Patent Grant
12090294
This application is the National Stage of International Application No. PCT/US2018/030688, filed May 2, 2018, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62,500,209, filed May 2, 2017; the disclosure of which is incorporated herein by reference in their entireties.
The embodiments described herein relate generally to the field of drug delivery and more particularly to systems, devices, methods, and kits for targeted delivery of a substance into ocular tissues.
The anterior region of the eye refers to the front portion of the eye and includes structures in front of the vitreous humour such as the cornea, iris, ciliary body and lens. The posterior region of the eye refers to the back portion of the eye (i.e., the portion of the eye behind the lens), and includes the vitreous humor, retina, choroid, and optic nerve. The sclera is an opaque, fibrous, protective outer layer of the eye. The sclera includes connective tissue that maintains the shape of the eye by offering resistance to internal and external forces. The suprachoroidal space is the potential space or area between the sclera and choroid in the posterior region of the eye. Many inflammatory and proliferative diseases in the posterior region of the eye require long-term pharmaceutical treatment.
Although there are known methods of delivery of substances (e.g., drugs) into the posterior region of the eye, there is a need for improved devices and methods. It is often difficult to deliver effective doses of a drug to the back of the eye using conventional delivery methods such as topical application, intravitreal administration (IVT), or systemic administration. For example, topical applications, such as eye drops, are useful in treating conditions affecting the exterior surface of the eye or tissues at the front of the eye, however, eye drops are often not sufficiently conveyed to the back of the eye, as may be required for treatment of some retinal diseases such as macular degeneration, diabetic retinopathy, uveitis, and the like. Moreover, there is a short drug-eye contact time using eye drops, which can lead to more frequent applications of the drug. Other topical applications, such as ointments, allow a prolonged drug-eye contact time, thus requiring less frequent applications, but the application process increases the possibility of contamination since the drug is often applied via a person's hand. Furthermore, drugs that are administered via topical application are hindered from reaching the posterior region of the eye by components of the anterior region of the eye, as well as physiologic processes such as tears, blinking, drug metabolism, and drug binding.
Some known methods of treatment employ intravitreal (IVT) administration. IVT administration can include multiple injections due to the limited half-life of many compounds in the vitreous, potentially causing trauma and increase the risk of cataract, retinal detachment, hemorrhage and endophthalmitis.
The delivery of drugs to the posterior region of the eye through systemic administration is limited by the outer and inner blood-retinal barriers. Moreover, other limitations for systemic application of drugs include potentially reduced time of therapeutic effects and potency due to the dilution and degradation of the drug before reaching the target tissue. Thus, systemic administration usually requires an increase in the quantity of drugs necessary to achieve therapeutic concentrations at the target tissue, which increases the risk of adverse effects due to the accumulation of the drug in other tissues throughout the body.
The suprachoroidal space (SCS) of the eye has been studied as a location for drug delivery to posterior segments. The SCS can be reached via surgical means and/or cannulation. Although SCS delivery improves targeting to sites of drug action compared to other means such as topical, intravitreal, or systemic administration, it would be advantageous to achieve precisely controlled targeting to desired sites of drug action within the eye. This disclosure addresses this and other needs.
Drug delivery to the suprachoroidal space (SCS) using a microneedle targets drugs to the choroid and adjacent retina. Although SCS delivery improves targeting to sites of drug action, further control of drug distribution and targeting to specific tissues and areas in specific tissues of the eye will enable more precise drug targeting, and more effective treatment. The present disclosure provides methods, systems, devices, and compositions for targeted drug delivery to ocular tissues, comprising the use of a pushing formulation and/or iontophoresis. In one aspect, the present disclosure provides methods for delivery of a drug formulation to a target tissue in the eye of a subject, the method comprising administering to the suprachoroidal space (SCS) of the subject a first formulation and a second formulation, wherein the first formulation comprises an active agent and the second formulation is a pushing formulation. In some embodiments, the pushing formulation is a formulation of higher density and/or viscosity relative to the first formulation such that the administration of the pushing formulation following the first formulation results in pushing the first formulation toward the posterior segment of the eye.
In one aspect, the present disclosure provides methods for delivery of a drug formulation to a target tissue in the eye of a subject, the method comprising administering to the suprachoroidal space (SCS) of the subject a formulation comprising an active agent and further comprising applying iontophoresis to the eye of the subject to localize the active agent to a target tissue in the eye. In one aspect, the present disclosure provides methods for delivery of a drug formulation to a target tissue in the eye of a subject, the method comprising using a combination of a pushing formulation and iontophoresis.
In some embodiments, the first formulation and the second formulation are administered to the SCS using a microneedle. In some embodiments, the microneedle is a hollow microneedle. In some embodiments, the microneedle is between about 600 μm and about 1200 μm in length. In further embodiments, the microneedle is between about 900 and 1100 μm in length. In further embodiments, the microneedle is about 750 μm in length. In some embodiments, the microneedle is about 900 μm in length. In some embodiments, the microneedle is about 1100 μm in length. In some embodiments, the microneedle size is 28 gauge or smaller. For example, in some embodiments, the microneedle is a 30 gauge microneedle, a 31 gauge microneedle, a 32 gauge microneedle, or a 33 gauge microneedle.
In some embodiments, the first formulation and the second formulation are administered to the SCS using a device containing both the first and second formulation. In some embodiments, the first formulation is administered to the SCS prior to administration to the SCS of the pushing formulation. In some embodiments, the first formulation has a lower viscosity than the pushing formulation. In some embodiments, the first formulation has a lower density than the pushing formulation. In some embodiments, the pushing formulation comprises a gel. In some embodiments, the pushing formulation comprises hyaluronic acid (HA). In some embodiments, the pushing formulation comprises about 1% (w/v), about 2% (w/v), about 3% (w/v), about 4% (w/v), or about 5% (w/v) HA. In some embodiments, the pushing formulation comprises a salt. For example, in some embodiments, the pushing formulation is a high-salt formulation. For example, in some embodiments, the pushing formulation comprises 9% sodium chloride (NaCl). In certain embodiments, the pushing formulation comprises about 4% (w/v) HA and about 9% NaCl.
In some embodiments, the first formulation comprises an active agent useful in the treatment of an ocular disease or disorder. In some embodiments, the first formulation comprises particles, e.g., a suspension of particles. In certain embodiments, the particles are microparticles or nanoparticles. In some embodiments, the first formulation comprising the active agent further comprises HA. In some embodiments, the first formulation comprises about 0.1% (w/v) HA, about 0.5% (w/v) HA, about 1% (w/v) HA, about 2% (w/v) HA, or about 3% (w/v) HA. In certain embodiments, the first formulation comprises about 1% (w/v) HA. In some embodiments, the first formulation comprises about 1% (w/v) HA and the pushing formulation comprises about 4% (w/v) HA.
In some embodiments, the target tissue of the eye is selected from the group consisting of the posterior pole, optic nerve, choroid, retina, vitreous humor, macula, iris, or ciliary body. In some embodiments, the methods provided herein comprise the use of a pushing formulation that pushes the drug formulation further posteriorly in the posterior segment of the eye. In some embodiments, the methods provided herein result in localization of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% of the first formulation and/or the active agent therein to a location in the eye that is at least about 3 mm posterior to the limbus. In further embodiments, the methods provided herein result in localization of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% of the first formulation and/or the active agent therein to a location in the eye that is at least about 6 mm posterior to the limbus. In some embodiments, the methods provided herein result in localization of at least 10%, at least 20%, at least 30%, or more of the first formulation and/or the active agent therein to a location in the eye that is at least 9 mm posterior to the limbus.
In one aspect, the present disclosure provides a device comprising a microneedle and a syringe or drug formulation reservoir, wherein the device comprises a first formulation and a second formulation, wherein the first formulation comprises an active agent and the second formulation is a pushing formulation. In some embodiments, the syringe is coupled to a microneedle. In some embodiments, the first formulation and the second formulation are substantially separate. For example, in some embodiments, the term “substantially separate” means there is little mixing or substantially no mixing of the first formulation and the second formulation. In some embodiments, there is mixing of the first and second formulations prior to, during, and/or after infusion of the formulations into the SCS, but the extent of the mixing does not prevent the pushing of the first formulation comprising the active agent further posteriorly in the posterior segment of the eye.
In some embodiments, the ocular disease or disorder is selected from the group consisting of uveitis, retinal vein occlusion, diabetic retinopathy, macular edema, diabetic macula edema, age-related macular degeneration, and glaucoma. In some embodiments, the disease or disorder amenable to treatment with the methods and compositions provided herein is selected from the group consisting of retinal vein occlusion, diabetic retinopathy, diabetic macula edema, and age-related macular degeneration, wherein the first formulation is injected to the posterior segment of the eye, and wherein the pushing formulation further pushes the first formulation posteriorly in the posterior segment of the eye. In some embodiments, the present disclosure provides methods wherein the active agent or drug in the first formulation flows or diffuses to the retina. In some embodiments, the disease or disorder amenable to treatment with the methods and compositions provided herein is glaucoma, and wherein the pushing formulation pushes the first formulation to the ciliary body.
In some embodiments, the present disclosure provides the use of a first formulation and a second formulation in a method of delivering a drug formulation to a target tissue in the eye of a subject, wherein the first formulation and second formulation are delivered to the suprachoroidal space (SCS) of the eye of the subject, wherein the first formulation comprises an active agent and the second formulation is a pushing formulation. In some embodiments, the present disclosure provides a first formulation and a second formulation for use in a method of treating a posterior ocular disease or disorder in a subject in need thereof, wherein the first formulation and second formulation are delivered to the suprachoroidal space (SCS) of the eye of the subject, wherein the first formulation comprises an active agent and the second formulation is a pushing formulation.
In some embodiments, the present disclosure provides the use of a first formulation and a second formulation in a method of delivering a drug formulation to a target tissue in the eye of a subject, wherein the first formulation and second formulation are delivered to the suprachoroidal space (SCS) of the eye of the subject, wherein the first formulation comprises a pushing formulation and the second formulation comprises an active agent. In some embodiments, the methods provide a means for pushing the active agent of the second formulation anteriorly. For example, in some embodiments, the methods provide a means for pushing an active agent toward the limbus of the eye. For example, in some embodiments, the methods provide a means for targeting an active agent to the ciliary body. In some embodiments, the present disclosure provides methods for treating a disease or disorder in a subject in need thereof, the method comprising administering to the SCS of the eye of the subject a first formulation that is a pushing formulation, and subsequently administering to the SCS of the eye of the subject a second formulation comprising a drug or active agent. In some embodiments, the disease or disorder is glaucoma.
In some embodiments, the methods provided herein involve iontophoresis, wherein the formulation comprising the active agent is administered to a region of the eye, e.g., the SCS, prior to the application of iontophoresis to the eye. In some embodiments, the formulation comprising the active agent is administered to the SCS concurrently with the application of iontophoresis to the eye. In some embodiments, the iontophoresis applied to the eye comprises applying a current with an absolute value of about 0.05 mA to about 0.8 mA. In some embodiments, the iontophoresis applied to the eye comprises applying a current with an absolute value of about 0.01 to about 0.7 mA. In some embodiments, the current has an absolute value of about 0.07 mA, about 0.08 mA, about 0.09 mA, about 0.1 mA, about 0.11 mA, about 0.12 mA, about 0.13 mA, about 0.14 mA, about 0.15 mA, about 0.16 mA, about 0.17 mA, about 0.18 mA, about 0.19 mA, about 0.2 mA, about 0.25 mA, about 0.3 mA, about 0.35 mA, about 0.4 mA, or about 0.5 mA. In some embodiments, a positive or negative current is used with an active agent and/or particle having an opposite polarity, for example, to move the active agent further posteriorly after injection. In some embodiments, the current with an absolute value provided herein is a positive current and is used with an active agent and/or particle having a negative charge. In some embodiments, the current with an absolute value provided herein is a negative current and is used with an active agent and/or particle having a positive charge. In other embodiments, a positive or negative current is used with an active agent and/or particle having the same polarity, for example to keep the active agent in the anterior part of the SCS (e.g., the ciliary body) after injection. For example, in some embodiments, the current with an absolute value provided herein is a negative current and is used with an active agent and/or particle having a negative charge: or the current with an absolute value provided herein is a positive current and is used with an active agent and/or particle having a positive charge
In some embodiments, the iontophoresis is applied to the eye for about 1 minute to about 10 minutes. In some embodiments, the iontophoresis is applied to the eye for about 3 minutes.
In one aspect, the present disclosure provides methods for delivery of a drug formulation to a target tissue in the eye of a subject, the method comprising (i) administering to SCS of the eye of the subject a first formulation and a second formulation, wherein the first formulation comprises an active agent and the second formulation is a pushing formulation: and (ii) applying iontophoresis to the eye of the subject to further localize the active agent to a target tissue in the eye. In some embodiments, the method results in localization of the active agent further posteriorly in the posterior segment of the eye, such as precise localization to desired tissues within the eye or specific areas on desired tissues within the eye. In some embodiments, the method results in localization of at least about 30% of the first formulation to a location in the eye that is at least about 6 mm posterior to the limbus. In further embodiments, method results in localization of at least about 50% of the first formulation to a location in the eye that is at least about 6 mm posterior to the limbus. In some embodiments, the iontophoresis is applied to the eye prior to the administration of the second formulation. In other embodiments, the iontophoresis is applied to the eye during and/or after administration of the second formulation. In one aspect, the present disclosure provides a method comprising (i) administering to the SCS of the eye of the subject a first formulation comprising an active agent: (ii) applying iontophoresis to the eye of the subject to localize the active agent to a target tissue in the eye: and (iii) administering to the SCS of the eye of the subject a second formulation, wherein the second formulation is a pushing formulation and wherein the second formulation further localizes the active agent to a target tissue in the eye.
Devices, methods, systems, compositions, and kits for ocular drug delivery are described herein.
As used herein, “ocular tissue” and “eye” include both the anterior segment of the eye (i.e., the portion of the eye in front of the lens) and the posterior segment of the eye (i.e., the portion of the eye behind the lens).
The term “suprachoroidal space,” is used interchangeably with suprachoroidal, SCS, suprachoroid and suprachoroidia, and describes the potential space in the region of the eye disposed between the sclera and choroid. This region primarily is composed of closely packed layers of long pigmented processes derived from each of the two adjacent tissues: however, a space can develop in this region as a result of fluid or other material buildup in the suprachoroidal space and the adjacent tissues. The “supraciliary space,” as used herein, is encompassed by the SCS and refers to the most anterior portion of the SCS adjacent to the ciliary body, trabecular meshwork and limbus. Those skilled in the art will appreciate that the suprachoroidal space frequently is expanded by fluid buildup because of some disease state in the eye or as a result of some trauma or surgical intervention. In the present description, however, the fluid buildup is intentionally created by infusion of a drug formulation into the suprachoroid to create the suprachoroidal space (which is filled with drug formulation). Not wishing to be bound by theory, it is believed that the SCS region serves as a pathway for uveoscleral outflow (i.e., a natural process of the eye moving fluid from one region of the eye to the other through) and becomes a real space in instances of choroidal detachment from the sclera.
As used herein, “non-surgical” ocular drug delivery devices and methods refer to methods and devices for drug delivery that do not require general anesthesia and/or retrobulbar anesthesia (also referred to as a retrobulbar block). Alternatively or additionally, a “non-surgical” ocular drug delivery method is performed with an instrument having a diameter of 28 gauge or smaller. Alternatively or additionally, “non-surgical” ocular drug delivery methods do not require a guidance mechanism that is typically required for ocular drug delivery via a shunt or cannula. As used herein, “surgical” ocular drug delivery includes insertion of devices or administration of drugs by surgical means, for example, via incision to expose and provide access to regions of the eye including the posterior region, and/or via insertion of a stent, shunt, or cannula. In certain aspects, the non-surgical methods for delivery to the SCS provided herein are achieved by injecting a drug or drug formulation to the SCS using a microneedle.
In some embodiments, features of the devices, formulations, and methods are provided in International Patent Application Publication Nos. WO2014/074823 (Application No. PCT/US2013/069156), WO2015/195842 (Application No. PCT/US2015/036299), and/or WO2017/120601 (Application No. PCT/US2017/012757), each of which is hereby incorporated by reference in its entirety for all purposes.
In some embodiments, the present disclosure provides systems, methods, and compositions wherein a drug formulation (e.g., a formulation containing an active agent) may be delivered to a particular action site depending on the ocular disease for which the subject is being treated. Exemplary target sites, associated indications, and active agents or drug formulations for treatment of the indication are provided below. The person of ordinary skill in the art will appreciate that other target sites, indications, and active agents/drug formulations are encompassed by the invention. For example, the present disclosure provides compositions and methods for delivery of active agents and drug formulations to the optic nerve. Other target sites, indications, and active agents include, without limitation:
Ocular diseases and disorders amenable for treatment by the methods, systems, compositions, kits, devices, and drug formulations described herein can include, but are not limited to, uveitis (e.g., infectious uveitis, non-infectious uveitis, chronic uveitis, and/or acute uveitis), macular edema, diabetic macular edema (DME), macular edema associated with uveitis (encompassing macular edema associated with infectious uveitis and macular edema associated with non-infectious uveitis), macular edema following retinal vein occlusion (RVO), and macular edema associated with RVO. In one embodiment, the posterior ocular disorder is an ocular inflammatory condition such as uveitis, scleritis, glaucoma, ocular sarcoidosis, optic neuritis, macular edema, diabetic retinopathy, macular degeneration, a corneal ulcer, an autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal disease, retinitis, ocular neovascularization, polypoidal choroidal vasculopathy, choroidal sclerosis, central sirrus choroidopathy, a multi-focal choroidopathy or a choroidal dystrophy (e.g., central gyrate choroidal dystrophy, serpiginous choroidal dystrophy, total central choroidal atrophy The condition in one embodiment is acute. In another embodiment, the condition is chronic.
Disorders caused by pathogenic organisms that can lead to infectious uveitis, macular edema associated with infectious uveitis, or other ocular disorders amenable to the treatment methods, systems, and compositions provided herein include, but are not limited to, toxoplasmosis, toxocariasis, histoplasmosis, herpes simplex or herpes zoster infection, tuberculosis, syphilis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, Behcet's disease, idiopathic retinal vasculitis, Vogt-Koyanagi-Harada Syndrome, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), presumed ocular histoplasmosis syndrome (POHS), birdshot chroidopathy, Multiple Sclerosis, sympathetic opthalmia, punctate inner choroidopathy, pars planitis, or iridocyclitis.
The term “subject” may be used interchangeably herein with “patient” and the like. In some embodiments, the subject is any animal, including any mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a human subject in need of treatment of an ocular disease or disorder.
Delivery Materials
Drugs, molecules, particles, hydrogels, polymers, diagnostics, therapeutics, cosmetics/cosmeceuticals, prostheses/implants and other agents (materials) can be delivered into the suprachoroidal space of the eye. The material to be delivered could carry a positive charge, negative charge or no charge, and if zwitterionic, a net positive charge, net negative charge or no net charge. Thus, in some embodiments, the active agent or drug formulation useful in the compositions, methods, and systems provided herein comprises a charged moiety. The charged moiety may be created using any known technique, and generally may include a moiety that is altered to have a different charge (i.e., neutral to positive, neutral to negative, negative to positive, etc.), an increased charge, or decreased charge. In some embodiments, the charged moiety is a moiety that is positively charged under assay or physiological conditions, which are typically neutral or slightly acidic (pH about 5 to about 7). The positively charged moiety may include an amine. In another embodiment, the charged moiety is a moiety that is negatively charged under assay or physiological conditions. The negatively charged moiety may include a carboxylate, a phosphate, or a combination thereof. In some embodiments, the “first formulation” or “active agent formulation” and the like comprises the charged moieties, drugs, molecules, particles, hydrogels, polymers, diagnostics, therapeutics, cosmetics/cosmeceuticals, prostheses/implants, other agents provided herein.
As provided throughout, in one embodiment, the methods described herein are carried out with a hollow or solid microneedle, for example, a rigid microneedle. As used herein, the term “microneedle” refers to a conduit body having a base, a shaft, and a tip end suitable for insertion into the sclera and other ocular tissue and has dimensions suitable for minimally invasive insertion and drug formulation infusion as described herein. That is, the microneedle has a length or effective length that does not exceed about 2000 microns and a diameter that does not exceed about 600 microns. Both the “length” and “effective length” of the microneedle encompass the length of the shaft of the microneedle and the bevel height of the microneedle. In some embodiments, the microneedle used to carry out the methods described herein comprises one of the devices disclosed in International Patent Application Publication No. WO2014/179698 (Application No. PCT/US2014/036590), filed May 2, 2014 and entitled “Apparatus and Method for Ocular Injection,” incorporated by reference herein in its entirety for all purposes. In some embodiments, the microneedle used to carry out the methods described herein comprises one of the devices disclosed in International Patent Application Publication No. WO2014/036009 (Application No. PCT/US2013/056863), filed Aug. 27, 2013 and entitled “Apparatus and Method for Drug Delivery Using Microneedles,” incorporated by reference herein in its entirety for all purposes.
In some embodiments, features of the devices, formulations, and methods are provided in International Patent Application Publication Nos. WO2014/074823 (Application No. PCT/US2013/069156), WO2015/195842 (Application No. PCT/US2015/036299), and/or WO2017/120601 (Application No. PCT/US2017/012757), each of which is hereby incorporated by reference in its entirety for all purposes. In one embodiment, the device used to carry out one of the methods described herein comprises the device described in U.S. Design Patent Application Ser. No. 29/506,275 entitled, “Medical Injector for Ocular Injection,” filed Oct. 14, 2014, the disclosure of which is incorporated herein by reference in its entirety for all purposes. In one embodiment, the device used to carry out one of the methods described herein comprises the device described in U.S. Patent Publication No. 2015/0051581 or U.S. Patent Publication No. 2017/0095339, which are each incorporated herein by reference in their entireties for all purposes.
In some embodiments, the words “proximal” and “distal” when used herein in relation to an operator of the device refer to the direction closer to and away from, respectively, an operator (e.g., surgeon, physician, nurse, technician, etc.) who would insert the medical device into the patient, with the tip-end (i.e., distal end) of the device inserted inside a patient's body first. Thus, for example, the end of a microneedle described herein first inserted inside the patient's body would be the distal end, while the opposite end of the microneedle (e.g., the end of the medical device being manipulated by the operator) would be the proximal end of the microneedle. In other embodiments, the words “proximal” and “distal” when used herein in relation to a device itself may refer to the direction closer to or away from, respectively, the indicated end of the device. Thus, in some embodiments, a microneedle coupled to a syringe containing an active agent formulation and a pushing formulation may comprise an active agent formulation that is proximal to the needle end and a pushing formulation distal from the needle end, such that upon insertion of the microneedle and infusion into the SCS of the eye, the active agent formulation enters the SCS prior to the entry into the SCS of the pushing formulation.
As used herein, the terms “about” and “approximately” generally mean plus or minus 10% of the value stated. For example, about 0.5 would include 0.45 and 0.55, about 10 would include 9 to 11, about 1000 would include 900 to 1100.
As used herein, the term “hollow” (e.g., in relation to a hollow microneedle) includes a single, straight bore through the center of the microneedle, as well as multiple bores, bores that follow complex paths through the microneedles, multiple entry and exit points from the bore(s), and intersecting or networks of bores. That is, a hollow microneedle has a structure that includes one or more continuous pathways from the base of the microneedle to an exit point (opening) in the shaft and/or tip portion of the microneedle distal to the base.
In one embodiment, the microneedle has an effective length of about 50 μm to about 2000 μm. In another particular embodiment, the microneedle has an effective length of from about 150 μm to about 1500 μm, or from about 300 μm to about 1250 μm, or from about 500 μm to about 1250 μm, or from about 500 μm to about 1500 μm, or from about 600 μm to about 1000 μm, or from about 700 μm to about 1000 μm. In one embodiment, the effective length of the microneedle is about 600 μm, or about 700 μm, or about 800 μm or about 1000 μm. In various embodiments, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of from about 50 μm to 600 μm, or from about 50 μm to about 400 μm, or from about 50 μm to about 500 μm, or from about 100 μm to about 400 μm, or from about 200 μm to about 600 μm, or from about 100 μm to about 250 μm, with an aperture diameter of about 5 μm to about 400 μm. In a particular embodiment, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of about 600 μm. Those skilled in the art will appreciate, however, that in embodiments in which the tip of the microneedle is beveled that the aperture diameter may be greater than the outer diameter of the proximal portion of the microneedle. The microneedle may be fabricated to have an aspect ratio (width:length) of about 1:1.5 to about 1:10. In one embodiment, the aspect ratio of the microneedle is about 1:3 to about 1:5. In another embodiment, the aspect ratio of the microneedle is about 1:4 to about 1:10.
The microneedle can have a straight or tapered shaft. In one embodiment, the diameter of the microneedle is greatest at the base end of the microneedle and tapers to a point at the end distal the base. The microneedle can also be fabricated to have a shaft that includes both a straight (i.e., untapered) portion and a tapered (e.g., beveled) portion. In various embodiments the microneedle has a bevel angle of about 5 degrees to about 30 degrees, of about 5 degrees to about 25 degrees, about 5 degrees to about 20 degrees, about 10 degrees to about 20 degrees, and about 10 degrees to about 30 degrees. The microneedles can be formed with shafts that have a circular cross-section in the perpendicular, or the cross-section can be non-circular. The tip portion of the microneedles can have a variety of configurations. The tip of the microneedle can be symmetrical or asymmetrical about the longitudinal axis of the shaft. The tips may be beveled, tapered, squared-off, or rounded. In various embodiments, the microneedle has a bevel height from about 50 μm to 500 μm, about 100 μm to about 500 μm, about 100 μm to about 400 μm, about 200 μm to about 400 μm, and about 300 μm to about 500 μm. In particular embodiments, the microneedle may be designed such that the tip portion of the microneedle is substantially the only portion of the microneedle inserted into the ocular tissue (i.e., the tip portion is greater than 75% of the total length of the microneedle, greater than 85% of the total length of the microneedle, or greater than about 95% of the total length of the microneedle). In other particular embodiments, the microneedle may be designed such that the tip portion is only a portion of the microneedle that is inserted into the ocular tissue and generally has a length that is less than about 75% of the total length of the microneedle, less than about 50% of the total length of the microneedle, or less than about 25% of the total length of the microneedle. For example, in one embodiment the microneedle has a total effective length between 500 μm and 1500 μm, wherein the tip portion has a length that is less than about 400 μm, less than about 300 μm, or less than about 200 μm.
In one embodiment, the height of the bevel is about 100 μm to about 500 μm. In another embodiment, the height of the bevel is about 500 μm or less, about 450 μm or less, about 400 μm or less or about 350 μm or less. In another embodiment, the height of the bevel is from about 200 μm to about 500 μm, or from about 100 μm to about 700 μm, or from about 200 μm to about 700 μm. In still other embodiments, the height of the bevel is from about 500 μm to about 900 μm, or from about 500 μm to about 800 μm, or from about 500 μm to about 700 μm. In this manner, the arrangement of the bevel can be such that the distal edge is sufficiently sharp such as to pierce a target tissue and penetrate into the vitreous without (i) substantially causing the target tissue to elastically deform or (ii) damaging internal structures of the eye, e.g., the lens or retina.
In one embodiment, the microneedle extends from a base. The base may be integral with or separate from and coupled (e.g., slidably coupled or fixedly coupled) to the microneedle. The base may be rigid or flexible. The base may be substantially planar or it may be curved, for example, in the shape of the ocular tissue surface at the site of injection or, for example, curved away from the ocular surface (e.g., convex) so as to minimize contact between the base and the ocular tissue. In some embodiments, desirably, the base is shaped to provide minimal contact with the surface of the eye at the point of insertion. For example, in such embodiments, the base may extend only a minimal distance from the microneedle shaft substantially perpendicular. In another embodiment, the base may be shaped so as to elevate the ocular tissue towards the microneedle so as to counteract the deflection of the ocular tissue and facilitate insertion of the microneedle into the ocular tissue (e.g., the base may extend from the microneedle toward the tip portion of the microneedle so as to “pinch” the ocular tissue). Some such embodiments may be based, at least in part, on the devices described in U.S. Pat. No. 6,743,211, incorporated herein by reference.
Microneedles may be manufactured using techniques described, for example, in U.S. Patent Application Publication No. 2006/0086689, U.S. Patent Application Publication No. 2006/0084942, U.S. Patent Application Publication No. 2005/0209565, U.S. Patent Application Publication No. 2002/0082543, U.S. Pat. Nos. 6,334,856, 6,611,707, 6,743,211 and PCT/US2014/36590, filed May 2, 2014, all of which are incorporated herein by reference in their entireties for all purposes.
In some embodiments, the microneedle comprises a fluid reservoir for containing the drug formulation and/or the hydrogel pushing formulation. In some embodiments, the fluid reservoir is in operable communication with the bore of the microneedle at a location distal to the tip end of the microneedle. The fluid reservoir may be integral with the microneedle, integral with the elongated body, or separate from both the microneedle and elongated body. In some embodiments, the microneedle is coupled to, attached to, or configured to allow attachment to a syringe comprising the drug formulation and/or the hydrogel pushing formulation.
Devices shown and described in International Patent Application No. WO2015/19584, entitled “METHOD AND DEVICES FOR TREATING POSTERIOR OCULAR DISORDERS,” and U.S. Pat. No. 9,180,047, entitled “APPARATUS AND METHODS FOR OCULAR INFECTION,” each of which is incorporated herein by reference in its entirety, can be used to perform the SCS injection portion of the methods provided herein.
Any composition or drug formulation suitable for ocular delivery may be injected using any suitable injector of the types shown and described herein. Any of the methods described herein can be performed use any suitable injector of the types shown and described herein. In this manner, the benefits of the targeted drug delivery via the methods and compositions provided herein can be realized.
In some embodiments, the methods and systems provided herein comprise targeted delivery of a drug to a desired location in the eye, wherein the delivered volume is at least about 20 μL, at least about 50 μL, at least about 100 μL, at least about 200 μL or at least about 500 μL. In some embodiments, the delivered volume is from about 10 μL to about 200 μL, e.g., from about 50 μL to about 150 μL. In some embodiments, the delivered volume is about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, about 250 μL, about 300 μL, about 350 μL, about 400 μL, or about 500 μL.
In some embodiments, the targeting of a drug formulation to and/or within the posterior segment of the eye is measured by determining how much of the drug formulation (e.g., by volume or by percent) is localized at least 3 mm posterior to the limbus, at least 4 mm posterior to the limbus, at least 5 mm posterior to the limbus, at least 6 mm posterior to the limbus, at least 7 mm posterior to the limbus, at least 8 mm posterior to the limbus, at least 9 mm posterior to the limbus, or at least 10 mm posterior to the limbus. In some embodiments, the targeting of a drug formulation and/or within the posterior segment of the eye is measured by determining how much of the drug formulation (e.g., by volume or by percent) is localized about 0-3 mm posterior to the limbus, about 3-6 mm posterior to the limbus, about 6-9 mm posterior to the limbus, or about 9 or more mm posterior to the limbus.
Hydrogel Pushing
In some embodiments, the present disclosure provide methods for delivery in the SCS using a hydrogel pushing strategy. In some embodiments, the hydrogel pushing strategy involves a two-step process or a two-formulation process. For example, in some embodiments, two different formulations are introduced (e.g., injected) into the SCS. One of the formulations is the “drug formulation” (used interchangeably herein with “particle formulation,” “drug particle formulation.” “active agent,” “active agent formulation,” and the like) and the other is the “pushing formulation” (referred to herein in some embodiments, as the “hydrogel formulation.” “hydrogel pushing formulation.” or the like). The drug formulation contains whatever materials are to be delivered to specific locations(s) in the SCS in a suitable carrier fluid (e.g., water) and containing suitable excipients (if needed). The pushing formulation may also contain the same or different materials to be delivered to specific locations(s) in the SCS, or may contain no such materials.
The drug and pushing formulations are introduced into the SCS substantially at the same time or are introduced into the SCS separately. For example, in some embodiments, the drug formulation and the pushing formulation are both loaded into the same microneedle device or microneedle coupled to a syringe. For example, formulations loaded into a microneedle coupled to a syringe are shown in schematically in
Through a single pressing of the syringe, the drug formulation can be injected into the SCS, with the pushing formulation following immediately behind (i.e., into the SCS). In some embodiments, the drug and pushing formulations are in the opposite order (i.e., drug formulation toward the plunger end). Thus, in some embodiments, the pushing formulation is administered to the SCS first and the drug formulation follows. In such embodiments, the drug formulation may be pushed anteriorly rather than posteriorly. In some embodiments, there are multiple regions within the syringe containing drug or pushing formulations. In some embodiments, the drug and pushing formulations could be introduced at substantially different times using the same or multiple syringes.
Once injected into the SCS, the drug and pushing formulations will occupy substantially different regions of the SCS. In some embodiments, over time, the pushing formulation expands in volume, which pushes at least a portion of the drug formulation to a different region of the SCS. This expansion in volume and further pushing is referred to herein as “spreading,” “hydrogel spreading.” “hydrogel swelling.” “pushing formulation spreading,” “pushing formulation swelling,” and the like. The pushing formulation may push the drug formulation toward specific targeted region(s) of the eye (e.g., to promote desired effects) and/or away from specific targeted region(s) of the eye (e.g., to prevent undesired effects). The timescale of pushing and/or spreading can substantially occur within minutes, hours, days, weeks, or longer, depending on the formulations used. In some embodiments, the pushing formulation continues to swell and push the first formulation toward the posterior segment for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 18 hours, at least 24 hours, or more. In some embodiments, the first formulation, following swelling, remains to the further posterior position for at least 1 day, at least 2, days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 2 weeks at least 3 weeks, at least 4 weeks, or longer after injection. In some embodiments, the swelling of the pushing formulation occurs as the formulation expands due to uptake of water from the eye tissue. In some embodiments, the swelling of the pushing formulation is further enhanced when the pushing formulation comprises a salt to drive osmotic flow into the formulation.
The drug and pushing formulations are designed according to a number of criteria. For example, in some embodiments, the formulations are biocompatible with the eye and satisfy other safety concerns. In some embodiments, the formulations are compatible with the active agents or drugs they deliver to the eye. In some embodiments, the formulations have a viscosity (e.g., dynamic viscosity) during injection low enough that allows them to flow into the SCS. In some embodiments, the viscosity is low enough to allow flow within the SCS during the pushing. In certain embodiments, the drug and pushing formulations do not substantially mix with each other. In one aspect, the goal of the hydrogel pushing procedure is for a separate pushing formulation to push the separate drug formulation and not have them substantially mix before or during the pushing. However, some mixing is acceptable, as long as the pushing formulation pushes at least a portion of the drug formulation to a different region of the SCS. The separation of the drug and pushing formulations can be due to thermodynamic and/or kinetic reasons. Thermodynamic reasons include the use of formulations that are at least substantially immiscible through use, for example, of different solvents/carrier fluids. Kinetic reasons include high viscosity that slows the mixing of the formulations.
In one aspect, the drug formulation has a lower viscosity than the pushing formulation during injection into the SCS and/or during the pushing within the SCS. This enables the pushing formulation to apply a force to the drug formulation while reducing the mixing of the two formulations. Pushing is achieved by swelling the pushing formulation. Swelling can be achieved by a number of different mechanisms and possibly triggered by a number of different mechanisms. The pushing formulation can form a gel that expands due to, for example and without limitation, physicochemical cues, such as change in pH, change in temperature, change in divalent cation concentration and other triggers of gel swell.
In some embodiments, the formulation can undergo a phase change, for example from liquid to gas, for example caused by a temperature change. In some embodiments, the pushing formulation can expand due to influx of other materials into the formulation, such as water from the surrounding tissues and/or the drug formulation. This could be accomplished by osmotic forces caused by higher solute content in the pushing formulation compared to surrounding fluids. In some embodiments, the formulations in a single syringe can comprise a drug particle phase and a swellable pushing hydrogel phase. The formulations to be injected in a single syringe can be a single or multiple formulations.
In some embodiments, the drug formulation can contain drugs, molecules, particles, hydrogels, polymers, diagnostics, therapeutics and other agents (materials). In some embodiments, the drug particle phase can have a positive or a negative charge, or no charge, and if zwitterionic, a net positive charge, net negative charge or no net charge without modifications.
In some embodiments, the pushing formulation can contain drugs, molecules, particles, hydrogels, polymers, diagnostics, therapeutics and other agents (materials) and it can have any charges or no charge, and if zwitterionic, a net positive charge, net negative charge or no net charge. In some embodiments, the pushing formulation comprises swellable or non-swellable materials. In some embodiments, the pushing formulation comprises or is a gel or an oil, such as silicone oil. In certain embodiments, the pushing formulation has a higher density relative to the drug formulation. In some embodiments, the drug formulation and pushing formulation are a single formulation having the drug or other material for delivery to the desired ocular tissue and having one or more characteristics that allow hydrogel pushing and/or swelling to push the entire formulation toward the posterior segment of the eye after injection.
In some embodiments, the drug formulation comprises particles. The particles of the drug formulations provided herein may be drug, or may be particles that contain drug. In some embodiments, the active agent or drug has a charge. In some embodiments, the active agent or drug has a positive charge or a negative charge. In some embodiments, the active agent or drug is within or associated with particles that have a charge. In some embodiments, the particles have a positive charge or a negative charge. In one embodiment, the drug formulation includes microparticles or nanoparticles, either of which includes at least one drug. Desirably, the microparticles or nanoparticles provide for the controlled release of drug into the suprachoroidal space and surrounding posterior ocular tissue. As used herein, the term “microparticle” encompasses microspheres, microcapsules, microparticles, and beads, having a number average diameter of from about 1 μm to about 100 μm, for example from about 1 to about 25 μm, or from about 1 μm to about 7 μm. “Nanoparticles” are particles having an average diameter of from about 1 nm to about 1000 nm. The microparticles, in one embodiment, have a D50 of about 3 μm or less. In a further embodiment, the D50 is about 2 μm. In another embodiment, the D50 of the particles in the drug formulation is about 2 μm or less. In another embodiment, the D50 of the particles in the drug formulation is about 1000 nm or less. In one embodiment, the drug formulation comprises microparticles having a D99 of about 10 μm or less. The microparticles, in one embodiment, have a D50 of about 3 μm or less. In a further embodiment, the D50 is about 2 μm. In another embodiment, the D50 of the particles in the drug formulation is about 2 μm or less. In another embodiment, the D50 of the particles in the drug formulation is about 1000 nm or less. In one embodiment, the drug formulation comprises microparticles having a D99 of about 10 μm or less. The microparticles, in one embodiment, have a D50 of about 3 μm or less. In a further embodiment, the D50 is about 2 μm. In another embodiment, the D50 of the particles in the drug formulation is about 2 μm or less. In another embodiment, the D50 of the particles in the drug formulation is about 100 nm to about 1000 nm. In one embodiment, the drug formulation comprises microparticles having a D99 of about 1000 nm to about 10 μm. The microparticles, in one embodiment, have a D50 of about 1 μm to about 5 μm or less. In another embodiment, the drug formulation comprises particles having a D99 of about 10 μm. In another embodiment, the D99 of the particles in the formulation is less than about 10 μm, or less than about 9 μm, or less than about 7 μm or less than about 3 μm. The microparticles or nanoparticles, in some embodiments, have a charge, such as a negative charge.
Microparticles and nanoparticles may or may not be spherical in shape. “Microcapsules” and “nanocapsules” are defined as microparticles and nanoparticles having an outer shell surrounding a core of another material. The core can be liquid, gel, solid, gas, or a combination thereof. In one case, the microcapsule or nanocapsule may be a “microbubble” or “nanobubble” having an outer shell surrounding a core of gas, wherein the drug is disposed on the surface of the outer shell, in the outer shell itself, or in the core. (Microbubbles and nanobubles may be respond to acoustic vibrations as known in the art for diagnosis or to burst the microbubble to release its payload at/into a select ocular tissue site.) “Microspheres” and “nanospheres” can be solid spheres, can be porous and include a sponge-like or honeycomb structure formed by pores or voids in a matrix material or shell, or can include multiple discrete voids in a matrix material or shell. The microparticles or nanoparticles may further include a matrix material. The shell or matrix material may be a polymer, amino acid, saccharride, or other material known in the art of microencapsulation.
The drug-containing microparticles or nanoparticles may be suspended in an aqueous or non-aqueous liquid vehicle. The liquid vehicle may be a pharmaceutically acceptable aqueous solution, and optionally may further include a surfactant. The microparticles or nanoparticles of drug themselves may include an excipient material, such as a polymer, a polysaccharide, a surfactant, etc., which are known in the art to control the kinetics of drug release from particles.
In some embodiments, the pushing formulation comprises hyaluronic acid (HA). In some embodiments, both the drug formulation and the pushing formulation comprise HA. In some embodiments, the pushing formulation comprises a higher % (w/v) HA than the drug formulation. In some embodiments, the drug formulation comprises 0% (w/v), about 0.1% (w/v), about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v), about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v), about 0.9% (w/v), about 1.0% (w/v), about 1.1% (w/v), about 1.2% (w/v), about 1.3% (w/v), about 1.4% (w/v), about 1.5% (w/v), about 1.6% (w/v), about 1.7% (w/v), about 1.8% (w/v), about 1.9% (w/v), about 2.0% (w/v), about 2.5% (w/v), about 3.0% (w/v), about 3.5% (w/v), about 4.0% (w/v), about 4.5% (w/v), about 5.0% (w/v) HA or more. In some embodiments, the pushing formulation comprises about 1% (w/v), about 1.5% (w/v), about 2% (w/v), about 2.5% (w/v), about 3% (w/v), about 3.1% (w/v), about 3.2% (w/v), about 3.3% (w/v), about 3.4% (w/v), about 3.5% (w/v), about 3.6% (w/v), about 3.7% (w/v), about 3.8% (w/v), about 3.9% (w/v), about 4.0% (w/v), about 4.1% (w/v), about 4.2% (w/v), about 4.3% (w/v), about 4.4% (w/v), about 4.5% (w/v), about 4.6% (w/v), about 4.7% (w/v), about 4.8% (w/v), about 4.9% (w/v), about 5.0% (w/v), about 5.5% (w/v), about 6.0% (w/v), about 6.5% (w/v), about 7.0% (w/v), about 7.5% (w/v), about 8.0% (w/v), about 8.5% (w/v), about 9.0% (w/v), about 10% (w/v), or more HA. In some embodiments, the drug formulation comprises about 0.1% (w/v) to about 2.5% (w/v) HA and the pushing formulation comprises about 2.5% (w/v) to about 5% (w/v) HA. In some embodiments, the drug formulation comprises about 0.5% (w/v) to about 1.5% (w/v) HA and the pushing formulation comprises about 3.0% (w/v) to about 5% (w/v) HA. In some embodiments, the drug formulation comprises about 1% (w/v) HA and the pushing formulation comprises about 4% (w/v) HA.
In some embodiments, one or more of the formulations comprises a salt. For example, in some embodiments, one or more of the formulations (e.g., the drug formulation or the pushing formulation) comprises a salt selected from the group consisting of NaCl, MgCl, MnCl2, CaCl2), ZnCl2, and KCl. In some embodiments, the pushing formulation is a high-salt formulation. In some embodiments, the pushing formulation comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% NaCl, or any other salt known in the art. For example, in some embodiments, the pushing formulation comprises about 9% NaCl. In some embodiments, increasing the salt concentration of the pushing formulation results in a pushing formulation that exhibits enhanced, increased, and/or more rapid pushing of the drug formulation further posteriorly in the posterior segment of the eye.
In some embodiments, the total volume injected into the suprachoroidal space of the eye (inclusive of drug formulation and pushing formulation) is about 10 μL, about 20 μL, about 30 μL, about 40 μL, about 50 μL, about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, about 225 μL, about 250 μL, about 300 μL, about 400 μL, or about 500 μL. In some embodiments, the drug formulation is present at an equal, a higher, or a lower amount relative to the pushing formulation. For example, in some embodiments, the total injection volume is 50 μL, the volume of the drug formulation 20 μL, and the volume of the pushing formulation 30 μL.
In some embodiments, the order of the formulations in a single syringe can be altered depending on the objective. For example, the drug particle formulation may be closer to the microneedle end and the pushing formulation may be distal to the microneedle end. In some embodiments, the drug particle formulation can be delivered to a greater extent toward anterior or posterior area depending on the sort and order of the formulations in a single syringe. This procedure can be conducted on any eye that contains, or can be made to contain, a suprachoroidal space, including human and animal eyes for medical, veterinary and other applications.
Iontophoresis
In one aspect, the present disclosure provides methods for targeted delivery to tissues within the eye of a subject in need thereof, comprising SCS injection and iontophoresis application. In some embodiments, for delivery in the SCS using iontophoresis, a two-step process is provided. In the first step, a drug formulation is introduced (e.g., injected) into the SCS. The drug formulation contains whatever materials are to be delivered to specific locations(s) in the SCS in a suitable carrier fluid (e.g., water) and containing suitable excipients (if needed). In the second step, an electric field is applied such that charged species move within the SCS by iontophoresis. “Iontophoresis” herein includes electrophoresis, electoosmosis, electrically enhanced diffusion and other electrokinetic phenomena.
In some embodiments, the drug formulation is be injected and iontophoresis applied into the SCS substantially at the same time. In other embodiments, the drug formulation is injected and iontophoresis is applied separately or concurrently. For example, if introduced at substantially the same time, the drug formulation in some embodiments is injected into the SCS and iontophoresis is applied before, during and/or after the injection. If introduced at substantially different times, the drug formulation could be injected in the absence of iontophoresis, and iontophoresis could be applied after the injection is finished.
In one aspect, using this approach, the region(s) of the SCS occupied by the drug formulation targeted using iontophoresis is different from that which would have been occupied if the same procedure had been followed but without using iontophoresis. If the iontophoresis is applied after the drug formulation is injected, then the drug formulation will occupy a different region of the SCS after the application of iontophoresis compared to before iontophoresis. A “different region” means that at least a portion of the drug formulation occupies a region of the eye that is different from the comparator region (e.g., without or before iontophoresis). The timescale of iontophoresis application can occur for seconds, minutes or possibly hours, depending on the conditions used and the objectives of the procedure.
In some embodiments, the drug formulation for use in the iontophoresis method contains materials to be delivered to specific locations(s) in the SCS. Materials may be charged (positively and/or negatively) with a net charge or a net neutral charge (e.g., zwitterionic) and/or they may be uncharged. Materials may be contained within carrier materials such as particles like nanoparticles, microparticles, liposomes, micelles, colloids and other structures. The carrier materials (used interchangeably herein with “containing materials”) may be charged (positively and/or negatively) with a net charge or a net neutral charge (e.g., zwitterionic) and/or they may be uncharged. The charge on the materials and the charge on the carrier materials influence the movement of the drug formulation in the SCS during iontophoresis. For example, if the net charge on the materials or on the carrier materials is negative, then the materials and the carrier materials will be moved away from the negative electrode and toward the positive electrode. As another example, if the net charge on the material or on the carrier materials is positive, then the materials and the carrier materials will be moved away from the positive electrode and toward the negative electrode. If there is no charge or no net charge on the material or on the carrier materials, then the materials and the carrier materials can be moved by electroosmosis. Electrically enhanced diffusion can be achieved, for example, by applying an alternating the electric field and/or alternating the current.
In one aspect, iontophoresis is applied by using at least two electrodes that are capable of generating an electric field within the SCS. For example, an electrode can be associated with the syringe used to inject the drug formulation. An electrode could be the needle, or part of the needle or attached to the needle used to inject the drug formulation. An electrode could be located within the barrel of the syringe, attached to the inner wall of the syringe, the plunger or another part of the syringe. In some embodiments, the electrode is located within the syringe, for example on the end of the plunger, and the wire is passed through the rubber stopper of the syringe. In some embodiments, an electrode is physically separate from the syringe and/or needle used for injection of the drug formulation. In some embodiments, there is an electrically conductive pathway from an electrode to the needle and/or syringe and/or through the needle and/or syringe. In some embodiments, there is a conductive pathway from an electrode to at least a portion of the SCS. In some embodiments, there is a conductive pathway from an electrode to and through the site of injection of materials into the SCS. Typically an electrode associated with the injection site would have a polarity (i.e., negative or positive electrode) that repels the materials and/or carrier materials, but not necessarily, depending on the location to which the materials are being targeted.
In some embodiments, an electrode is located distant from the injection site. In some embodiments, an electrode located distant from the injection site has a polarity (i.e., negative or positive electrode) that attracts the materials and/or carrier materials. In some embodiments, the distant location would typically be somewhere on the head or neck, possibly the ear or forehead or other skin surface on the head or neck. The distant location could be within the head, such as within the mouth or nose. The skin could be prepared with an conductive gel, by sandpapering the skin or other methods known in the art to facilitate good electrical contact between an electrode and skin and to reduce the electrical resistance of the skin.
In some embodiments, a conductive material is applied at a site of an electrode to facilitate passage of current and/or heat transfer. For example, in some embodiments, an electrically conductive material is used to increase the effective contact area of an electrode with the skin, eye or other tissue it contacts to reduce the current density for a given current. For example, a thermally conductive material is used to facilitate heat transfer away from an electrode and/or contact area with the skin, eye or other tissue it contacts to reduce heating at those sites.
Without an iontophoresis application, the materials injected using a microneedle localize in the suprachoroidal space, with precise location depending on the material, the formulation, the injection procedure and other parameters. The distribution of the injected materials can be changed with application of an iontophoresis. For example, in some embodiments, the injected material can be delivered to a greater extent toward one or the other of the electrodes, depending on the charge of the material, the electrode polarity and other factors (e.g., positively charged materials will move away from the positive electrode and toward the negative electrode). Movement caused by the current can be by electrophoresis, electroosmosis, electromigration, iontophoresis or other phenomena that move charged and/or uncharged materials due to an electric field or current. In this manner, precise targeting to specific tissues and areas can be achieved.
In one aspect, the electric field or current is applied by controlling the voltage, controlling the current, or both. In some embodiments, a constant voltage is maintained. In some embodiments, a constant current is maintained. In other embodiments, the voltage and/or current is changed over time.
The electric field and/or current is selected by balancing multiple parameters including sufficient force to move materials to a desired location(s), and preferably not to cause damage, pain, side effects or other adverse effects to the eye, the body, or the operator. In some embodiments, the iontophoresis is applied using a current having an absolute value of about 0.01 mA, about 0.05 mA, about 0.10 mA, about 0.15 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA, about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, or about 1.0 mA. The polarity of the current is selected depending on the net charge of the drug or particles and the location to which the drug or particles is to be targeted (e.g., anteriorly or posteriorly to the injection site) as described herein. In some embodiments, the iontophoresis is applied using a positive current of about 0.01 mA, about 0.05 mA, about 0.10 mA, about 0.15 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA, about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, or about 1.0 mA, and the method is performed using particles or active agent having a net negative charge. In other embodiments, the iontophoresis is applied using a negative current of about 0.01 mA, about 0.05 mA, about 0.10 mA, about 0.15 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA, about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, or about 1.0 mA, and the method is performed using particles or active agent having a net negative charge. In still other embodiments, the polarity of the current and the drug or particles is the same.
In one aspect, the iontophoresis methods provided herein can be conducted on any eye that contains, or can be made to contain, a suprachoroidal space, including human and animal eyes for medical, veterinary and other applications.
In some embodiments, the electrodes are designed to minimize pH changes during application of the electric field and/or current, because pH changes can damage tissue, can alter the charge on materials and tissue and can have other effects that influence safety and efficacy of the procedure. In some embodiments, an electrode can be associated with a needle and/or syringe. In one embodiment, the needle itself can be an electrode (e.g., an electrically conductive needle). In another embodiment, the electrode can be placed in the interior of the syringe, for example in fluid and/or electrical communication with the contents of the syringe. The electrode can be attached to the plunger in the syringe or to the side-wall of the syringe. In one embodiment, the electrode can be placed around the microneedle so that the electrode can attach on the eye tissues or not eye tissues in the electric communication via the microneedle or eye tissues or the injection hole.
An electrode can be in electrical communication with a tissue of the eye and/or a tissue not part of the eye. In some embodiments, the electrode is in electrical communication with a surface of the eye, such as the cornea, or conjunctiva, or sclera, or in the periocular space. In some embodiments, the electrode is in electrical communication with a surface not of the eye, such as the skin or the oral mucosa. For example, the skin could be on the head, the face, the ear (e.g., the ear lobe), the nose, the forehead, or the temple. In some embodiments, the site of electrical communication with an electrode could be treated to facilitate good electrical contact with the body, such as by application of electrically conductive gel and abrasion of the site (e.g., abrasion with sandpaper). In one aspect, the present disclosure provides a kit for targeted delivery of a substance to a region of the eye, wherein the kit comprises the electrodes, microneedles, and syringes provided herein.
Combined Hydrogel Pushing and Iontophoresis
In one aspect, the present disclosure provides compositions, systems, methods, devices, and kits for drug administration to targeted portions of the eye using a combination of hydrogel pushing and iontophoresis. Precise delivery to target tissues and areas can be modulated by using SCS injection and a combination of both the hydrogel pushing and iontophoresis approaches described herein. The various events—injection of drug formulation, injection of pushing formulation, application of iontophoresis—can be done all at the same time, two at the same time or none at the same time. For example, in some embodiments, the drug formulation and pushing formulation are performed concurrently or sequentially, and iontophoresis is applied following the injection of the drug and pushing formulations. In other embodiments, the iontophoresis may be applied before or during injection of the drug and/or pushing formulations. In such embodiments, the drug formulation may be be pushed by the pushing formulation and the iontophoresis application further posteriorly in the eye. In still other embodiments, the pushing formulation may be administered first, followed by concurrent or sequential administration of the drug formulation and iontophoresis application. In certain embodiments, a drug formulation is administered by SCS injection using a microneedle, iontophoresis is applied after injection of the drug formulation, and a pushing formulation is injected into the SCS using a microneedle after application of iontophoresis.
The present invention is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way.
A study was conducted to assess the targeting of drug delivery by hydrogel pushing in conjunction with injection into the suprachoroidal space of the eye and to study the effects of varied formulation characteristics in the methods provided herein. Drug particle formulations comprising red fluorescent particles and 0%, 1%, 2%, or 4% HA were prepared. The drug particle formulations at a volume of 20 μL were loaded into a microneedle with a 4% HA pushing formulation at a volume of 30 μL, and the formulations were infused into the SCS of rabbit eyes ex vivo. Immediately after injection of the formulations, the ex vivo eye was frozen and dissected to assess the extent to which the various formulations pushed to the posterior pole of the eye.
Next, the effects of incubation at different temperatures on the particle delivery toward the back of the eye was assessed. The 1%/4% formulation was injected in a 50 μL volume into the SCS of rabbit eyes ex vivo and eyes were incubated for 0 hr, 6 hrs at 4° C., 6 hrs at room temperature (RT), or 6 hrs at 37° C. Distributions of the red fluorescent particles in the SCS in each condition are shown in
The study showed that using the 1%/4% formulation, 14.1±5.4% of the particles was delivered toward the back of the eye (i.e., >6 mm posterior to the limbus) right after injection: and 54.3±10.2% of particles were delivered >6 mm posterior to the limbus after 6 h at 37° C. This demonstrated the ability of the pushing formulation to move more than half of the particles to the back part of the SCS. This pushing was facilitated not only by the increase in hydrogel volume upon contact with water in the eye, but also because the viscosity of the HA pushing hydrogel was decreased at 37° C.(relative to room temperature at which it was injected).
To further assess the effects of the pushing formulation, a study was conducted to observe the effect of injecting various drug particle formulations without a pushing formulation included.
A further study was conducted to assess the ability of a silicone oil formulation to perform the pushing function. Silicone oil was used in place of the HA pushing hydrogel.
Next, analysis of particle delivery toward the back of the eye using a high salt (9% sodium hydrochloride) HA as the pushing formulation was assessed, to determine whether a high salt HA hydrogel can increase osmotic flow of water into the hydrogel, to increase the pushing effect. 9% sodium chloride was added to the 4% HA pushing formulation, loaded into a microneedle with the red fluorescent drug particle formulation. The formulations were injected into the rabbit eyes ex vivo or in vivo.
The results of the study are provided in
In summary, the study showed that the salts in the HA hydrogel drastically enhanced the pushing effect compared to the normal HA 4% hydrogel pushing formulation without added salt. The drug particles were pushed by the high-salt HA hydrogel formulation such that they were precisely targeted to the back of the eye, as shown schematically in
A study was conducted to assess the change in thickness of the SCS upon administration of hydrogel pushing formulations. HA hydrogel and high-salt HA hydrogel formulations were tested.
The results of the study showed that both formulations resulted in increased thickness: high salt in the HA hydrogel resulted in increased thickness relative to the non-high salt HA hydrogel, particularly at 4 hours after injection. The high-salt HA hydrogel pushing formulation pushed the particles of the first formulation further from the injection site.
Although SCS delivery improves targeting to sites of drug action, further control of drug distribution within the SCS would enable more precise targeting of drug to, for example, the posterior pole. In this Example, studies were conducted to assess whether application of an electric field within the SCS can drive charged molecules and particles, and thereby localize drug delivery to specific sites within the SCS of the eye.
New Zealand White rabbit eyes were injected ex vivo with 50 μL, 100 μL, or 200 μL of a formulation comprising red fluorescent particles. The particles were of 20 nm diameter and with a −50 mV zeta potential. The microneedle used was a hollow microneedle with a 30-gauge and 750 μm length. The syringe connected to the microneedle was modified by embedding a Ag/AgCl electrode in the chamber of the syringe, which was connected to a DC power supply. Either no current (i) or 0.14 mA for 3 minutes (ii) was applied. After injection, the eye was snap frozen and cut into 8 scleral petals. Fluorescent images of each eye were acquired, and particle extraction was performed for the distribution analysis. The percent particle distribution at 0-3 mm: 3-6 mm: 6-9 mm: or 9)+mm was assessed for each group.
Next, the effect of altering the current on drug particle targeting was assessed. The time of iontophoresis was held at 3 min, and an injection volume of 200 μL was used. Iontophoresis currents of 0) mA, 0.14 mA, and 0.7 mA were tested.
A study was conducted to determine the effect of the application time of iontophoresis. The iontophoresis current was held at 0.14 mA and the injection volume of 200 μL was used. Iontophoresis application times of 1.5 min, 3 min, and 5 min, were compared.
To assess the SCS collapse of the rabbit eye ex vivo, thickness of the SCS was measured by an ultrasound probe.
A study of the effect of the iontophoretic direction within the SCS was conducted, with the anode at the injection site and the cathode at the optic nerve. A schematic of the study is provided in
Together, the ex vivo studies showed that charged particles injected into the SCS were delivered more preferentially to the anterior or posterior portions of the SCS, depending on the electric current and its polarity. Accordingly, the iontophoresis method provided herein is a viable strategy for targeting drug delivery to specific regions within the SCS.
Histology images of the rabbit eye after in vivo injection and iontophoresis were taken to determine if the procedure caused any damage to the eyes.
Suprachoroidal space (SCS) injection using a microneedle has been demonstrated as a means to better target drug delivery specifically to the posterior eye (e.g., macula and optic nerve). Injecting into the SCS, a potential space between the choroid and sclera, allows drug to flow circumferentially at the choroid-sclera interface typically from an anterior injection site to near the limbus with high bioavailability. The safety and tolerability of SCS injection using a microneedle have been shown in clinical trials. Although SCS injection targets drug delivery to choroid and retina, it does not specifically target the posterior pole. Moreover, typical SCS injection volumes (e.g., ≤100 μL in the rabbit eye) are insufficient to flow injected drugs around the macula or optic disk. Greater targeting efficiency within the SCS could provide still better safety and efficacy.
To advance drug targeting to posterior SCS, a previous study (e.g., described herein in Example 2) introduced iontophoresis-mediated drug delivery methods wherein charged drug model particles were delivered to the back of the eye via the SCS. Although over 50% of the drug particle was delivered further posteriorly to the posterior segment of the SCS (i.e., >6 mm posterior to the limbus), there was still around 25% of the drug particles around injection sites (i.e., <3 mm posterior to the limbus).
Thus, the present study was conducted to determine if the addition of hyaluronic acid (HA) hydrogel pushing formulation into the SCS, administered right before or after the iontophoresis, would further deliver the drugs around the injection site to the posterior. The HA hydrogel injection not only pushes the particles round the injection site, but also transfer the particles further toward the posterior by hydrogel swelling. Schematic diagrams of the process are provided in
In the combination drug delivery system, a customized Ag/AgCl electrode was located to around a microneedle for iontophoresis. The system was applied to rabbit eyes ex vivo (
A 30 gauge hollow microneedle, 750 μm in length, was used to inject negatively charged fluorescent particles into the SCS of the rabbit eye ex vivo. A customized ring type Ag/AgCl electrode was attached around a microneedle and the electrode was connected to a DC power supply. A polydimethylsiloxane (PDMS) microdevice was fabricated to apply iontophoresis to the rabbit eye ex vivo and provide similar injection conditions to in vivo injection. Two 0.75 inch diameter holes were made and connected by a single channel, 0.75×0.2×2.2 inch. A rabbit eye and a disk typed Ag/AgCl electrode (0.5 inch diameter) were placed in the holes. The channel was filled with Hank's balanced salt solution (HBSS) buffer. 50 μL of the particle solution was infused into the SCS through the microneedle, simultaneously with application of electric current (0.5 mA) for 3 minutes from the injection site to another Ag/AgCl electrode. To deliver the particles around the injection site (the anterior SCS) to the back of the eye, 50 μL of 4% (w/v) hyaluronic acid hydrogel was infused into the SCS right after the iontophoresis. To confirm the effect of the HA hydrogel swelling, the injected rabbit eyes were incubated in HBSS buffer at 37° C., for 6 h. After the injection and the incubation, particle distribution in the SCS was analyzed.
The results of the study are provided in
An additional study was conducted to determine if applying iontophoresis after hydrogel pushing, rather than immediately before hydrogel pushing, would increase or decrease particle delivery to the posterior SCS.
Based on the ex vivo results, SCS injection into the New Zealand White rabbit eyes was tested in vivo. The results are provided in
Together, the results of the study showed that iontophoresis and hydrogel pushing in the suprachoroidal space can target delivery of particles to the back of the eye, which may be of use for drug delivery of posterior ocular diseases.
In addition, to confirm the safety of this drug delivery system, intraocular pressure (IOP) was measured after the injection for 2 weeks and the injected rabbit eyes were analyzed in vivo 2 days and 2 weeks after the injection by histology. Although the IOP was lowered about 4 mmHg right after the injection, it recovered around 9 days after the injection (
Publications, patents and patent applications cited herein are specifically incorporated by reference in their entireties. While the described invention has been described with reference to the specific embodiments thereof it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adopt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the described invention. All such modifications are intended to be within the scope of the claims appended hereto.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2018/030688 | 5/2/2018 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2018/204515 | 11/8/2018 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20200061357 A1 | Feb 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62500209 | May 2017 | US |
