JP2020514404A - Intraocular drug delivery device and related methods - Google Patents

Abstract

Devices, systems, and methods for delivery of an active agent from the lens capsule of a subject to the posterior segment include intraocular active agent delivery comprising the active agent dispersed within a biodegradable active agent matrix. The device may be included. The active agent comprises dexamethasone and the delivery device is adapted to fit within the lens capsule or ciliary groove of the eye. The delivery device may be inserted into the lens capsule or ciliary groove of the eye during cataract surgery or for the treatment of uveitis. [Selection diagram]

Description

  The present invention relates to systems, methods and devices for the sustained and targeted (topical) delivery of pharmaceutically active agents to the eye of a subject. Accordingly, the invention encompasses the fields of polymer chemistry, materials science, polymer science, drug delivery, formulation science, pharmaceutical science, and medicine, especially ophthalmology.

  Age-related macular degeneration (AMD) and glaucoma are two of the leading causes of blindness in the United States and around the world. Current glaucoma therapy generally requires multidrug administration, in which subjects are often prescribed several topical agents that must be applied to the eye at different frequencies, sometimes up to 3 or 4 times daily. And These dosing regimens are often difficult for subjects to consistently follow, and many individuals require surgical treatment such as intraocular shunts or trabeculectomy with significant associated complications. Will come to.

  Subjects with macular degeneration are often required to receive monthly intravitreal injections. Such injections are painful and can lead to retinal detachment, endophthalmitis, and other complications. Moreover, these injections are generally performed only by retinal surgeons who are a small part of the ophthalmic community, causing barriers and increased costs in eye care delivery.

  Postoperative surgical inflammation may include increased intraocular pressure (IOP) and cystoid macular edema (CME), adhesion formation, posterior capsule opacification (PCO), and secondary glaucoma. Related to the increase of. Patient compliance is a concern in the management of post-operative inflammation, as multiple eye drops must be given multiple times per day at regular intervals over several weeks. Poor compliance impairs the efficacy of topical drugs, which are more limited by corneal absorption and have very variable intraocular concentrations during the course of treatment. Uveitis specifically refers to inflammation of the middle layer of the eye called the "uvea", but in common use it can refer to any inflammatory process involving the interior of the eye. Uveitis is estimated to contribute to approximately 10% of blindness in the United States.

  Post-operative cataract surgery inflammation can be well controlled by improving patient compliance. Available literature and experience indicate that drug penetration is poor after topical administration and higher systemic concentrations mean frequent systemic adverse events. All of these factors underscore the need for sustained intraocular delivery of the pharmaceutically active agent to effectively control inflammation.

  The method of delivering an active agent to the posterior segment of a subject's eye can include placing a biodegradable active agent matrix within the lens capsule of the subject to deliver the active agent to the posterior segment of the eye. The biodegradable active agent matrix comprises an active agent present in an amount that delivers a therapeutically effective dose of the active agent from the lens capsule to the posterior segment of the eye.

  Therefore, the more important features of the present invention have been outlined in somewhat broader terms so that the detailed description that follows can be better understood and its contribution to the art may be more appreciated. Other features of the invention will be apparent from the following detailed description of the invention in conjunction with the accompanying drawings and claims, or may be taught by the practice of the invention.

6 is a photograph showing a bioerodible dexamethasone implant (BDI) according to some examples of the present disclosure. 6 is a bar graph showing the amount of active agent present in various ocular tissues after implantation of an intraocular device, according to a further aspect of the invention. 3 is a graph of in vitro release rate of an exemplary BDI implant. Data are presented as mean ± SD (n = 3). Time-versus-concentration profile of an exemplary BDI implant with 120-160 μg dexamethasone (DXM) in aqueous humor and vitreous humor of New Zealand White (NZW) rabbits. Time vs. concentration profile of an exemplary BDI implant with 120-160 μg DXM in the iris / ciliary body of the NZW rabbit and in the retina / choroid. Figure 3 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the aqueous humor of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in New Zealand white rabbit vitreous humor. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the retina / choroid of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the iris / ciliary body of New Zealand White rabbits. 3 is a graph showing the effect of croscarmellose concentration on drug release for some exemplary BDI implants. 3 is a graph of in vitro release rate of an exemplary BDI implant. Data are presented as mean ± SD (n = 3). 3 is a graph of the in vitro release rate of another exemplary BDI implant. Data are presented as mean ± SD (n = 3). Figure 3 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the aqueous humor of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in New Zealand white rabbit vitreous humor. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the retina / choroid of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the iris / ciliary body of New Zealand White rabbits. FIG. 6 is a graph of retinal thickness versus time profile of an exemplary BDI implant and topical eye drop compared to a normal control. Figure 3 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the aqueous humor of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in New Zealand white rabbit vitreous humor. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the retina / choroid of New Zealand White rabbits. FIG. 6 is a graph of time versus concentration profile of an exemplary BDI implant and topical eye drops in the iris / ciliary body of New Zealand White rabbits. FIG. 6 is a graph of retinal thickness versus time profile of an exemplary BDI implant and topical eye drop compared to a normal control. These drawings depict only exemplary embodiments of the invention and are therefore not to be considered limiting of its scope. It will be readily appreciated that the components of the present invention may be arranged, sized, and designed in a wide variety of different configurations, as generally described herein and shown in the drawings.

  The following detailed description of exemplary embodiments of the invention refers to the accompanying drawings, which form a part of the specification and illustrate exemplary embodiments in which the invention can be practiced. Indicated as. Although these exemplary embodiments have been described in sufficient detail to enable those skilled in the art to practice the invention, other embodiments may be implemented and depart from the spirit and scope of the invention. It should be understood that various modifications can be made to the present invention without doing so. Accordingly, the following more detailed description of embodiments of the present invention is not intended to limit the scope of the invention as claimed, but for purposes of illustration only, and not limitation. It is presented in order to describe the features and characteristics of the invention, describe the best mode of operation of the invention and to fully enable those skilled in the art to practice the invention. Therefore, the scope of the present invention should be defined only by the appended claims.

  As used in this specification and the appended claims, the singular forms "a", "an", "the" include plural referents unless the context clearly dictates otherwise. It must be. Thus, for example, reference to "a drug" includes reference to one or more of such drugs, and "an excipient" refers to such excipients. "Filling," including reference to one or more of these, refers to one or more of such steps.

Definitions In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

  As used herein, "active agent," "bioactive agent," "pharmaceutically active agent," and "drug" are measurable when administered to a subject in a significant or effective amount. Can be used interchangeably to refer to a drug or substance that has a specified or selected physiological activity. These terms are well known in the pharmaceutical and medical arts.

  As used herein, "formulation" and "composition" may be used interchangeably herein and refer to a combination of two or more elements or substances. In some embodiments, the composition can include an active agent, excipient, or carrier to enhance delivery, depot formation, etc.

  As used herein, an "effective amount" refers to an amount of an ingredient that, when included in a composition, is sufficient to achieve its intended compositional or physiological effect. Accordingly, a "therapeutically effective amount" is a substantially non-toxic but sufficient amount of an active agent to achieve a therapeutic result that treats or prevents conditions for which the active agent is known to be effective. Refers to. It is understood that various biological factors can affect a substance's ability to perform its intended task. Thus, an "effective amount" or "therapeutically effective amount" may, in some cases, depend on such biological factor. Further, achievement of therapeutic effect can be measured by a physician or other qualified medical practitioner using assessments known in the art, although individual variations and responses to treatment are subjective to the achievement of therapeutic effect. It is recognized that it can be a judgment. However, the determination of effective amounts is well within the ordinary skill in the pharmaceutical and nutritional and medical arts.

  As used herein, "subject" refers to a mammal that can benefit from the administration or methods of the compositions listed herein. Examples of subjects include humans, and can also include other animals such as horses, pigs, cows, dogs, cats, rabbits, aquatic mammals.

  As used herein, the term “intraocular lens” refers to a lens utilized to replace the crystalline lens of the subject's eye. Such intraocular lenses can be synthetic or biological in nature. Moreover, in some aspects, the term "intraocular lens" can also refer to the original natural lens associated with the eye.

  As used herein, the term "ciliary groove" refers to the space between the dorsal root of the iris of the eye and the ciliary body.

  As used in the present invention, the term "substantially" refers to the complete or near-perfect extent or degree of an act, characteristic, property, condition, structure, item, or result. For example, an object that is "substantially" surrounded means that the object is completely surrounded or nearly completely surrounded. The exact acceptable degree of deviation from absolute completeness may depend, in some cases, on the particular context. However, generally speaking, closeness is to have the same overall result as if absolute and total perfection were obtained. The use of “substantially” is equally applicable when used in a negative sense to refer to the complete or near-total absence of an act, feature, characteristic, condition, structure, item, or result. is there. For example, a composition "substantially free" of particles may be completely devoid of particles, or nearly completely devoid of particles such that the associated effect is the same as if the composition were completely devoid of particles. Either. In other words, a composition “substantially free” of an ingredient or element may still actually contain such items, unless their measurable effect is present.

  As used herein, the term "about" refers to a numerical range endpoint by providing that a given value can be "slightly above" or "slightly below" the endpoint. Used to provide sex.

  As used in the present invention, a plurality of items, structural elements, components, and / or materials may be shown in a common list for convenience. However, these lists should be interpreted as if each element of the list was individually recognized as a separate and unique element. Thus, an individual element of such a list shall be construed as a de facto equivalent of any other element of the same list, solely on the basis of their presentation in a common group, with no indication to the contrary. Should not be done

  As used herein, the term "at least one of" is intended to be synonymous with "one or more." For example, “at least one of A, B, and C” explicitly includes only A, only B, only C, and combinations of each.

  Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that the form of such ranges is merely used for convenience and brevity and, therefore, does not merely include the numerical values explicitly recited as limiting the range, as if each numerical value and part The ranges should be flexibly construed to include all individual numerical values or subranges subsumed within that range as if explicitly stated. By way of example, a numerical range of "about 1 to about 5" is to be construed to include not only the explicitly recited values of about 1 to about 5 but also individual values and subranges within the indicated range. Should be. Thus, included in this numerical range are individual values such as 2, 3, and 4 and subranges such as 1-3, 2-4, and 3-5. This same principle applies to ranges enumerating only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.

  Any steps recited in a claim of any method or process may be performed in any order, and not limited to the order presented in the claims, unless explicitly stated otherwise. The means-plus-function or step-plus-function limitation refers to the limitation of the particular claim to all of the following conditions: a) "means for" or "step for" Will be used only if "(step for)" is explicitly listed, and b) the corresponding function is explicitly listed. The structure, material or operation supporting the means-plus-function is explicitly listed in the description herein. Therefore, the scope of the invention should be determined solely by the appended claims and their legal equivalents, rather than by the description and examples provided herein.

Intraocular Drug Delivery Devices Intraocular drug delivery devices provide multiple implants or complex eye drops by providing an implantable and biodegradable intracapsular reservoir so that subsequent surgery is often unnecessary. By reducing the need for drug regimens, improved ocular drug delivery can be provided. In addition, the device can deliver a variety of different agents, or combinations of different agents.

  Disclosed and described are novel intraocular drug delivery devices, systems, and related methods for providing sustained release of an ocular active agent over an extended period of time. One problem associated with many eye diseases such as age-related macular degeneration (AMD) is that the subject must undergo painful intraocular injection, which has a significant risk of retinal detachment, vitreous hemorrhage, and endophthalmitis. There is always sex. Intraocular drug delivery devices allow sustained release of the active agent over time, thus eliminating the need for frequent intraocular injections.

  It should be noted that angiogenesis is an important pathobiological process in various eye diseases such as AMD, proliferative diabetic retinopathy, vascular occlusive disease, and radiation retinopathy. In addition, the incidence of glaucoma is increasing worldwide. Many other diseases, including severe uveitis in AMD and geographic atrophy can be treated using such intraocular drug delivery devices. Thus, implantable and generally sutureless drug delivery devices for placement in the anterior segment of the eye have great potential for improving the quality of life of a subject.

  The drug delivery device can deliver dexamethasone or other anti-inflammatory or therapeutic agent continuously at a near zero order rate for two or more weeks. Treatment of uveitis requires long-term (6-8 weeks) sustained delivery of anti-inflammatory agents. The biggest drawback associated with topical eye drops is that negligible concentrations of the drug reach the posterior segment of the eye, especially the retina / choroid. Designed and disclosed drug delivery devices provide continuous delivery of dexamethasone and / or other therapeutic agents to both the anterior and posterior segments of the eye at near zero order rates, thus effectively controlling inflammation. You can

  Thus, there is an opportunity to improve the management of AMD, postoperative surgical inflammation, and uveitis patients undergoing cataract surgery by sustained release of pharmaceutically active agent (s). Accordingly, the present invention provides systems, devices, and related methods for delivery of active agents to the eye of a subject. In some examples, the systems, devices, and related methods can be positioned within the anterior segment of the subject's eye (eg, within the capsular bag) to deliver the active agent to the posterior segment of the subject's eye. Non-limiting examples of ocular regions found in the posterior segment of the eye can include at least one of the vitreous humor, choroid, and retina. In addition to delivering the active agent to the posterior segment of the eye, the active agent can also be delivered to the anterior segment of the eye. The anterior segment of the eye can include at least one of aqueous humor, iris, and capsular bag. In one aspect, the intraocular device can be sutureless. A sutureless device may be defined as a device or structure that can be inserted and retained within the capsular bag without the need for suturing to hold the device in place.

  More specifically, in some embodiments, the device is implantable within the capsular bag during cataract surgery, essentially "convening" cataract extraction, thus eliminating the need for additional surgical procedures. You can One advantage of "catching" cataract extraction is the ability to deliver steroids, antibiotics, and / or various non-steroidal agents directly to the eye after surgery, and thus complications such as cystic macular edema. Help to minimize. In other aspects, the device can be implanted in surgery that is separate from cataract treatment, eg, following a previous cataract extraction with reopening of the capsular bag. For example, the device may be macular degeneration, retinal vein or arterial occlusion, diabetic retinopathy, macular edema (eg from diabetes, uveitis, intraocular surgery, etc.), retinal degeneration when neuroprotective agent delivery is indicated. Can be implanted after cataract surgery for treatment such as.

  In one embodiment, the device may be provided in the form of an implant containing the active agent within a biodegradable or bioerodible polymer matrix. The biodegradable active agent matrix can include a therapeutically effective amount or an amount of an active agent that delivers a therapeutically effective dose of the active agent from the lens capsule to the posterior segment of the eye. The therapeutically effective amount or dose may vary depending on the particular therapeutic agent used in the biodegradable active agent matrix. In addition, the therapeutically effective amount or dose may vary depending on the severity of the condition being treated. Nevertheless, the active agent may be present in an amount that facilitates delivery of the active agent from the anterior segment of the eye (eg, the capsular bag) to the posterior segment of the eye.

  A therapeutically effective amount or dose may typically range from about 50 micrograms (mcg) to about 10 milligrams (mg), depending on the active agent used and the severity of the condition. In some particular examples, the therapeutically effective amount or therapeutically effective dose may range from about 50 mcg to about 600 mcg. In yet another example, a therapeutically effective amount or dose can range from about 100 mcg to about 400 mcg, about 100 mcg to about 300 mcg, or about 200 mcg to about 400 mcg. More specifically, the active agent is typically present in the implant at a concentration of about 5% to about 25%, or about 5% to about 15%, or about 10% to about 20%. Can exist in. Furthermore, depending on the dosage requirements, one, two, or more implants can be implanted in one eye to achieve a therapeutically effective dose.

  The biodegradable active agent matrix can be configured to bioerode to provide a therapeutically effective amount of controlled release over a period of days, weeks, or months. In some examples, the therapeutically effective amount may be released over a period ranging from about 1 week to about 10 weeks. In other examples, the therapeutically effective amount may be released over a period ranging from about 1 week to about 3 weeks, about 2 weeks to about 6 weeks, or about 5 weeks to about 8 weeks. In cases such as retinal vein / arterial occlusion, diabetic retinopathy, macular edema, or retinal degeneration, the time period can often range from 2 months to 12 months, and in some cases 2.5 months to 5 months. For example, bioerodible lipid polymers and / or bioerodible polycaprolactone can be used as the sustained release matrix material.

  Note that in addition to the amount of active agent present in the biodegradable active agent matrix, other additional factors can affect the delivery of the active agent to the posterior segment of the eye. For example, intracapsular positioning of the device within the capsular bag can affect delivery of the active agent to the posterior segment of the eye. In some instances, positioning the implant at a location below and around the intraocular lens (IOL) or within the capsule around the lower periphery can provide suitable delivery of the active agent to the posterior segment of the eye. .. Typically, the implant may also be located in the lower portion of the capsular bag. For example, the implant may be oriented in the lower perimeter surrounding the intraocular lens, such as at least 180 degrees, the annular perimeter, as long as the line of sight is not obstructed.

  Further, the molecular weight and size of the active agent can affect the delivery of the active agent to the posterior segment of the eye. Thus, in some examples, the active agent can have a molecular weight of 250,000 Daltons (Da) or less. In yet another example, the activator can have a molecular weight of 170,000 Da or less. In yet a further example, the activator can have a molecular weight of 500 Da or less.

  Various eye conditions such as AMD (neovascular or atrophic), glaucoma, diabetic retinopathy, retinopathy of prematurity, uveitis, corneal transplant rejection, cystic fibrosis, posterior capsule opacification, retinal vein occlusion, infection Many active agents are known for the treatment or prevention of. Any suitable active agent for incorporation into the biodegradable active agent matrix, such as steroids, NSAIDs, antibiotics, anti-VEGF agents, PDGF-B inhibitors (Fovista®), integrin antagonists, complement antagonists, etc. , Or a combination of these may be used. Non-limiting examples of suitable active agents include dexamethasone, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis®), sunitinib, pegaptanib (Macugen®), moxifloxacin. , Gatifloxicin, besifloxacin, timolol, latanoprost, brimonidine, nepafenac, bromfenac, diclofenac, ketorolac, triamcinolone, difluprednate, fluocinolide, aflibercept, etc., or combinations thereof. The treatment plan can further include various photodynamic therapies and the like. In one particular example, the active agent can include dexamethasone.

  The bioerodible polymer matrix can include one or several excipients that can depend on the duration of active agent delivery. Non-limiting examples of activator matrix materials can include polymeric and non-polymeric materials. Specific non-limiting examples of suitable matrix materials include PLGA (different ratios of lactic acid to glycolide content and end groups such as acid or ester ends), PVA, PEG, PLA, PGA, hydroxypropylcellulose, sodium carboxymethylcellulose. , Croscarmellose sodium, polycaprolactone, hyaluronic acid, albumin, and biodegradable polymers such as sodium chloride block copolymers thereof. Specific copolymers such as polylactic acid-polyglycolic acid block copolymer (PLGA), polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropylmethyl cellulose (HPMC), polycaprolactone-polyethylene glycol block copolymer, and croscarmellose. Can be particularly effective. In one aspect, the active agent matrix comprises about 45-80% PLA and 55-20% PGA, such as about 65% PLA and 35% PGA, in some cases about 50% PLA and 50%. It may be a PLGA with PGA. In another alternative embodiment, the weight ratio of PLGA, dexamethasone and crocarmellose sodium is even 60-90 / 5-25 / 5-5-25 or 50-75 / 10-40 / 10-40. Good. In another aspect, the biodegradable active agent matrix comprises low melting point fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, capric acid, oleic acid, palmitoleic acid, and mixtures thereof. In one aspect, the biodegradable active agent matrix can include a pharmaceutically acceptable disintegrant. In one example, the disintegrant may be a super disintegrant. Non-limiting examples of suitable disintegrants include cross-linked cellulose (eg, croscarmellose, Ac-Di-Sol, NYMCE ZSX, PRIMELLOSE, SOLUTAB, VIVASOL), microcrystalline cellulose, alginate, cross-linked PVP (eg, CROSSPOVIDONE). , KOLIDON, POLYPLASDONE), crosslinked starch, soybean polysaccharide, calcium silicate, salts thereof and the like.

  Typically, the delivery devices herein can target relatively short delivery durations, such as less than 8 weeks. In some examples, the active agent has a delivery duration of about 2 weeks to about 6 weeks. The delivery duration can be a function of the type of polymer used in the matrix, the copolymer ratio, and other factors. Particularly suitable polymers are poly (lactic-co-glycolide), hydroxypropylmethylcellulose, hydroxylmethylcellulose, polyglycolide-polyvinylalcohol, cloth, although other biodegradable polymers such as those already listed may be suitable. At least one of carmellose, polycaprolactone, eudragit L100, eudragit RS100, poly (ethylene glycol) 4000, poly (ethylene glycol) 8000, and poly (ethylene glycol) 20,000 may be mentioned. In one example, the biodegradable active agent matrix can include poly (lactic-co-glycolide) having a copolymer ratio of 10/90 to 90/10, and in another case 52/48 to 90/10. In one particular aspect, the copolymer ratio may be about 50/50. In another specific example, the copolymer ratio may be 52-78 / 48-22, and in another specific example 60-90 / 40-10. Degradation rates may depend on such rates, but additional alternative approaches such as device coating, particle encapsulation, etc. may also be useful.

  Homogeneous delivery devices can be formed, for example, by mixing a polymeric material with a loading amount of active agent to form a matrix dispersion. The loading dose may be selected to correspond to the desired dose during spreading. The loading can take into account diffusion properties of the polymer and active agent, residual active agent, delivery time, and the like. The matrix dispersion can then be formed into device shapes using any suitable technique. For example, the matrix dispersion can be cast, sprayed and dried, extruded, stamped and the like. Such configurations are most often formed using a biodegradable matrix, although non-biodegradable materials can also be used. In one alternative formulation, the device may be formed in situ from a suspension of the active agent in a biodegradable polymer matrix precursor. When delivered to the target site, the biodegradable polymer matrix precursor can form a biodegradable active agent matrix in situ (via precipitation and / or polymerization).

  The homogeneous delivery device described above may provide certain efficacy for the treatment of uveitis and post-operative cataract surgery inflammation. For example, dexamethasone can be dispersed within the biodegradable active agent matrix. Dexamethasone doses may vary, but generally about 100 mcg to about 400 mcg may be effective for these indications. More specifically, due to various factors such as age, secondary complications, pre-existing conditions, some patients may be classified as low risk, while others may be classified as high risk. In most cases, low risk patients can benefit from low doses of about 100 mcg to about 150 mcg. In contrast, high risk individuals may be administered high doses of about 250 mcg to about 350 mcg. Some biodegradable implants can be specifically designed and tested for the treatment of post-operative surgical inflammation and can deliver pharmaceutically active agents for up to about 2 weeks or longer. Still other biodegradable implants can be designed and tested for the treatment of post-operative surgical inflammation and uveitis and can deliver active agents up to about 6-8 weeks or longer. Furthermore, depending on the severity of the inflammation, one, two or more implants may be implanted in the eye during surgery.

  The active agent delivery device can optionally include additional active agents or other desired therapeutically beneficial substances. In one aspect, for example, the device can include at least one secondary active agent. If the active agent delivery device comprises more than one active agent, the active agent matrix may be homogeneous or heterogeneous. In some examples, the active agent delivery device can include multiple active agents and can be homogeneous. In some examples, the active agent delivery device can include multiple active agents and can be heterogeneous. For example, one active agent can be coated on the surface of the implant. In yet another example, implants can be formulated to have pre-specified areas or layers that include different active agents. In yet another example, implants can be formulated to have pre-specified areas or layers with the same active agent but at different concentrations. For example, in some cases, the outer region or layer of the implant has a higher concentration of active agent, with a higher initial dose or burst of active agent followed by a lower dose of long-term over a period of days or weeks. Can be delivered. Further, in some examples, different regions of the implant may be adapted to biodegrade at different rates. In yet another example, the agent can optionally be coated on the implant to reduce the incidence of capsule fibrosis. Non-limiting examples of such agents include anti-cell proliferative agents, anti-TGF-beta agents, a5b1 integrin antagonists, rapamycin and the like.

  The ocular active agent delivery device may be configured to fit within the lens capsule or ciliary groove of the eye. The delivery device can be shaped into any shape that allows for insertion into the capsular bag or ciliary groove. For example, the implant can be round, square, crescent-shaped, or donut-shaped. However, other suitable shapes can include, but are not limited to, disks, pellets, rods, and the like. Dimensions may vary, but typical dimensions may range from a width of about 0.5 mm to about 4 mm and a thickness of about 0.2 mm to about 1 mm. The total mass of the delivery device can vary, but in most cases the total mass can be 0.2 mg to 4 mg, or about 1.5 mg to about 2.5 mg. For example, a total mass of about 2 mg can provide an effective active agent volume while balancing the overall size to fit within the target tissue area.

  In some particular examples, the implant may be shaped as a disc or pellet. In this case, the implant typically has a diameter in the range of about 0.4 millimeters (mm) to about 3 mm, about 0.5 mm to about 1.5 mm, or about 0.7 mm to about 1.3 mm. You can Further, in some examples, disc or pellet shaped implants typically have a size of about 0.2 mm to about 2 mm, about 0.8 mm to about 1.5 mm, or about 0.3 mm to about 1.0 mm. It can have a range of thicknesses. An example of pellets or disks is shown in FIG. 1 and has a diameter of about 2-2.5 mm and a thickness of about 1.0-1.5 mm. In one particular example, the implant can have a circular edge, hemispherical, or semi-circular shape.

  In yet another particular example, the implant may be shaped as a rod. In this case, the implant can typically have a diameter in the range of about 0.05 mm to about 2 mm, about 0.1 mm to about 1.0 mm, or about 0.2 mm to about 0.8 mm. Further, in some examples, rod-shaped implants typically range from about 0.5 mm to about 5 mm, about 1.0 mm to about 3.0 mm, or about 1.5 mm to about 2.5 mm. It can have a length.

  Yet another aspect of the invention provides a method of delivering an active agent to the eye of a subject. When considering various examples and embodiments of the implantable devices, systems, and methods described herein, each of these respective considerations also apply to each of the other aspects of the invention. Note that you get. Thus, for example, when considering the implantable device itself, this consideration is also relevant to the methods discussed herein and vice versa.

  With this in mind, in some specific examples, methods place a biodegradable active agent matrix described herein within the capsular bag of a subject to deliver the active agent to the posterior segment of the eye. Can be included. The biodegradable active agent matrix can include an amount of active agent that delivers a therapeutically effective dose of the active agent from the lens capsule to the posterior segment of the eye.

  In some examples, the method can include performing cataract removal surgery on the subject's eye, removing an existing lens from the subject's eye, and inserting an intraocular lens into the subject's eye. And placing a biodegradable active agent matrix within the capsular bag. In some examples, the biodegradable active agent matrix or implant can be associated with an intraocular lens. In this case, the delivery device may be attached to or removed from the intraocular lens. The delivery device may be associated by actual contact or sufficient proximity while allowing effective diffusion of the active agent to the target area of the eye. Biodegradable systems have been used in routine cataract surgery to provide short-term / limited-time delivery of post-operative drugs while minimizing or eliminating the need for eye drop use by patients. Can have real value. The lens that is removed may be the natural lens of the eye, or it may have been previously inserted into the eye as a result of a previous procedure.

  Many ways of placing the device in the eye are envisioned. For example, in one aspect, the implant can be associated with the intraocular lens prior to inserting the intraocular lens into the eye. In such cases, it may be necessary to configure the implant to suit any requirements of the surgical procedure. For example, cataract surgery is often performed through a small incision. One standard size incision is about 2.75 mm, but the device may be compatible with smaller or larger incision sizes. Thus, the intraocular lens assembly can be shaped to allow insertion through this small opening. Thus, the active agent delivery device may also be configured to be inserted into the intraocular lens assembly, for example, depending on the resilient and flexible material shape and / or choice of the implant. In addition, the active agent delivery device may also be physically attached or detached from the intraocular lens assembly prior to insertion of the assembly into the eye. In another aspect, after insertion of the lens into the eye, the implant can be positioned within the capsular bag and optionally associated with the intraocular lens assembly. The capsular bag can be easily re-incised for patients with previous cataract surgery. Thus, the insertion of the delivery device can be performed immediately before the insertion of the intraocular lens or later as a separate procedure.

Example 1:
Standard clear corneal lens emulsification (Acrysof SA60AT; Alcon) implantation using an intraocular lens was performed on 35 rabbits. At the time of each surgery, an intraocular device containing the active agent was inserted into the capsular bag of each rabbit. Rabbits were divided into 4 groups depending on the active agent in the intraocular device. The device was loaded with 5-15 mg of either Avastin, Timolol, Brimonidine, or Latanoprost. Each group was evaluated to determine intraocular device and lens stability, cystic fibrosis, and cataract wound and anterior segment healing. Subgroups of eyes were evaluated weekly for inflammation for 4 weeks and harvested at month 1 for histopathological assessment of pouch and CDR integrity.

Example 2:
The surgery and setting described in Example 1 was repeated except that aqueous humor and vitreous humor collections were performed biweekly and assayed for drug concentration using HPLC and / or ELISA. In each drug group, half of both eyes were taken at 1 month and the other half at 2 months. This was accomplished as follows: Rabbits were sacrificed and the eyes were frozen immediately after removal of the eyes in liquid nitrogen to prevent drug perturbation and redistribution within ocular tissues. The eyes were then dissected into three parts (aqueous humor, vitreous, and retina / choroid layer) to assess anatomical toxicity and tissue drug concentration. The intraocular device was retrieved and evaluated for residual drug content. The distribution profile of the intraocular device was compared to a conventional intravitreal injection of 2.5 mg / 0.1 cc Avastin® for direct comparison of different delivery methods.

  At 2 and 4 months, the eyes from the remaining subgroup of rabbits were removed, fixed in 10% formalin, embedded in paraffin, stepwise dissected, stained with hematoxylin and eosin (H & E), Were inspected for changes in physiology.

Example 3:
After lens extraction, three intraocular devices were implanted into the eyes of New Zealand white rabbits under general anesthesia (lens emulsification technique). Two of the devices were loaded with Avastin and one was loaded with the contrast agent Galbumin as a control. The location of the proper intraocular device was verified by MRI and clinical examination.

  Rabbits were sacrificed, eyes were removed and assayed 1 week after implantation. Avastin was detected in the retina and intravitreous by ELISA at concentrations of 24-48 mcg / mL and was absent in control rabbit eyes. Figure 5 shows the amount of Avastin assayed per ocular area 1 week after implantation.

Example 4:
PLGA [poly (d, l-lactide-co-glycolide), MW 7000-17000, to confirm placement of the implant within the capsular bag and delivery of the drug both before and after the eye for short and long periods. , Acid-terminated], hydroxypropylmethylcellulose (HPMC), and dexamethasone were used to prepare microparticles. PLGA microspheres loaded with dexamethasone were prepared using standard oil-in-water (o / w) emulsion-solvent extraction method. An amount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mL acetonitrile. An amount of 40 mg dexamethasone and 10 mg HPMC was dispersed in the PLGA solution by vortexing for 5 minutes. The organic phase was then emulsified and homogenized in 20 mL of a 2% (w / v) PVA (MW 90 kDa) solution. The resulting emulsion was poured into 200 mL of 2.0% (w / v) PVA (MW 90 kDa) solution and stirred for 6 minutes in an ice bath. The contents were stirred at room temperature for 8 hours and the dichloromethane and acetonitrile were evaporated to form a cloudy microparticle suspension. Microparticles were separated by centrifugation, washed twice, resuspended in deionized water and lyophilized to give lyophilized particles. The prepared microparticles were characterized and pelletized using a benchtop pellet press equipped with a 2 mm die set to form implants.

  These implants were sterilized and implanted in the lens capsule of rabbit eyes. Two dose groups were used (300 and 600 μg) and 2 rabbits were sacrificed at 1, 2, 4, 6 weeks from each of the low and high dose groups and various tissue samples (aqueous humor, glass Body fluids, IOLs, iris / ciliary body, and retina / choroid) were collected and samples were analyzed by the validated LC / MS / MS method. Microspheres were in the range of 6 ± 2 μM as confirmed by Zetasizer nano and SEM micrographs. The drug loading in the microparticles was over 99% and the final yield was 60% (ie encapsulation efficiency). The drug load was determined as drug load rate = (weight of drug loaded / weight of microspheres) × 100. Dose-related pharmacokinetics with near zero order kinetics were observed in rabbits for up to 6 weeks. Furthermore, dexamethasone flow was bidirectional from the intracapsular space to both the anterior and posterior chambers. There were no cells or fibrin formation in the anterior and posterior chambers of the eye. Histological examination revealed that all tissues examined were normal and showed no signs of inflammation.

  Once all study animals were isolated and randomized, they were acclimated to laboratory conditions. All positive control and implant groups received lens emulsification and intraocular lens (IOL) insertion in both eyes. Groups III and IV received one and two implants per eye, respectively.

Group I: normal control group; n = 6
Group II: lens emulsification and IOL insertion; DXM eye drops (tapering up to 4 weeks) and antibiotic eye drops (up to 2 days); positive control group; n = 6
Group III: lens emulsification and IOL insertion; BDI implant low dose (1 implant per eye) and antibiotic eye drops, up to 2 days post surgery (twice daily); n = 8.
Group IV: lens emulsification and IOL insertion; BDI implant high dose (2 implants per eye) and antibiotic eye drops, up to 2 days post surgery (2 times daily), n = 8.

  The in vitro release rate results are shown in FIG. All batches exhibited a biphasic release pattern with an initial burst release on day 1 followed by a slow and sustained release. The burst effect was slightly higher with implants containing HPMC.

  A total of 16 animals (32 eyes) received the implant. Dexamethasone concentrations are presented in Figures 11-14. The implant slowly disintegrated over 4 weeks and completely disappeared at 6 weeks. Therapeutic concentrations of DXM were found with minimal systemic exposure up to week 6 (<40 ng / mL at high doses), whereas dexamethasone eye drops had higher systemic exposure (150 ng during week 1). / ML). Mean PK parameters for BDI-2 implants and positive control groups in aqueous humor, vitreous humor, retina / choroid, and iris / ciliary body are shown in Tables 1 and 2.

  Intraocular pressure was normal in all groups. Furthermore, there were no signs of anterior or posterior chamber inflammation as assessed by slit-lamp biomicroscopy and confirmed by histological examination. Implants maintained retinal thickness while there was a trend towards increased retinal thickness in animals treated with dexamethasone eye drops.

  PLGA polymers decompose through hydrolysis to lactic acid and glycolic acid, which then decomposes further into carbon dioxide and water before removal from the body. The implant did not move to the center and obstruct the visual field.

  BDI-1 implants were prepared according to the partial solvent casting method, followed by evaporation and removal of residual solvent by drying the product under high vacuum for 3 days. PLGA [poly (d, l-lactide-co-glycolide), molecular weight 7,000 to 17,000, acid end], hydroxypropylmethylcellulose (HPMC), croscarmellose sodium (crosslinked sodium carboxymethylcellulose), hydroxypropylcellulose, and dexamethasone Various implants were prepared for use in several different compositions.

  The dried particles were directly pelletized using a benchtop pellet press equipped with a 2 mm die set to form implants.

  Selected BDI-1 implants (from an in vitro release study, FIG. 7) were sterilized and implanted within the capsular bag of rabbit eyes. Two implants with different compositions and doses were tested in vivo in NZW rabbits to establish pharmacokinetics. Two rabbits were sacrificed on days 2, 6, 10 and 15 and various tissue samples (aqueous humor, vitreous humor, IOL, iris / ciliary body, and retina / choroid) were collected and a valid LC / The sample was analyzed by the MS / MS method. Pharmacokinetics with near zero order kinetics were observed in rabbits for up to 15 weeks. Furthermore, dexamethasone flow was bidirectional from the intracapsular space to both the anterior and posterior chambers. There were no cells or fibrin formation in the anterior and posterior chambers of the eye. Histological examination revealed that all tissues examined were normal and showed no signs of inflammation.

  The in vitro release rate results are shown in FIG. All batches exhibited a smooth release pattern on day 1 with an initial burst release, followed by a slow and sustained release. The burst effect was slightly higher with implants containing HPMC.

  A total of 8 animals (16 eyes) received implants containing 120 μg DXM. DXM concentrations are presented in Figures 8 and 9. Implants slowly erode over 10 days and reach trough levels of DXM by day 15. The implant is expected to have 80% of its mass degraded by 15 days and fully degraded by 20 days. Therapeutic concentrations of DXM were found with minimal systemic exposure up to day 15 (<23 ng / mL), whereas dexamethasone eye drops had higher systemic exposure (> 150 ng / mL during week 1). , Company data).

Example 5:
A number of biodegradable implants were prepared with PLGA, croscarmellose sodium, and dexamethasone according to Table 3 below.

  The drug release profile of each of the listed formulations was obtained using an in vitro drug release model. Individual drug release profiles are presented in FIG. As shown in FIG. 10, increasing the amount of croscarmellose can enhance the rate of drug release from the biodegradable implant as compared to the biodegradable implant prepared with PLGA alone.

Example 6:
Two biodegradable dexamethasone implants (BDI) were prepared using different formulations including PLGA, croscarmellose, and dexamethasone. The first BDI was configured to deliver 200 mcg dexamethasone over a 2 week period. The second BDI was configured to deliver 300 mcg dexamethasone over a 6 week period. The drug release profile was evaluated using an in vitro drug release model. Release profiles for the first and second BDIs are shown in Figures 11 and 12, respectively.

  In addition, these implants were sterilized and implanted in the lens capsule of rabbit eyes. The implant slowly degraded over the course of the weeks until it completely disappeared. Mean PK parameters for the first BDI implant and positive control groups in aqueous humor, vitreous humor, retina / choroid, and iris / ciliary body are shown in Tables 4 and 5.

  Dexamethasone concentration profiles for each of the ocular regions are presented in Figures 13-16. In addition, the retinal thickness of each of the test subjects was measured over time and compared to the retinal thickness of the test subject treated with the topical formulation and the control subject with normal retinal thickness. These results are shown in FIG. As shown in Figure 17, a therapeutically effective dose can reduce retinal thickening associated with ocular conditions as compared to retinal thickening without treatment or as compared to treatment with topical formulations.

  The mean PK parameters of the second BDI implant in the aqueous humor, vitreous humor, retina / choroid, and iris / ciliary body and the positive control group are shown in Tables 6 and 7.

  Dexamethasone concentration profiles for each of the eye regions are presented in Figures 18-21. In addition, the retinal thickness of each of the test subjects was measured over time and compared to the retinal thickness of the test subject treated with the topical formulation and the control subject with normal retinal thickness. These results are shown in FIG. As shown in FIG. 22, a therapeutically effective dose can reduce retinal thickening associated with ocular conditions as compared to retinal thickening without treatment or as compared to treatment with topical formulations.

  It should be understood that the above configurations are merely illustrative of the application of the principles of the invention. Many modifications and alternative constructions can be devised by those skilled in the art without departing from the spirit and scope of the invention. Thus, although the present invention has been described above with particularity and detail in connection with what is presently considered to be the most practical and preferred embodiments of the invention, size, material, shape, form, function, and operation. It will be apparent to those skilled in the art that numerous modifications, including but not limited to modalities, assemblies and uses, can be made without departing from the principles and concepts described herein.

Post-operative cataract surgery inflammation can be well controlled by improving patient compliance. Available literature and experience indicate that drug penetration is poor after topical administration, and higher systemic concentrations mean frequent systemic adverse events. All of these factors underscore the need for sustained intraocular delivery of the pharmaceutically active agent to effectively control inflammation.
Prior art document information relating to the invention of this application includes the following (including documents cited at the international stage after the international application date and documents cited upon domestic transfer to another country).
(Prior art document)
(Patent document)
(Patent Document 1) US Patent Application Publication No. 2011/0230963
(Patent Document 2) International Publication No. 1995/017900
(Patent Document 3) US Patent Application Publication No. 2013/0302398
(Patent Document 4) US Pat. No. 8,663,194
(Non-patent document)
(Non-patent document 1) Normal Polymers, "Normal", 31 January 2016 (31.01.2016), retried on 23 February 2018 from https: // web. archive. org / web / 201601311164109 / http: // normalpolymer. com / poly-DL-lactide-co-glycolide. php; entire document, specifically pg 1 para 2
(Non-patent document 2) EyeWiki, "Cystoid Macular Edema", 26 January 2014 (26.01.2014), retrieved on 25 February 2018 from https: // web. archive. org / web / 201401260773222 / http: //eyewiki.org. aaa. org / Cystoid_Macular_Edema; entire document, especially pg 1 para 1

Claims (25)

A method of delivering an active agent to the posterior segment of a subject's eye, comprising:
Disposing a biodegradable active agent matrix within the capsular bag of the subject and delivering the active agent to the posterior segment of the eye, wherein the disposing step comprises disposing the biodegradable active agent matrix at the lens capsule. A biodegradable active agent matrix to deliver a therapeutically effective dose of the active agent from the lens capsule to the posterior segment of the eye. Including the method.   The method of claim 1, wherein placing the biodegradable active agent matrix within the capsular bag is performed during cataract surgery of the eye of the subject.   2. The method of claim 1, wherein placing further comprises placing the biodegradable active agent matrix within the lower peripheral sac.   The method of claim 1, wherein the posterior segment of the eye comprises at least one of vitreous humor, choroid, and retina.   The biodegradable active agent matrix is poly (lactic acid-co-glycolide), polylactic acid-polyglycolic acid block copolymer (PLGA), hydroxypropylmethyl cellulose, hydroxylmethyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropyl. 2. The composition of claim 1, comprising at least one of cellulose, sodium carboxymethyl cellulose, polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropylmethyl cellulose (HPMC), and polycaprolactone-polyethylene glycol block copolymer. Method.   The biodegradable active agent matrix comprises a low melting point fatty acid selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, capric acid, oleic acid, palmitoleic acid, and mixtures thereof. The method of claim 1.   The method of claim 1, wherein the biodegradable active agent matrix comprises poly (lactic acid-co-glycolide) having a copolymer ratio of 52/48 to 90/10.   The method of claim 1, wherein the biodegradable active agent matrix comprises poly (lactic acid-co-glycolide) having a copolymer ratio of about 50/50.   The method of claim 1, wherein the biodegradable active agent matrix comprises a disintegrant.   The method according to claim 9, wherein the disintegrant is croscarmellose or a salt thereof.   The method of claim 1, wherein the biodegradable active agent matrix is shaped as a disk, rod, or pellet.   9. The method of claim 8, wherein the disc or pellet has a diameter in the range of about 0.4 mm to about 3 mm, and a thickness in the range of about 0.2 mm to about 2 mm.   The method of claim 1, wherein the biodegradable active agent matrix is shaped as a rod.   11. The method of claim 10, wherein the rod has a diameter in the range of about 0.05 mm to about 2 mm and a length in the range of about 0.5 mm to about 5 mm.   The active agent is dexamethasone, prednisolone, bevacizumab, ranibizumab, sunitinib, pegaptanib, moxifloxacin, gatifloxicin, besifloxacin, timolol, latanoprost, brimonidine, nepafenac, blomfenac, diclofenorfuronoc, pretracone, ketorolac, pretazol, ketorax, pretnazol, pretnizolone, pefaptanib, bromfenac, diclofenorfuronoc, ketorolac, pretazolone. The method of claim 1, wherein the element is selected from the group consisting of aflibercept and combinations thereof.   2. The method of claim 1, wherein the active agent is one or more of dexamethasone, moxifloxacin, ketorolac, or bromfenac.   The method of claim 1, wherein the activator has a molecular weight of 250,000 Daltons (Da) or less.   The method of claim 1, wherein the activator has a molecular weight of 500 Da or less.   The method of claim 1, wherein the active agent is present in the biodegradable active agent matrix in an amount of about 100 mcg to about 400 mcg.   The method of claim 1, wherein the active agent is present in the biodegradable active agent matrix in an amount of about 5% to about 25% by weight.   2. The method of claim 1, wherein the active agent has a delivery duration that ranges from about 2 weeks to about 6 weeks.   The method of claim 1, wherein the active agent has a delivery duration ranging from 2 months to 12 months.   The method of claim 1, wherein a therapeutically effective dose of the active agent is also delivered to the anterior segment of the eye.   18. The method of claim 17, wherein the anterior segment comprises at least one of aqueous humor and iris.   The method of claim 1, wherein the therapeutically effective dose reduces retinal thickening associated with an ocular condition as compared to retinal thickening without treatment.

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