interconnecting channels 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 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 corresponding to an in situ concentration within a range from about 0.05 ug/mL to about 4 ug/mL, for example from 0.1 ug/mL to about 4 ug/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 in which the grains comprise an average size of no more than about 20 um. For example, the sintered material may comprise grains of material in which the grains comprise an average size of no more than about 10 um, an average size of no more than about 5 um, or an average size of no more than about 1 um. The channels 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 can be sized to inhibit penetration of microbes including bacteria and fungal spores through the sintered material. Additionally, the sintered material comprises a wettable material to inhibit bubbles within the channels of the material.
The sintered material can comprise 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 metal, ceramic, glass or 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 may comprise a plurality of rigid porous structures coupled to the reservoir 140 and configured to release the therapeutic agent 110 for the extended period. For example, additional rigid porous structure can be disposed along the container, for example the end of the container may comprise the porous structure 150, and an additional porous structure 150 can be disposed along a distal portion of the container, for example along a tubular sidewall of the container.
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 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 can comprise a volume of the formulation, for example 50 uL. 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 100 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 100 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 ug/mL, and the values of the range of therapeutic concentrations can be at least about 3 ug/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 100, for example through the penetrable barrier. The reservoir 140 of the container can have a chamber to contain a volume of the therapeutic agent 110, for example 35 uL, and a mechanism to release the therapeutic agent 110 from the chamber to the vitreous humor 30.
The volume of the container 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 can comprise 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 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 may comprise no more than the volume of the formulation, such that at least a portion of the formulation injected into the reservoir 140 passes through the reservoir and comprises a bolus injection to treat the patient immediately. As the volume of the reservoir 140 is increased, the amount of formulation released to the eye through the porous structure 150 upon injection can decrease along with the concentration of active ingredient of the therapeutic agent 110 within the reservoir, 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 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 uL, and the reservoir 140 may comprise a volume of about 100 uL and provide therapeutic vitreous concentrations of at least about 3 ug/mL for six months with 50 uL of Lucentis™ injected into the reservoir.
The chamber may comprise a substantially fixed volume and the release rate mechanism can comprise 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 to the second side 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 can correspond to the paths of the channels around the sintered grains of material, and may correspond, for example, to the paths of channels 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. The molded rigid porous structure 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 porous structure 150 may comprise interconnecting nano-channels, for example formed with a sintered nano-material. The sintered nanomaterial may comprise nanoparticles sintered so as to form a plurality of interconnecting channels as described herein, and can be made of a suitable size so as to provide an RRI as described herein. For example, the porous structure 150 comprising interconnecting nano-channels may comprise a decreased cross sectional area so as to provide a low RRI as described herein, such as an RRI of about 0.001 or more, for example an RRI of 0.002. The area can be increased and thickness decreased of the porous structure 150 comprising interconnecting channels so as to provide an increased RRI, for example of about 5. The RRI of the porous structure 150 comprising the plurality of interconnecting channels may comprise a value within a range from about 0.001 to about 5, for example from about 0.002 to about 5, for example a sintered porous material based on the teachings described herein. Injection of therapeutic agent 110 into the device 100 as described herein can be performed before implantation into the eye 10 or alternatively when the therapeutic device 100 is implanted into the eye 10.
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. 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. When the valve 703V is open and therapeutic agent is injected, spent media 703 from the container reservoir of the therapeutic device 100 can passe to the second container of the injector 701, such that at least a portion of the spent media 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 can be injected into therapeutic device 100 when the valve 703V is open such that the first portion of the formulation is exchanged with material disposed within the reservoir; the valve 703V can then be closed and a second portion of the formulation can be 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 can be 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. Additionally, the needle 189 may comprise a dual lumen needle, for example as described with reference to
The vent 189V may comprise a resistance to flow of the injected formulation, and the porous structure 150 may comprise a resistance to flow. The resistance to flow of the vent 189V can be lower than the resistance to flow of the porous structure 150 so as to inhibit release of a bolus when the therapeutic formulation is placed in the reservoir 140 chamber. Alternatively, the injector 701 can inject a bolus as described herein.
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 injector 701 can comprise a mechanism to maintain the rate of flow into the device 100 and limit a maximum amount of flow, for example with a spring. The mechanism may comprise one or more of a mechanical mechanism, an electrical mechanism, a pneumatic mechanism, or 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 is coupled to the therapeutic device 100 implanted in the eye 10 at a depth for injection. The operator can then depress the plunger.
In some embodiments the plunger comprises a telescopic joint and a spring, such that the joint can be slid together such that the plunger is urged downward to contact the stop. When the plunger is urged downward, the spring can be compressed when the ends of the telescopic joint come together. The compressed spring urges the piston toward the therapeutic device 100 such that the formulation of therapeutic agent 110 is injected into the therapeutic device 100 with the force of the spring. The valve 703V can close as described above. The second portion of the injection corresponding to the bolus injection is injected into the therapeutic device 100 and through porous structure 150.
For example, 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 can 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 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 an first axis and a second curve along a second axis different than the first curve.
The retention structure 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 the pars plana 25 of the eye (see
The retention structure 120 may comprise structures corresponding to structure of the cross-sectional area. For example, the extension 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 extending around an access port to the therapeutic device 100, as described above. The indentation 1201 and extension 122 may each comprise an elliptical or oval profile with a first long (major) axis of the ellipse extending in the first direction and a second short (minor) axis of the ellipse extending in the second direction. The long axis can be aligned so as to extend circumferentially along the pars plana 25 of the eye 10, and the short axis can be aligned so as to extend toward the pupil of the eye 10, such that the orientation of device 100 can be determined with visual examination by the treating physician.
The penetrable barrier 184, for example the septum, can be inserted into the access port 180. The penetrable barrier may comprise an elastic material sized such that the penetrable barrier can be inserted into the access port 180. The penetrable barrier may comprise one or more elastic materials such as siloxane or rubber. The penetrable barrier may comprise tabs 184T to retain the penetrable barrier 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 140 container 130 of the device 100 may comprise a rigid biocompatible material that extends at least from the retention structure 120 to the rigid porous structure, such that the reservoir 140 comprises a substantially constant volume when the therapeutic agent 110 is released with the rigid porous structure so as to maintain a stable release rate profile, for example when the patient moves. Alternatively or in combination, the reservoir 140 container 130 may comprise an optically transmissive material such that the reservoir 140 container 130 can be translucent, for example transparent, such that the chamber of reservoir 140 can be visualized when the device 100 is loaded with therapeutic agent 110 outside the patient prior to implantation, for example when injected with a formulation of therapeutic agent 110 prior to implantation in the physician's office. This visualization of the reservoir 140 can be helpful to ensure that the reservoir 140 is properly filled with therapeutic agent 110 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 140 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 140 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 release in accordance with the volume of the reservoir 140 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 140 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 140.
The support 160S of the expandable barrier 160 can provide a substantially constant volume of the reservoir 140 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 110 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 140 chamber having the substantially constant volume.
Expandable Therapeutic Device Having a Substantially Constant Reservoir Chamber Volume Configured to Decrease Cross-Sectional Size for Removal
The therapeutic device 100 may comprise an expandable device that can be collapsible in cross-section for removal and comprises a substantially constant reservoir volume and substantially constant release rate index when expanded such that the device can be tuned to receive an amount of formulation of therapeutic agent 110. The expandable device may comprise an expandable therapeutic device comprise the retention structure to couple to the sclera, a penetrable barrier and a flexible support coupled to a flexible barrier. The flexible support can be expandable from a first elongate narrow profile configuration having a first length and a first cross-sectional size to a second wide profile configuration having a second length and a second cross-sectional size. The second wide profile configuration can define a chamber having a substantially constant volume when placed in the eye 10, in which the first length greater than the second length, and the first cross-sectional size can be smaller than the second cross-sectional size. The flexible support and the flexible barrier can have sufficient flexibility so as to increase the length from the second length to the first length and decrease the cross-sectional size from the second size to the first size when an elongate structure is advanced through the penetrable barrier.
The therapeutic device may comprise an expandable and collapsible container shaped with a support structure positioned away from visual path so as to increase chamber reservoir volume without inhibiting vision. In addition, the therapeutic device may comprise a collapsible cross-section for removal. The therapeutic device may comprise a substantially fixed expanded volume, such that the substantially fixed volume is tuned to receive injection of therapeutic agent 110. The substantially fixed volume may comprise a volume fixed to within +/−50%, for example to within +/−25%. The therapeutic device may comprise a collapsed cross-sectional size of 1 mm or less for insertion and insertion size, but could be up to 2 mm.
The therapeutic device may comprise a volume sized to receive injection from about 1 uL to about 100 uL (most formulations are 50 uL injection), for example a chamber reservoir of 100 uL in the expanded substantially fixed volume configuration.
The Expandable support frame may comprise one or more of the following: a support frame comprising wire, nitinol, thermoplastic, etc.; coupling to a flexible barrier comprising one or more of a balloon, sheet, membrane, or membrane define the shape of chamber with the support and barrier; support frame can be on inside, outside or within flexible barrier material, self-expanding material or actuated, or combinations thereof; expandable for small insertion incision, for example when the length of the device decreases to expand the cross-sectional size to define the chamber having substantially constant volume, collapsible for removal through incision, for example when the length of the device increases to decrease cross-sectional size for removal, one or more support configurations, braided support (elongated/thin to position the expandable device, e.g. with mandrel). Expansion volume of reservoir may be limited to no more than 0.2 mL, such that IOP is not substantially increased when the device expands to the substantially constant volume wide profile configuration.
The support 160S may comprise a first proximal annular portion 160SA, for example a ring structure, a second distal annular portion 160SB, for example a ring structure, and struts 160SS extending axially therebetween. The struts 160SS can extend axially from the first proximal annular portion 160SA comprising the first ring structure to the second ring structure. The first proximal portion 160SA may support the penetrable barrier 184 and be sized to receive the elongate structure. The second distal annular portion 160B can be coupled to the rigid porous structure 150, for example with the flange, such that the elongate structure can urge the porous structure 150 axially along axis 100A so as to increase the length from second length L2 to first length L1 to remove the therapeutic device.
The support 160 may comprise a flexible material, for example a shape memory material or flexible metal or plastic, such that the struts 160SS extending from the proximal ring structure to the distal ring structure can be compressed when placed in the cannula as described above and then separate to define the chamber when passed through the cannula in to the eye 10 so as to define the reservoir 140 chamber having the substantially constant volume. When the elongate structure urges the rigid porous structure away from the proximal end coupled to the coupling so as to increase the length of device 790, the cross-sectional width is decreased to remove the expandable therapeutic device 790.
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 110 can be released along the flow path, such that the flow of vitreous humor 30 transports the therapeutic agent 110 to the retina 26. The porous structure 150 can be disposed on a distal portion of the therapeutic device 100, for example on a distal end, and the reservoir 140 can be sized for delivery for the extended time. The retention structure 120 can be proximally located. The therapeutic device 100 can be sized such that the porous structure 150 is positioned in the flow path corresponding to the target region. A 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 25 or other location such that the therapeutic agent 110 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 100. 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 140 can be sized with the release rate index so as to release the therapeutic agent 110 for an extended time substantially greater than the treatment time of a corresponding bolus injection. The device 100 can also be tuned to release the therapeutic agent 110 based on the half life of the therapeutic agent 110 in the eye 10. The device volume and release rate index can comprise parameters that can be tuned together based on the volume of formulation injected and the half life of the therapeutic agent 110 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
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 can be substantially constant, the max value of Cv will correspond to conditions that maximize the Rate from the device 100. At a given time since injection into the device (e.g., 180 days), the maximum Cv can be 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)=500× and g(x)=exp(−xt)
d(Rate)/dx=f′(x)g(x)+f(x)g′(x)=500(1−xt)exp(−xt)
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 100 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 110, 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 140 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 100 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 140 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 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 100. The corresponding Cv is about 3.19 ug/mL at 180 days based on the rate of drug released from the device 100 at 180 days and the rate of the drug from the vitreous (k corresponding to a half life of about 9 days). A device 100 with a container reservoir volume of 63 uL and RRI of 0.044 can also provide the optimal Cv at 180 days since the ratio of Vr to PA/TL may also be 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 140 can be substantially fixed, the volume of the reservoir 140 can vary, for example within about +/−50% as with an expandable reservoir 140 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 110 and the type of eye 10, 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 110 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 110 in the human vitreous humor 30, or an animal vitreous humor 30, 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 110 in the eye 10 based on the type of eye 10 and the therapeutic agent 110, such that the reservoir 140 and porous structure 150 can be tuned together so as to receive the volume of formulation and provide therapeutic amounts for the extended time.
Once filled, the outside of the reservoirs can be rinsed of excess fluorescein by submerging in PBS.
The initial release rate (averaged over 0.5-4 days) can be proportional to the area of the exit port opening.
The cumulative amount released into the vials is shown in
An experiment can be performed to screen chromatographic media (Bio-Rad) for binding to Human IgG (Jackson ImmunoResearch, ChromPure). Columns can be packed with the ten media listed below and equilibrated in 20 mM acetate buffer pH 4.5.
Then, 0.5 mL aliquots of 1 mg/mL antibody in 20 mM acetate buffer pH 4.5 can be gravity-driven through the column and the collected solution assessed qualitatively for color change using a BCA™ protein assay kit (Pierce). Of the media tested, Macro-Prep CM Support, Macro-Prep High S Support, and Macro-Prep Ceramic Hydroxapatite Type II 40 um each can be successfully bound IgG. Subsequently, PBS can be washed through the columns and the IgG released from all three of these media.
Future Exit Port Studies
The experiments described in Examples 1-3 can be repeated with agitation to explore the impact of mixing induced by eye movement. In addition, the experiments can be performed at body temperature where delivery rates would be expected to be higher based upon faster diffusion rates at higher temperature.
Diffusion rates of BSA (MW 69 kDa) may be representative of diffusion rates of Lucentis™ and Avastin™, globular proteins with MW of 49 and 150 kDa, respectively. Selected experiments could be repeated to confirm individual delivery rates of these therapeutic agents.
Device prototypes closer to the embodiments described in the body of the patent could be fabricated from metals (e.g., titanium or stainless steel) or polymers (e.g., silicone or polyurethane). Exit ports of defined areas can be created via ablation or photo-etching techniques. In the case of polymers, exit ports can also be created by molding the material with a fine wire in place, followed by removal of the wire after the polymer is cured. Access ports can be created using membranes of silicone or polyurethane. Needle stops and flow diverters can be fabricated from metal or a rigid plastic.
Device prototypes can be tested with methods similar to those described in Example 1. Drug delivery rates can be measured for pristine devices as well as devices that have been refilled. Methods such as absorbance and fluorescence can be used to quantitate the amount of therapeutic agent 110 that has been delivered as a function of time. Enzyme-Linked ImmunoSorbent Assays (ELISA) can be used to monitor the stability of the biological therapeutic agent 110 in the formulations at 37° C. and can be used to determine the concentration of biologically active therapeutic agent 110 delivered as a function of time.
Future Membrane Studies:
Experiments could be performed with a range of candidates to identify membranes that 1) would be a barrier to bacteria and cells without much resistance during refilling; 2) may contribute to controlling the delivery rate of the therapeutic agent 110; and 3) would be biocompatible. Candidate membranes would have pore sizes of 0.2 μm or smaller, approaching the size of the therapeutic agents. A variety of fixtures can be used to secure a membrane between a donor solution and a receiver solution to measure permeation rates. In addition, performance of membranes can be tested in device prototypes using methods similar to what was done in Example 3.
In addition, porous membranes could include cellulose acetate, nylon, polycarbonate, and poly(tetrafluoroethylene) (PTFE), in addition to regenerated cellulose, polyethersulfone, polyvinylidene fluoride (PVDF).
Developing Binding Formulations and Conditions:
Once media and conditions have been screened via the batch or flow-through methods, devices can be fabricated containing the binding media in place or with binding media injected along with the therapeutic agent 110. Formulations can be prepared with the desired excipients, and therapeutic agent 110 delivery rates can be monitored similarly to the method used in Example 1.
Additional media to test for binding include ion exchange and bioaffinity chromatography media based on a hydrophilic polymeric support (GE Healthcare) that bind proteins with high capacity, and a hydrophilic packing material from Harvard Apparatus made from poly(vinyl alcohol) that binds more protein than silica.
A change in pH could modulate the binding of antibody to media. For example, binding of antibody would be expected in a formulation with cationic exchange media at an acidic pH. As the pH becomes more neutral, the antibody may be released from the media. Formulations could be tested that provide acidic pH for finite durations (i.e., a few months). Once the pH has become neutral, the release of antibody from the binding media could drive a higher release rate, resulting in a more constant release rate profile. The binding media itself may have some buffering capacity that could dominate until physiological buffer diffuses into the device.
Alternatively, the formulation can include a buffer with a buffering capacity selected to dominate during the first few months. With time, the formulation buffer can diffuse out of the device 100 and physiological buffer can diffuse into the device 100, which can result in a change of pH towards physiological pH (i.e., neutral). The kinetics of this change can be modulated by use of a polymeric buffer, with a higher molecular weight buffer remaining in the device 100 for longer periods of time. Polypeptides are attractive as biocompatible polymeric buffers because they degrade to amino acids. Buffers are optimal near their pKa. The table below lists the pKa of the side chains of amino acids of interest.
The formulation could include a polyester, such as PLGA, or other biodegradable polymers such as polycaprolactone or poly-3-hydroxybutyrate, to generate hydrogen ions for a finite amount of time. The degradation rate can be modulated by, for example, changing the composition or molecular weight of the PLGA, such that the degradation is completed within a few months, contributing to reaching neutral pH in the last few months of delivery.
The pH could also be modulated electrochemically. Suitable electrode materials include inert or non-consumable materials such as platinum or stainless steel. Water hydrolysis occurs at the electrode interfaces and the products of hydrolysis are hydronium ions at the anode and hydroxyl ions at the cathode.
Rationale for Device Length:
At least some device designs do not extend more than about 6 mm into the vitreous so as to minimize interference with vision. In addition, it can be beneficial to have the device extend into the vitreous since then drug can be released a distance from the walls of the globe. Macromolecules, such as antibodies, can be primarily eliminated from the vitreous by a convection process rather than a diffusion process. (see, for example, Computer Simulation of Convective and Diffusive Transport of Controlled-Release Drugs in the vitreous Humor, by Stay, M S; Xu, J, Randolph, T W; and V H Barocas, Pharm Res 2003, 20(1), pp. 96-102.)
Convection can be driven by the pressure generated by the secretion of aqueous humor by the ciliary body, with flow in the vitreous directed towards the retina 26. With exit ports extending into the vitreous, it may be more likely that drug will be convected towards the back of the eye and the central retina, as opposed to a device with ports flush with the globe likely delivering more of the therapeutic agent to the peripheral retina.
The release study described in Example 1 using 23 and 30 gauge needles was and can be continued through ten weeks. The results may be compared with a model relating the change of concentration in the reservoir to the release rate from the reservoir based upon Fick's Law of diffusion. This simple model may assume the concentration in the reservoir is uniform and the concentration in the receiving fluid or vitreous is negligible. Solving the differential equation can yield the following cumulative release of a therapeutic agent from a reservoir with one orifice:
Cumulative Release=1−cR/cR0=1−exp((−DA/LVR)t),
Reservoirs can be fabricated from syringes and sintered porous titanium cylinders (available from Applied Porous Technologies, Inc., Mott Corporation or Chand Eisenmann Metallurgical). These can be sintered porous cylinders with a diameter of 0.062 inches and a thickness of 0.039 inches prepared from titanium particles. The porosity can be 0.17 with mean pore sizes on the order of 3 to 5 micrometers. The porous cylinder can be characterized as 0.2 media grade according to measurements of bubble point. The porous cylinders can be press-fit into sleeves machined from Delrin. The sleeves can be exposed one entire planar face to the solution in the reservoir and the other entire planar face to the receiver solution in the vials, corresponding to an area of approximately 1.9 square millimeters. The tips can be cut off of 1 mL polypropylene syringes and machined to accept a polymer sleeve with outer diameter slightly larger than the inner diameter of the syringe 188. The porous cylinder/sleeve can be press-fit into the modified syringe 188.
A solution can be prepared containing 300 mg/mL bovine serum albumin (BSA, Sigma, A2153-00G) in phosphate buffered saline (PBS, Sigma, P3813). Solution can be introduced into the syringes by removing the piston and dispensing approximately 200 microliters into the syringe barrel. Bubbles can be tapped to the top and air can be expressed out through the porous cylinder. Then BSA solution can be expressed through the porous cylinder until the syringe 188 holds 100 uL as indicated by the markings on the syringe 188. The expressed BSA solution can be wiped off and then rinsed by submerging in PBS. The reservoirs can then be placed into 4 mL vials containing 2 mL PBS at room temperature. Collars cut from silicone tubing can be placed around the syringe barrels to position the top of the reservoir to match the height of PBS. The silicone tubing can fit inside the vials and also serve as a stopper to avoid evaporation. At periodic intervals, the reservoirs can be moved to new vials containing PBS. The amount of BSA transported from the reservoir through the porous cylinder can be determined by measuring the amount of BSA in the vials using a BCA™ Protein Assay kit (Pierce, 23227).
Reservoirs can be fabricated from syringes and porous sintered titanium cylinders similar to that described in Example 5. The porous sintered titanium cylinders (available from Applied Porous Technologies, Inc., Mott Corporation or Chand Eisenmann Metallurgical) can have a diameter of 0.082 inch, a thickness of 0.039 inch, a media grade of 0.2 and were prepared from titanium particles. The porosity can be 0.17 with mean pore sizes on the order of 3 to 5 micrometers. The porous cylinder can be characterized as 0.2 media grade according to measurements of bubble point. The porous cylinders can be press fit into sleeves machined from Delrin. The sleeves can expose one entire planar face to the solution in the reservoir and the other entire planar face to the receiver solution in the vials, corresponding to an area of approximately 3.4 square millimeters. The tips can be cut off of 1 mL polycarbonate syringes and machined to accept a polymer sleeve with outer diameter slightly larger than the inner diameter of the syringe 188. The porous cylinder/sleeve can be press fit into the modified syringe 188. A kapton film with adhesive can be affixed to the surface exposed to the receiving solution to create a mask and decrease the exposed area. In the first case, the diameter of the mask can be 0.062 inches, exposing an area of 1.9 square millimeters to the receiving solution. In a second case, the diameter of the mask can be 0.027 inches, exposing an area of 0.37 square millimeters.
Three conditions can be run in this study: 1) 0.062 inch diameter mask, 100 uL donor volume, at room temperature in order to compare with reservoirs with unmasked porous cylinders in Example 5; 2) 0.062 inch diameter mask, 60 uL donor volume, at 37° C.; and 3) 0.027 inch diameter mask, 60 uL donor volume, at 37° C. The syringes can be filled with a solution containing 300 mg/mL bovine serum albumin (BSA, Sigma, A2153-00G) in phosphate buffered saline (Sigma, P3813), similar to Example 5. In addition, 0.02 wt % of sodium azide (Sigma, 438456-5G) can be added as a preservative to both the BSA solution placed in the reservoirs and the PBS placed in the receiving vials and both solutions can be filtered through a 0.2 micron filter. The amount of BSA solution dispensed into the syringe 188 can be weighed and the amount expressed through the porous cylinder was determined by rinsing and measuring the amount of BSA in the rinse. Assuming unit density for the BSA solution, the amount dispensed can be 113+/−2 uL (Condition 1) and 66+/−3 uL (Condition 2). Subtracting off the amount in the rinse can yield a final reservoir volume of 103+/−5 uL (Condition 1) and 58+/−2 uL (Condition 2). The reservoirs can then be placed into 5 mL vials containing 1 mL PBS at 37° C. in a heating block. At periodic intervals, the reservoirs can be moved to new vials containing PBS and the BSA concentrations can be determined in the receiving solutions using the method described in Example 5.
Prototype devices can be fabricated from tubing and sintered porous stainless steel cylinders (available from Applied Porous Technologies, Inc., Mott Corporation or Chand Eisenmann Metallurgical) which are cylindrical with diameter 0.155 inch and thickness 0.188 inch prepared from 316L stainless steel particles. The porous cylinder can be characterized as 0.1 media grade according to measurements of bubble point. This study can be performed with these large, off-the-shelf porous cylinders with an area of 12 mm2 in order to characterize the resistive properties of 0.1 media grade stainless steel.
These devices can be prepared using Teflon-FEP heat shrink tubing (Zeus, #37950) and a hot air gun to shrink around the porous cylinders on one end and a custom prepared septum on the other end (Nusil MED1 4013 silicone molded to 0.145 inch diameter). The reservoir volume (46+/−2 uL) can be determined from the difference in weight between empty systems and systems loaded with PBS. The PBS can be loaded by submerging the systems in PBS and drawing a vacuum. The systems can then be sterilized by heating to 250° F., 15 psi for 15 minutes, submerged in PBS in microcentrifuge tubes placed in a pressure cooker (Deni, 9760). Two 30G needles can be inserted into the septum to displace the PBS with BSA solution. One can be used to inject the BSA solution and the other can be bent and used as a vent for the displaced PBS. Sufficient BSA solution was injected to fill the needle hub of the vent to approximately ¾ full. Similar to Example 6, the BSA and PBS can contain sodium azide and the nominal concentration can be 300 mg/mL BSA. The devices can be placed into 1.5 mL microcentrifuge tubes containing 1 mL PBS and kept at 37° C. in a heating block. Pieces of silicone tubing (tight fit with inside of tube, hole for septum) can be used to suspend the devices in the PBS with the bottom of the septum approximately the same height as the PBS. The concentrations in the first tubes can contain BSA from the filling process and can be discarded. At periodic intervals, the devices can be moved to new tubes containing PBS and the BSA concentrations can be determined in the receiving solutions using the method described in Example 5.
Prototype devices can be fabricated from tubing and sintered porous stainless steel cylinders (available from Applied Porous Technologies, Inc., Mott Corporation or Chand Eisenmann Metallurgical) which can be cylindrical in diameter at 0.031 inch, and thickness 0.049 inch prepared from 316L stainless steel particles. The porous cylinder can be characterized as 0.2 media grade according to measurements of bubble point. This porous cylinder can be obtained as a custom order with properties determined from a previous study with a large diameter 0.2 media grade porous stainless steel cylinder (data no shown) and predictions based on the model described herein. The area of each face of this porous cylinder can be 0.5 mm2.
These devices can be prepared using Teflon-FEP heat shrink tubing (Zeus, 0.125 inch OD) and a hot air gun to shrink around the porous cylinder on one end and a custom prepared septum on the other end (Nusil MED1 4013 silicone molded to 0.113 inch diameter). The reservoir volume (17+/−1 uL) can be determined from the difference in weight between empty systems and systems filled with PBS. The PBS was loaded by submerging the systems in PBS and drawing a vacuum. Dry devices can be submerged in PBS in microcentrifuge tubes and sterilized by heating to 250° F., 15 psi for 15 minutes in a pressure cooker (Deni, 9760). Two 30G needles can be inserted into the septum to fill the devices with PBS. One can be used to inject the PBS and the other can be bent and used as a vent. After weighing the PBS filled devices, two new needles can be inserted through the septum and sufficient BSA solution can be injected to fill the needle hub of the vent to approximately ¾ full. The remaining details of the experiment can be the same as Example 7.
The vitreous concentrations of a therapeutic agent 110 can be predicted based on the equations described herein. Table 4A shows values of parameters applied for each of Simulation 1, Simulation 2, Simulation 3, Simulation 4, and Simulation 5. The half-life and vitreous volume can correspond to a monkey model (J. Gaudreault et al., Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration, Invest Ophthalmol V is Sci 2005; 46: 726-733) (Z. Yao et al., Prevention of Laser Photocoagulation Induced Choroidal Neovascularization Lesions by Intravitreal Doses of Ranibizumab in Cynomolgus Monkeys, ARVO 2009 abstract D906). The parameter PA/FL can be varied to determine the release rate profile. For example, the value of A can be about 1 mm2, the porosity can be about 0.1 (PA=0.1 mm2) and the length about 1 mm and the channel fit parameter that may correspond to tortuousity can be about 2 (FL=2 mm), such that PA/TL is about 0.05 mm. A person of ordinary skill in the art can determine empirically the area, porosity, length and channel fit parameter for extended release of the therapeutic agent 110 for the extended period based on the teachings described herein.
Table 4B shows vitreous concentrations calculated for a 0.5 mg bolus injection of Lucentis™ injected into the eye of a monkey using, for example, equations described herein and the half-life measured for the monkey listed in Table 4A. For example, the first column used the measured Cmax (Gaudreault et al.) while the second used a calculated Cmax based on the dose and volume of the vitreous. The average concentration of Lucentis™ can be about 46 ug/ml. The minimum therapeutic concentration of Lucentis™ can be about 0.1 ug/mL, which may correspond to about 100% VGEF inhibition (Gaudreault et al.). Table 4B indicates that a bolus injection of 0.5 mg Lucentis™ can maintain a vitreous concentration above 0.1 ug/mL for about a month whether using the measured or calculated Cmax. This can be consistent with monthly dosing that has been shown to be therapeutic in clinical studies.
Tables 4C1, 4C2, 4C3 4C4, and 4C5 show an example of the calculated concentration of Lucentis™ in the vitreous humor for Simulation 1, Simulation 2, Simulation 3, Simulation 4, and Simulation 5 respectively. These results can indicate Lucentis™ vitreous concentrations may be maintained above the minimum therapeutic level for about a year or more when released from a device 100 with porous structure 150 characterized by PA/FL≤0.0225 mm and a reservoir volume ≥10 uL.
Simulation 5 can correspond to the devices used in the experiment described in Example 8. This device can have a reservoir volume of 17 uL and porous structure 150 characterized by PA/FL=0.047 mm. When this device 100 is loaded with Lucentis™, the loading dose can correspond to ⅓ of the 50 uL currently injected monthly. Calculations that predict vitreous concentrations can indicate that this device with one-third of the monthly dose may maintain Lucentis™ therapeutic concentrations for about 6 months. While half of the dose is delivered in the first month and more than 98% delivered at 6 months, therapeutic levels may still be maintained for 6 months.
The ability of the device 100 to release therapeutic agent 110 for an extended time can be described by an effective device half-life. For the device in Example 8, the effective device half-life can be 29 days for delivery of Lucentis™. The device can be configured by selection of the reservoir volume and a porous structure 150 with an appropriate PA/FL to achieve the desired effective half-life.
For example, Z. Yao et al. (Prevention of Laser Photocoagulation Induced Choroidal Neovascularization Lesions by Intravitreal Doses of Ranibizumab in Cynomolgus Monkeys, ARVO 2009 abstract D906) have performed a preclinical study to determine the lowest efficacious Lucentis™ dose in cynomolgus monkeys that leads to 100% prevention of laser photocoagulation treatment-induced Grade IV choroidal neovascularization (CNV) Lesions.™ This model has been shown to be at least somewhat relevant to AMD. Intravitreal injection of Lucentis™ at all doses tested can completely inhibit the development of Grade IV CNV lesions. Table 4D shows predictions of Lucentis™ vitreous concentrations for the lowest total amount of Lucentis™ investigated (intravitreal injection of 5 ug on days 1, 6, 11, 16, 21 and 26), using the equations described herein and pharmacokinetic parameters listed in Table 4A. This data indicates that it may be not necessary to achieve the high Cmax of a 0.5 mg single bolus injection in order to be therapeutic.
The concentration profiles of a therapeutic agent 110 comprising Lucentis™ can be determined as shown below based on the teachings described herein and with drug half-life of nine days for Lucentis™ in the human eye. The examples shown below for injections of the commercially available formulation Lucentis™ and the nine day half life can show unexpected results, and that a volume of formulation corresponding to a monthly bolus injection into the device 100 as described herein can provide therapeutic benefit for at least about two months. The device 100 volume and the porous structure 150 can be tuned to receive the predetermined volume of formulation and provide sustained release for an extended time. Additional tuning of the device 100 can include the half-life of the therapeutic agent 110 in the eye, for example nine days for Lucentis™, and the minimum inhibitory concentration of the therapeutic agent 110 as determined based on the teachings as described herein.
Although
For example, an optimal RRI for the concentration of ranibizumab at 180 days for a reservoir volume of 125 uL and a 50 uL injection of Lucentis™ can be calculated based on the equations as described herein, and can be about 0.085. Although the optimal value can be 0.085, the above graphs may show that the reservoir and release rate index can be tuned to provide therapeutic amounts of ranibizumab above a minimum inhibitory concentration of 3 ug/mL with many values of the RRI and reservoir volume, for example values within about +/−30% to +/−50% of the optimal values for the predetermined quantity of Lucentis™ formulation.
Table 4E shows example values of parameters used to determine the ranibizumab concentration profiles as in
The therapeutic concentration profiles of examples of
Based on the teachings described herein, a person of ordinary skill in the art can determine the release rate index and volume of the therapeutic agent 110 based on the volume of formulation injected into the device 100 and minimum inhibitory concentration. This tuning of the device volume and release rate index can be based on the volume of formulation injected and may produce unexpected results. For example, with a clinically beneficial minimum inhibitory concentration of about 4 ug/mL, a single bolus injection corresponding to a one month injection can provide a therapeutic benefit for an unexpected three or more months, such as four months. Also, for a clinically beneficial minimum inhibitory concentration of at least about 1.5 ug/mL, a single bolus injection corresponding to a one month injection can provide a therapeutic benefit for an unexpected twelve or more months. The clinically beneficial minimum inhibitory concentration can be determined empirically based on clinical studies as described herein.
Although the examples of
Triamcinolone acetonide is a corticosteroid that can be used to treat uveitis and other diseases involving ocular inflammation. A 4 mg intravitreal injection of a suspension of triamcinolone acetonide may be administered to patients unresponsive to topical corticosteroids. Calculations as described herein can be and were performed to determine characteristics of a device 100 that would release therapeutic amounts for an extended period of time.
Consider a device with 10 uL reservoir volume loaded with 0.4 mg using a commercial drug product (40 mg/mL triamcinolone acetonide). Calculations performed using a value of 19 ug/mL for the solubility of triamcinolone acetonide measured at 37° C. in 0.2 M potassium chloride with a diffusion coefficient of 5 e-6 cm2/s representative of a small molecule. The target release rate can be 1 ug/day based upon published clinical data. As an example, consider the 0.2 media grade stainless steel characterized in Example 8 with P/F=0.12 and a thickness of 0.5 mm. Using these values, the calculations can suggest that therapeutic release rates could be achieved with a device 100 containing a porous cylinder with an area of 5 mm2. This could be achieved with a cylindrical device having an inner diameter of 2 mm and a length of porous tubing of 1 mm. Alternatively, the end of the device could be a porous cup with height of 0.8 mm (0.5 mm thick porous face plus 0.3 mm length) of porous tubing.
Assuming a typical value of 3 hours for the half-life of a small molecule in the vitreous, these calculations can suggest the device can achieve a steady state triamcinolone acetonide vitreous concentration of 0.12 ug/mL.
Assuming a typical value of 3 hours for the half-life of a small molecule in the vitreous, these calculations indicate that the device 100 will achieve a substantially steady state triamcinolone acetonide vitreous concentration of 0.12 ug/mL in a rabbit or monkey (vitreous volume of 1.5 mL) or 0.04 ug/mL in a human eye (vitreous volume of 4.5 mL). The steady state vitreous concentration can be maintained until there is no longer solid triamcinolone acetonide of the suspension in the reservoir. As shown in
First Study: The data can be measured with a 16 uL volume reservoir as follows: 25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, Mott Corporation); Substantially similar materials as Example 8 above (Teflon heat shrink tubing and silicone septum); 37C; Data is truncated when one of two replicates formed a bubble. See data in Table 5A below.
Second Study: The data can be measured with a 33 uL reservoir as follows: 25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, Mott Corporation); Machined from solid beading, closed with a metal rod; 37C; Data is truncated when one of two replicates formed a bubble.
SS can be the average of the squared difference between predicted and measured rates, and % CV refers to the coefficient of variation, a known statistical parameter.
Table 5D shows an update to Table 5B showing example experimental results for up to 130 days. Similarly, Table 5E is an example update to Table 5C. In both cases, the RRI was determined by fitting the rate data from each device. For the analysis of data up to 130 days, the first data point is excluded from the fit because the model assumes the maximum delivery rate occurs at time zero while there is some startup time often associated with measured release profiles. The startup time may be related to the time it takes to displace all of the air in the frit. Use of different techniques to displace the air in the frit may reduce the startup time.
This early data has some noise that can be related to experimental issues, such as contamination from excess protein that may be present on the screw from filling the device and was not completely rinsed off at the start of the experiment. The contamination can occur randomly as receiver liquid may rinse off the protein while transferring the device from vial to vial at some time points but not others. For example, a more accurate assessment of RRI can be obtained by using devices that had fewer or no outliers, as indicated by low values of SS. When this is done, the RRIs from Table 5D and 5E can be 0.014 and 0.030 mm, respectively. Similar values for RRI can be obtained from data up to 45 days and data up to 130 days, which can support the validity of the model.
Numerical calculations can be performed to determine therapeutic device sizes, release rate profiles and expected therapeutic agent 110 concentration in the reservoir. The concentration in the reservoir may correspond to the useful lifetime of the device, or time between injections of therapeutic agent 110 into the reservoir or other replacement of the therapeutic agent.
Table 6A shows the number of days the therapeutic agent 110 can be released from the device with concentration amounts at or above the MIC. The number of days can correspond to an effective lifetime of the device or effective time between injections into the device. The calculations can show the number of days of the extended time release based the RRI and MIC for a 20 uL reservoir volume having a drug concentration disposed therein of 10 mg/ml. For example, the RRI ranged from 0.01 to 0.1 and the MIC ranged from 0.1 to 10, and can be determined with experimental and clinical studies as described herein. The half-life of therapeutic agent 110 in the vitreous can be modeled as 9 days, based on human data. The Cmax indicates the maximum concentration of therapeutic agent 110 in the vitreous humor 30, for example within a few days of placement or injection of the therapeutic agent 110 in the device 100 These data can indicate that the device 100 can maintain the concentration of therapeutic agent for about 756 days, 385 days, 224 days, and 62 day for MIC's of 0.1, 0.5, 1, 2 and 4 ug/ml, respectively. For example, the therapeutic agent 110 may comprise Lucentis™ having an MIC of about 0.5 and the device 100 may maintain therapeutic concentrations of the agent for one year. These numerical data can also show a concentration of therapeutic agent 110 released from the device 100 within a range of the current clinical bolus injections. For example, the Cmax can range from 2.1 to 11.9 based on the RRI from 0.01 to 0.1 respectively, such that the maximum release of therapeutic agent 110 such as Lucentis™ is within a safe range for the patient.
The stability of the therapeutic agent 110 such as Lucentis™ in the reservoir can be adjusted based on the size of the reservoir and time between injections or removal. The therapeutic agent 110 can be selected and formulated so as to comprise a stability suitable for use in the therapeutic device 100.
Table 6B. Shows example calculations for time (days) above the MIC for a therapeutic device 100 comprising a 20 μL Volume, Vitreous T1/2=9 days, and Drug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B include similar components to the embodiments of Table 6A and the improved time above MIC achieved with concentration of 40 mg/ml. For example, the time above the MIC can be 1079, 706, 546, 385, 225, 95, for MIC's of 0.1 0.5, 1, 2, 4, and 7 ug/ml, respectively. For example, the therapeutic agent 110 may comprise Lucentis™ having an MIC of about 0.5 and the device 100 may maintain therapeutic concentrations of the therapeutic agent 110 for about 2 years. These numerical data can also show a concentration of therapeutic agent 110 released from the device 100 within a range of the current clinical bolus injections. For example, the Cmax ranges from 8.4 to 47.6 based on the RRI from 0.01 to 0.1 respectively, such that the maximum release of therapeutic agent 110 such as Lucentis™ is within a safe range for the patient.
A person of ordinary skill in the art can conduct experiments to determine the stability of the therapeutic agent 110 such as Lucentis™ in the reservoir, and adjust the size of the reservoir, time between injections or removal. The therapeutic agent 110 can be selected and formulated so as to comprise a stability suitable for use in the therapeutic device 100.
Table 6C. Shows calculations for time (days) above the MIC for a therapeutic device 100 comprising a 50 μL Volume, Vitreous T1/2=9 days, and Drug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B include similar components to the embodiments of Table 6A and the improved time above MIC achieved with concentration of 40 mg/ml. For example, the time above the MIC can be 2706, 1737, 1347, 944, 542 and 218, for MIC's of 0.1 0.5, 1, 2, 4, and 7 ug/ml, respectively. For example, the therapeutic agent 110 may comprise Lucentis™ having an MIC of about 0.5 and the device 100 may maintain therapeutic concentrations of the therapeutic agent 110 for more than about 2 years. These numerical data can also show a concentration of therapeutic agent 110 released from the device within a range of the current clinical bolus injections. For example, the Cmax can range from 9.1 to 64.7 ug/ml based on the RRI from 0.01 to 0.1 respectively, such that the maximum release of therapeutic agent 110 such as Lucentis™ is within a safe range for the patient.
A person of ordinary skill in the art can conduct experiments to determine the stability of the therapeutic agent 110 such as Lucentis™ in the reservoir, adjust the size of the reservoir, and time between injections or removal. The therapeutic agent 110 can be selected and formulated so as to comprise a stability suitable for use in the therapeutic device 100.
The examples shown in Tables 6A to 6C can be modified in many ways based on the teachings described herein. For example, the 50 uL reservoir may comprise an expanded configuration of the reservoir after injection of the therapeutic device 100. The reservoir and/or quantity of therapeutic agent 110 can be adjusted so as to provide release for a desired extended time.
The porous frit structure as described herein can be used with many therapeutic agents, and may limit release of therapeutic agent 110 that has degraded so as to form a particulate, for example. Work in relation to embodiments can suggest that at least some therapeutic agents can degrade so as to form a particulate and that the particulate comprising degraded therapeutic agent 110 may have an undesired effect on the patient, and the porous frit structure as described herein may at least partially filter such particulate so as to inhibit potential side effects of degraded therapeutic agent 110.
Table 6D shows examples of sizes of therapeutic devices that can be constructed in accordance with the teachings described herein, so as to provide a suitable volume of the drug reservoir within the container and such devices may comprise many lengths, widths and structures as described herein. For example the frit outside diameter (hereinafter “OD”) can be configured in many ways and may comprise about 1 mm, for example, or about 0.5 mm. The length of the frit (thickness) may comprise about 1 mm. The volume of the frit can be, for example, about 0.785 uL, or about 0.196 uL, for example. The volume of the reservoir can be from about 0.4 uL to about 160 uL, for example. The volume of the therapeutic device 100 can be from about 0.6 uL to about 157 uL, and can be positioned in many ways, for example with a lumen and may comprise a substantially fixed volume reservoir or an expandable reservoir. The cross sectional width of the device 100 may correspond to many sizes, for example many radii, and the radius can be within a range from about 0.3 mm to about 3.5 mm, for example. The cross-section width and corresponding diameters of the device 100 can be within a range from about 0.6 mm to about 7 mm. The length of the device 100, including the porous structure, container and retention structure can be many sizes and can be within a range from about 2 mm to about 4 mm, for example. The device 100 may comprise a substantially fixed diameter, or alternatively can be expandable, and may comprise fixed or expandable retention structures, as described herein.
Studies of the release of fluorescein from reservoirs through porous frit structures can be and were conducted so as to determine the release of small molecule drugs through the porous frit structure. The fluorescein model example demonstrates that the porous frit structures and reservoirs as described herein can be suitable for use with small molecule drug delivery. The release profiles of Avastin™, Lucentis™ and BSA in conjunction with the fluorescein data can show that the porous frit structures and reservoirs can be used for sustained release of many drugs, molecules and therapeutic agents of many molecular weights and sizes.
UV absorbance at 492 nm with a plate reader. The determined RRI based on measurements is 0.02, consistent with the model for release of the therapeutic agents as described herein.
The experiments used the following: 10 mg/mL Lucentis™; Machined poly(methyl methacrylate) surrogate with screw; and a Reservoir Volume 30 uL; 37C. All porous frit structures are 316L SS, Mott Corporation. Data shown are measured data from all devices except for a few samples that showed either bubble growth or low receiver volume.
Table 6E shows example results for 39 out of 48 devices and are included in the table and graphs shown below. The data from the in vitro studies shown in Table 6E can show that Lucentis™ can be delivered with the device having porous frit structure. The diameter can range from about 0.031″ to 0.038″, and the length can range from about 0.029 to 0.049. The media grade can range from about 0.1 to 0.3, and the RRI can range from about 0.014 to 0.090. The data can show very low variability suitable in in vivo human treatment, with the % CV below 10% in at least some instances, and less than 3% for four of five device configurations measured.
Although some measurements were excluded, this exclusion may be appropriate and associated with in vitro testing conditions that differ substantially from the in vivo model. For example, five devices were excluded due to bubble growth (10%), and four were excluded due to receiver volume issues at one timepoint for that device (8%). The latter can be an experimental error associated with the volume of the receiver below the assumed value due to evaporation from inadequately sealed vials or due to pipetting error. In some instances the in vitro experimental test apparatus can be sensitive to bubble formation that may differ substantially from the in vivo model as the living eye can resorb oxygen from the therapeutic devices. Bubbles can form as receiver fluid is heated to 37° C. and gas concentrations are greater than their solubilities at 37° C. To minimize the occurrence of bubble formation, receiver solutions were degassed before insertion of the devices. These experimental in vitro studies can suggest that degassing of samples can be helpful with the in vitro assays.
The above experimentally measured data can show an example stable release of the Lucentis™ for 30 days for a wide range of frit diameters, thicknesses and media grades consistent with the release rate model of the porous structure 150 and reservoir as described herein. For example, the media grade, thickness, diameter and reservoir volume can be tuned to provide sustained release for a predetermined period of time above a predetermined targeted minimum inhibitory concentration. When combined with the Avastin™ and Fluorescein data, these data can show that stable release can be achieved for extended times for many therapeutic agents consistent with the release model as described herein.
The relative characteristics of sample elements can be determined by subjecting the frit to a number of mechanical tests, including but not limited to pressure decay and flow. These tests can be combined with drug release rate information, for example the RRI, so as to determine the release profile of the devices. These tests can be used with the porous structure positioned on the therapeutic device 100, so as to quantify flow through the porous structure of the device 100 and determine suitable of the porous structure 150. Similar tests can be used to quantify the porous structure 150 prior to mounting on the therapeutic device 100. At least some of the therapeutic devices can be evaluated with the gas flow of the porous structure 150 mounted on a partially assembled therapeutic device 100, for example as a quality control check In some embodiments, the flow test can be performed on the partially assembled or substantially assembled therapeutic device 100 prior to insertion of the therapeutic agent 110 into the reservoir and prior to insertion into the patient, so as to ensure that the porous structure 150 is suitable for release of the therapeutic agent 110 and affixed to the device 100, for example a support of the therapeutic device 100.
These tests may utilize a variety of working fluids, but will most likely use a readily available gas such as air or nitrogen. To date, flow and pressure decay tests have been used to identify different frit characteristics that may be correlated to other test results such as chemical or pharmacologic performance.
Each of the test methods above may use a mechanical connection of the test specimen to the test hardware and a number of techniques have been explored and employed. These fixtures can include both a means of reliably securing the specimen (such as heat recoverable tubing, elastic tubing, press fits into relatively rigid components, etc.) and a means of coupling (such as a Luer, barbed fitting, quick connect coupling, etc.) that allow convenient and repeatable attachment to the test hardware.
Each of the desired tests can be developed using commercially available solutions, or by assembling readily available instrumentation to create a custom test arrangement. Again, both of these approaches have been evaluated. A working system can consist of a means for connecting a test specimen, a controllable source (usually, but not limited to pressure), a manometer (or other pressure measurement device), and one or more transducers (pressure, flow, etc.) used to measure the test conditions and/or gather data for further analysis.
One method of pressure decay testing can be performed with the hardware shown schematically in
An example test procedure can pressurize the system to slightly greater than 400 mmHg as displayed by the manometer. The computer and DAQ can be configured to begin data acquisition as the pressure drops below 400 mmHg, and a data point can be taken approximately every 0.109 seconds. While the test can be stopped at any time, it is likely that standard discreet points along the course of pressure decay data would be selected so as to allow direct comparison of frit flow performance (e.g. time for decay from 400 mmHg to 300 mmHg, and from 400 mmHg to 200 mmHg)
Using a similar hardware set-up, flow thru the test specimen can also be characterized. In this test, the source pressure can be constantly regulated to a known pressure and the flow of a working fluid can be allowed to flow thru a mass flow meter and then thru the fixtured test frit. As in the pressure decay test, the specific characteristics of the frit can determine the rate at which the working fluid will flow through the system. For additional accuracy, pressure at the otherwise open end of the fixture test frit may be regulated to control the backpressure, and therefore the pressure drop across the specimen.
Flow testing may have advantages over pressure decay testing due to the instantaneous nature of the method. Rather than waiting for the pressure to drop, the flow thru a sample can be stabilized quickly enabling testing of large number of samples to be performed in rapid fashion.
In an example test procedure, a regulated compressed cylinder would supply the system with a constant source pressure of 30 psig and a constant back pressure of 1 psig. The test fluid can flow through the test frit at a characteristic rate (which is dependent on the pressure, but is expected to be in the 10-500 sccm range) as measured by the mass flow meter.
Table 7 shows a table that can be used to determine release of therapeutic agent 110, for example the RRI, based on the flow of a gas such as oxygen or nitrogen through the porous structure. The flow through the porous structure 150 can be measured with a decay time of the gas pressure, for example with the flow rate across the porous structure 150 with a pressure drop across the porous frit structure, as described herein. The flow rate and RRI can be determined based on the media grade of the material, for example as commercially available media grade material available from Mott Corp. The therapeutic agent 110 can be measured through the porous structure 150, or a similar test molecule. The initial measurements can measure the RRI for Avastin™ with the porous frit structures shown. Based on the teachings described herein, a person of ordinary skill in the art can conduct experiments to determine empirically the correspondence of flow rate with a gas to the release rate of the therapeutic agent 110.
The above partially populated table shows the amount and nature of frit data that can collected. It is contemplated to use some form of non-destructive testing (i.e. not drug release testing) so as to enable:
a) QC receiving inspection testing of frits
b) QC final device assembly testing
One of ordinary skill can demonstrate a correlation between one or more “flow” tests and the actual drug release testing which relies on diffusion rather than forced gas flow. The data suggests that flow testing of frits can be both repeatable and can fall in line with expectatons.
Preliminary testing can also indicate that the test for the frit alone can be substantially similar to the frit as an assembled device.
Although administration of the standard dose of Lucentis™ (500 μg) via direct intravitreal injection can be shown to be effective in reducing symptoms of patients suffering from wet AMD, the below clinical studies can indicate that a lower concentration can be used to treat wet AMD. A device as described herein can be used to treat AMD with a minimum inhibitory concentration in vivo in human patients (hereinafter “MIC”) with a smaller amount than corresponds to the 500 ng monthly bolus injection. For example, 5 ug Lucentis™ injections can be administered so as to obtain a concentration profiles in situ in humans in accordance with Table 4D and
The study can be designed to detect quickly a positive response to Lucentis™ treatment. A reduction of retinal thickness can be an indicator of positive response to Lucentis™ therapy and a marker of drug effect that can be used to quickly identify a positive effect of drug treatment. The reduction in retinal thickness can correspond to subsequent improvement in vision. Hence, the low dose MIC study can assess the condition of retinal thickness both before and after patient's exposure to low dose bolus administration of Lucentis™, so as to determine the MIC.
OCT (Optical Coherence Tomography) imaging can be used to assess the condition of the region of the macula at the back surface of the treated eye. The OCT technique can rely on the measurement of certain properties of light (e.g. echo time, intensity of reflection) that can be directed at the area of study and can measure very small amounts of reflected light. Because these cellular features can be essentially transparent it is possible to use OCT methodology to generate three dimensional representations of the area.
The anatomical region of patients suffering from wet AMD can typically involve disturbances to the structural make-up of the various cellular layers of the back surface of the eye, notably including areas of retinal thickening often involving accumulations of subretinal fluid. In more advanced stages these areas of fluid accumulation can involve cyst-like formations easily evaluated via OCT.
The OCT images generated in the study can enable various types of assessments to be made regarding the condition of the anatomical region of interest. One type of OCT image can comprise a topographic map of the entire region of the macula. This image type can be referred to as the “macular cube”. The macular cube OCT images are typically displayed as color images and in the case of the macular cube the image provides an indication of overall topography of the disease/lesion location. These macular cube images can be used to identify regions of the macular of interest.
The regions of interest can be analyzed with a two dimensional representation of the cross section of the retinal wall at one longitudinal scan location of the OCT image. In these “OCT scan” images is it possible to interrogate very local areas of interest more specifically. The OCT scans can be carefully selected to directly compare the thickness and anatomical structure of specific sites within a lesion, pre and post treatment, for the purpose of assessing the effect of injected drug including a reduction in sub-retinal fluid.
Macular cube images and OCT scan images can be measured before and after Lucentis™ treatment for each patient enrolled in the study. The OCT images can be measured the day after injection and at 2-3 days post injection. An ophthalmologist reviewed the OCT images from the patients enrolled in the study, and patients can be considered to have responded to Lucentis™ treatment when the OCT scans show a decrease in size of the lesion from one or more of the post-injection examinations.
Table 8 shows the results for nine patients enrolled in a study. The patients received doses from 5 to 20 ug, corresponding to initial Lucentis™ concentrations in the vitreous from 1 to 4 ug/ml. Based on the above criteria, a positive response was identified in all nine patients. In at least some instances with the 5 um injection, the decrease in size of the lesion was noted approximately 2-4 days post-op, and the decrease was substantially attenuated by one week post-op, consistent with the approximately 9 day in vivo half-life of Lucentis™. These data indicated that the MIC for a sustained release device may be approximately 1 ug per ml or less. As the therapeutic agent 110 may have a cumulative effect, the MIC can be lower for a sustained release as described herein than the bolus injection described with reference to the MIC study. Further studies can be conducted by one or ordinary skill in the based on the teachings described herein to determine empirically the MIC for a sustained release device and cumulative effect of the drug over the time of release.
These studies showed that the retention structure comprising the oval flange and oval narrow portion can seal the incision formed in the sclera and permit dark field visualization of the implanted device. The device can be implanted temporally in the patient, for example superior/temporally or inferior/temporally such that the implant can be disposed temporally and under the eyelid so as to have a minimal effect on vision and appearance of the patient.
Devices made similar to Example A. A suspension formulation was generated by adding dorzolamide Hydrochloride (LGM Pharma) at 100 mg/mL in PBS+0.02% sodium azide, adjusted to pH 7.4. The dissolved concentration (i.e., solubility) was measured at 9 mg/mL at 37C. Nine devices were injected with the suspension formulation using a 19 G needle. Drug concentrations were measured by HPLC. A constant drug release rate of 17 ug/day was measured for 120 days for all devices, as shown below. The release rate can be substantially constant while crystal remains in the reservoir chamber, and the rate of release can correspond to the RRI of the porous frit structure of the therapeutic device 100. Increasing the amount of drug in the reservoir chamber from 100 mg/mL to 200 mg/mL can increase the extended time this device 100 delivers a constant rate from more than 4 months to more than 8 months, for example. The RRI of the porous structure 150 can be configured to release an intended amount of therapeutic agent 110 each day based on the teachings and porous structures described herein. The amount released per day can be within a range from about 1 ug per day to about 100 ug per day, for example. The therapeutic devices can be configured with a release rate of the porous structure 150, so as to release therapeutic amounts of dorzolamide for indications such as macular edema within a range from about 1 ug/day to about 100 ug/day, for an extend time of at least about one month, for example at least about 2 months, for example 3 months.
Devices made similar to Example A. Ten devices were injected with commercially available formulation of 25 mg/mL methotrexate in saline (Bedford). Drug concentrations were measured by UV. Two devices were stopped at 4 weeks for other purposes and eight devices have completed close to 6 months of drug release, as shown below.
Table 10 shows the RRI determined based on measured amounts of methotrexate for a 25 mg/mL solution injected into the therapeutic devices.
A second, larger study can be and was performed similar to above using three formulation strengths: 25, 8, and 1 mg/mL Methotrexate. The lower concentrations can be diluted from the full strength commercial formulation using saline. The number of devices can be filled at each strength of 12, 12, and 10 devices for 15, 8, and 1 mg/mL strengths, respectively. At 8 weeks, two devices can be stopped for each strength, leaving 8-10 devices whose release rates can be collected through 100 days, as shown below.
Table 11 shows the RRI determined based on the reservoir volume and measured amounts of Methotrexate.
The diffusion coefficient for Methotrexate can be estimated at 5×10−6 cm2/s at 37C. The volume of the device was approximately 25 uL. The Device Effective Half-life is about 60 days for both studies shown above. The 25 mg/mL and the 8 mg/mL devices each included one apparent outlier (not shown). The data can show that therapeutic amounts of methotrexate can be released for at least about 30 days, for example 90 days or more. The therapeutic devices can be configured with one or more of a release rate, a reservoir volume or a concentration of methotrexate, so as to release therapeutic amounts of Methotrexate for indications such as uveitis and diabetic macular edema within a range from about 0.001 ug/day to about 20 ug/day, more preferably within a range from about 0.01 ug/day to about 2 ug/day, for an extend time of at least about one month, for example at least about 2 months, for example 3 months.
Devices made similar to Example A. A total of ten devices were injected with Ketorolac Tromethamine (Spectrum) dissolved in HPLC Grade water; 5 devices received a 60 mg/mL and 5 devices received a 300 mg/mL formulation. Drug concentrations can be and were measured by UV. All ten devices have completed over 5 months of drug release, as shown below.
Table 12 shows the RRI experimentally determined based on measured amounts of Ketorolac. The measured amounts of ketorolac and corresponding RRIs can correspond to the intended values based on the reservoir volume and intended RRI of the porous frit structures. The data can appear to include one device outlier (not shown).
The diffusion coefficient for Ketorolac can be estimated at 6×10−6 cm2/s at 37C. The volume of the device was approximately 25 uL. The Device Effective Half-life can be about 41 days with a 60 mg/mL formulation and about 54 days with a 300 mg/mL formulation. The 60 mg/mL devices can include one apparent outlier (not shown). The 60 mg/mL devices released about 4 ug/day at 90 days. The 300 mg/mL devices released about 27 ug/day at 90 days and about 12 mg/mL at 150 days. These data can show that the therapeutic devices can be configured to release therapeutic amounts of ketorolac into the vitreous humor 30 for indications such as uveitis and diabetic macular edema. The therapeutic devices 100 can be configured with one or more of a release rate, a reservoir volume or a concentration of ketorolac, so as to release therapeutic amounts of ketorolac within a range from about 0.1 ug/day to about 1000 ug/day, more preferably from about 1 ug/day to about 100 ug/day for an extend time of at least about one month, for example at least about 2 months, for example 3 months.
As used herein, like identifiers denote like structural elements and/or steps.
Any structure or combination of structures or method steps or components or combinations thereof as described herein can be combined in accordance with embodiments as described herein, based on the knowledge of one of ordinary skill in the art and teachings described herein. In addition, any structure or combination of structures or method steps or components or combinations thereof as described herein may be specifically excluded from any embodiments, based on the knowledge of one of ordinary skill in the art and the teachings described herein.
While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of 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 claims priority of U.S. Provisional Patent Application Ser. No. 61/515,832 entitled SMALL MOLECULE DELIVERY WITH IMPLANTABLE THERAPEUTIC DEVICE and filed on Aug. 5, 2011. The disclosure of the Provisional Patent Application is hereby incorporated by reference in its entirety. This subject matter of this patent application is related to U.S. patent application Ser. No. 12/696,678 filed 29 Jan. 2010, entitled “Posterior Segment Drug Delivery,” the full disclosure of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2012/049654 | 8/3/2012 | WO | 00 | 8/8/2014 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2013/022801 | 2/14/2013 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 2564977 | Hu et al. | Aug 1951 | A |
| 2585815 | McLintock | Feb 1952 | A |
| 2886497 | Butler | May 1959 | A |
| 3232117 | Gilmont | Feb 1966 | A |
| 3416530 | Ness | Dec 1968 | A |
| 3618604 | Ness | Nov 1971 | A |
| 3641237 | Gould et al. | Feb 1972 | 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 |
| 5277912 | Lowe et al. | Jan 1994 | A |
| 5282829 | Hermes | Feb 1994 | A |
| 5300114 | Gwon et al. | Apr 1994 | A |
| 5322691 | Darougar et al. | Jun 1994 | A |
| 5334189 | Wade | Aug 1994 | A |
| 5336175 | Mames | Aug 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 |
| 5476511 | Gwon et al. | Dec 1995 | A |
| 5519030 | Shigemitsu et al. | May 1996 | A |
| 5554132 | Straits et al. | Sep 1996 | A |
| 5562915 | Lowe et al. | Oct 1996 | A |
| 5578042 | Cumming | Nov 1996 | A |
| 5681572 | Seare, Jr. | Oct 1997 | A |
| 5725493 | Avery et al. | Mar 1998 | A |
| 5766242 | Wong et al. | Jun 1998 | A |
| 5770076 | Chu et al. | Jun 1998 | A |
| 5773019 | Ashton et al. | Jun 1998 | A |
| 5797898 | Santini, Jr. et al. | Aug 1998 | A |
| 5807581 | Rosenblatt et al. | Sep 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 |
| 6472162 | Coelho et al. | Oct 2002 | B1 |
| 6534524 | Kania et al. | Mar 2003 | B1 |
| 6551291 | de Juan, Jr. et al. | Apr 2003 | B1 |
| 6573293 | Tang et al. | Jun 2003 | B2 |
| 6605066 | Gravagna et al. | Aug 2003 | B1 |
| 6663668 | Chaouk et al. | Dec 2003 | B1 |
| 6669950 | Yaacobi | Dec 2003 | B2 |
| 6685940 | Andya et al. | Feb 2004 | B2 |
| 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 |
| 6878714 | Askew et al. | Apr 2005 | B2 |
| 6932983 | Straub et al. | Aug 2005 | B1 |
| 6976982 | Santini, Jr. et al. | Dec 2005 | B2 |
| 6986900 | Yaacobi | Jan 2006 | B2 |
| 6995162 | Chen et al. | Feb 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 |
| 7105530 | Boloor et al. | Sep 2006 | B2 |
| 7117870 | Prescott | Oct 2006 | B2 |
| 7125905 | Tang et al. | Oct 2006 | B2 |
| 7141023 | Diermann et al. | Nov 2006 | B2 |
| 7141152 | Le Febre | Nov 2006 | B2 |
| 7141581 | Bender et al. | 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 |
| 7211600 | Lipson et al. | May 2007 | B2 |
| 7235576 | Riedl et al. | Jun 2007 | B1 |
| 7262203 | Boloor et al. | Aug 2007 | B2 |
| 7276050 | Franklin | Oct 2007 | B2 |
| 7297709 | Dai et al. | Nov 2007 | B2 |
| 7351834 | Riedl et al. | Apr 2008 | B1 |
| 7452913 | Sun et al. | Nov 2008 | B2 |
| 7468065 | Weber et al. | Dec 2008 | B2 |
| 7476510 | Kapur et al. | Jan 2009 | B2 |
| 7528255 | Riedl et al. | May 2009 | B2 |
| 7572924 | Tang et al. | Aug 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 |
| 7687643 | Tasker et al. | Mar 2010 | B2 |
| 7709049 | Chappa | May 2010 | B2 |
| 7772404 | Borchardt et al. | Aug 2010 | B2 |
| 7883717 | Varner et al. | Feb 2011 | B2 |
| 7893040 | Loftsson et al. | Feb 2011 | B2 |
| 7897623 | Riedl et al. | Mar 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 |
| 7943782 | Henry | May 2011 | B2 |
| 7960564 | Borchardt et al. | Jun 2011 | B2 |
| 7973068 | Demopulos et al. | Jul 2011 | B2 |
| 7989631 | Alva et al. | Aug 2011 | B2 |
| 8058445 | Tasker | Nov 2011 | B2 |
| 8063091 | Dai et al. | Nov 2011 | B2 |
| 8114885 | Boloor et al. | Feb 2012 | B2 |
| 8277830 | de Juan, Jr. et al. | Oct 2012 | B2 |
| 20020026176 | Varner et al. | Feb 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 |
| 20030003129 | Yaacobi | Jan 2003 | A1 |
| 20030005945 | Onishi et al. | Jan 2003 | A1 |
| 20030014036 | Varner et al. | Jan 2003 | A1 |
| 20030118649 | Gao et al. | Jun 2003 | A1 |
| 20030119177 | Gruber et al. | Jun 2003 | A1 |
| 20030176854 | Rodstrom | Sep 2003 | A1 |
| 20030185872 | Kochinke | Oct 2003 | A1 |
| 20030212383 | Cote et al. | Nov 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 |
| 20040208910 | Ashton et al. | Oct 2004 | A1 |
| 20040209359 | Yayon et al. | Oct 2004 | A1 |
| 20040230183 | Breegi et al. | Nov 2004 | A1 |
| 20040247487 | Commercon et al. | 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 | 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 |
| 20050181018 | Peyman | Aug 2005 | A1 |
| 20050244467 | Nivaggioli et al. | Nov 2005 | A1 |
| 20050244469 | Whitcup et al. | Nov 2005 | A1 |
| 20050244472 | Hughes 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 |
| 20060189608 | Bingaman | 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 |
| 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 |
| 20070219632 | Castillejos | 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 |
| 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 | 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 |
| 20080269318 | Romano | Oct 2008 | A1 |
| 20080286338 | Rosenthal et al. | Nov 2008 | A1 |
| 20080292679 | Lyons et al. | Nov 2008 | A1 |
| 20080293691 | Brigandi et al. | Nov 2008 | A1 |
| 20090005864 | Eggleston | Jan 2009 | A1 |
| 20090036827 | Cazzini | Feb 2009 | A1 |
| 20090043253 | Podaima | Feb 2009 | A1 |
| 20090047335 | Rastelli et al. | Feb 2009 | A1 |
| 20090074786 | Dor et al. | Mar 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 |
| 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 |
| 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 |
| 20100197512 | Trinkle et al. | Aug 2010 | A1 |
| 20100216702 | Szkudlinski et al. | Aug 2010 | A1 |
| 20100221309 | Myers et al. | Sep 2010 | A1 |
| 20100223979 | Ploehn et al. | Sep 2010 | A1 |
| 20100227904 | Kabra et al. | Sep 2010 | A1 |
| 20100255061 | de Juan, Jr. et al. | 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 |
| 20100331548 | Liu 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 |
| 20110281901 | Gupta | Nov 2011 | A1 |
| 20120028918 | Gupta | Feb 2012 | A1 |
| 20120029445 | de Juan, Jr. et al. | Feb 2012 | A1 |
| 20120029470 | Juan, Jr. et al. | Feb 2012 | A1 |
| 20120040986 | Riedl et al. | Feb 2012 | A1 |
| 20130012531 | King et al. | Jan 2013 | A1 |
| 20130245544 | de Juan, Jr. et al. | Sep 2013 | A1 |
| 20130324942 | de Juan, Jr. et al. | Dec 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 101327356 | Dec 2008 | CN |
| 101600476 | Dec 2009 | CN |
| 102365109 | Feb 2012 | 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 |
| 2004-524866 | Aug 2004 | JP |
| 2009-514888 | Apr 2009 | JP |
| 2009-523821 | Jun 2009 | JP |
| 2009-529968 | Aug 2009 | JP |
| 2010-521470 | Jun 2010 | JP |
| WO-8804573 | Jun 1988 | WO |
| WO-9007545 | Jul 1990 | WO |
| WO-9528984 | Nov 1995 | WO |
| WO-9729850 | Aug 1997 | WO |
| WO-9825982 | Jun 1998 | WO |
| WO-0048660 | Aug 2000 | WO |
| WO-0126714 | Apr 2001 | WO |
| WO-0150943 | Jul 2001 | WO |
| WO-0168016 | Sep 2001 | WO |
| WO-02053128 | Jul 2002 | 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-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-2007064752 | Jun 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-2008052145 | May 2008 | WO |
| WO-2008060359 | May 2008 | WO |
| WO-2008061043 | 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-2009143288 | 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-2011069053 | Jun 2011 | WO |
| WO-2011075481 | Jun 2011 | WO |
| WO-2011079232 | Jun 2011 | WO |
| WO-2012042421 | Apr 2012 | WO |
| WO-2013033176 | Mar 2013 | WO |
| WO-2013151568 | Oct 2013 | WO |
| Entry |
|---|
| PCT Search Report dated Dec. 6, 2012 for PCT application No. PCT/US2012/049654. |
| AMD Preclinical Studies. Anti-Factor D Fab Specifically Inhibits the Alternative Pathway. The Association for Research in Vision and Ophthalmology, Inc. 2010. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Janoria et al., Novel Approaches to Retinal Drug Delivery, Expert Opinion Drug Delivery, 2007. |
| 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>>. |
| “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. |
| 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. |
| 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. |
| “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. |
| 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 Fron Formulation Development to Manufacturing, editors AK Kulshreshtha, et al., Spinger, 2010. |
| 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; 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. |
| 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). |
| 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). |
| Number | Date | Country | |
|---|---|---|---|
| 20140358125 A1 | Dec 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61515832 | Aug 2011 | US |
