JP2015074641A - Intraocular drug delivery device and accompanying method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an administration of a suspension to continuously delivery active agent into the eyeball by being inserted into the lens capsule or ciliary sulcus of the eyeball in a cataract surgery or the treatment of uveitis, or to provide a device formed into a disk or pellet form, and to provide a system and a method.SOLUTION: The invention provides a biodegradative active agent matrix, for example, a suspension of an intraocular active agent containing an active agent (e.g., dexamethasone) dispersed into a polymer such as poly (lactic acid-co-glycolide), or a delivery device formed into a disk or a pellet form.

Description

  The present invention relates to systems, methods and devices for continuous and targeted (local) delivery of a pharmaceutically active agent into a subject's eye. The present invention therefore relates to the fields of polymer chemistry, material science, polymer science, drug delivery, formulation science, pharmacy and medicine, especially ophthalmology.

  Age-related macular degeneration (AMD) and glaucoma are two leading causes of blindness in the United States and worldwide. Current glaucoma treatments often prescribe several topical medications that must be applied to the eye at varying frequencies, sometimes requiring up to 3 or 4 multidrugs per day And These regimens are often difficult for subjects to follow consistently, and many patients progress to conditions that require surgical treatment, such as intraocular shunting or trabeculectomy, and severe Has serious accompanying complications.

  Subjects with macular degeneration are often required to receive intravitreal injections monthly. Such injections are painful and can cause retinal detachment, endophthalmitis and other complications. Furthermore, these injections are performed only by a few retinal surgeons, an ophthalmic group, resulting in increased costs and bottlenecks in the treatment of the eye.

  Post-operative surgical inflammation is associated with increased intraocular pressure (IOP) and increases the likelihood of cystoid tissue macular edema (CME), adhesion formation, posterior capsule opacification (PCO) and secondary glaucoma. Patient compliance is important in the treatment of post-operative inflammation because multiple eye drops need to be instilled multiple times per day in treatments over several weeks. The lack of adherence to medication impairs the efficacy of topical drugs, which are further limited by corneal absorption and have very diverse intraocular concentrations during the course of treatment. Uveitis refers specifically to inflammation of the middle layer of the eyeball, referred to as “uvea”, but in common usage refers to any inflammatory process that affects the interior of the eyeball. Uveitis is estimated to cause about 10% of blindness in the United States.

  Postoperative cataract surgery inflammation can be well controlled by improving patient compliance. Drug permeation after local administration shown by available literature and experience gained is inadequate, and higher systemic concentrations imply frequent systemic adverse events. All these factors emphasize the need for sustained intraocular delivery of pharmaceutically active agents that effectively reduce inflammation.

  Devices, systems and methods for delivery of an active agent to a subject's eye can include an intraocular active agent delivery device comprising an active agent dispersed within a biodegradable active agent matrix. .

FIG. 1 is a top view of an active agent delivery device in the form of a disc. FIG. 2 is a side view of an active agent delivery device in the form of a disc. FIG. 3 is a graphical representation of the amount of active agent present in various ocular tissues after implantation of an intraocular device according to a further aspect of the present invention. FIG. 4 is a photograph showing a biodegradable dexamethasone graft (BDI). FIG. 5 is a graph of in vitro release kinetics of BDI-1 implantation. Data are shown as mean ± SD (n = 3). FIG. 6 is the time versus concentration profile for BDI-1 transplantation with 120-160 μg of dexamethasone (DXM) in aqueous humor and vitreous humor of New Zealand white rabbits (NZW). FIG. 7 is the time versus concentration profile for BDI-1 implantation with 120-160 μg of DXM in the iris / ciliary body and retina / choroid of NZW rabbits. FIG. 8 is a graph of the in vitro release kinetics of dexamethasone from a BDI-2 graft (containing 300 μg DXM). Data are presented as mean ± SD (n = 3) [Formulation A: PLGA 50:50, M.P. W. 7,000-17000, Formulation B: PLGA 65:35, M.M. W. 17000-32000, Formulation C: PLGA 50:50, M.I. W. 7,000-17000 (50%), PLGA 65:35, M.M. W. 17000-32000 (50%), formulation D: PLGA 50:50, M.M with 10% hydroxypropyl methylcellulose (HPMC). W. 7,000-17000]. FIG. 9 is a graph of time versus BDI-2 transplantation and topical eye drop concentration profile in aqueous humor of New Zealand white rabbits. FIG. 10 is a graph of time versus concentration profile of BDI-2 transplantation and topical eye drops in vitreous humor of New Zealand white rabbits. FIG. 11 is a graph of time versus concentration profile of BDI-2 transplantation and topical eye drops in New Zealand white rabbit retina / choroid. FIG. 12 is a graph of time versus corneal thickness of New Zealand white rabbits in four groups, standard control, topical eye drops, BDI and normal control.

  These drawings are merely representative of exemplary embodiments of the present invention and therefore should not be considered as limiting its scope. It will be readily appreciated that the components of the present invention can be arranged, sized and designed in a wide variety of different structures, as described and illustrated herein.

  The following detailed description of illustrative embodiments of the present invention will be made with reference to the accompanying drawings, which form a part hereof, and are illustrative of the ways in which the present invention may be practiced. An embodiment is shown. Although these illustrative embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, other embodiments may be recognized and various modifications of the invention may be made. It should be understood that it may be made without departing from the spirit and scope of the present invention. Accordingly, the following more detailed description of embodiments of the invention is not intended to limit the scope of the invention as claimed, but describes the best mode of operation of the invention. However, in order to fully enable one of ordinary skill in the art to practice the invention, the described features and characteristics of the invention are not limited and are presented for illustrative purposes only. Accordingly, the scope of the invention is defined only by the appended claims.

  As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. You have to be careful. Thus, for example, reference to “a drug” includes reference to one or more of such drugs, and reference to “excipient” includes reference to one or more of such excipients. “Filling” 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 below.

  As used herein, “active agent”, “bioactive agent”, “pharmaceutically active agent”, and “drug” are measurable specifics when administered to a subject in significant or effective amounts. May be used interchangeably to refer to drugs or substances having a physiological activity or selected physiological activity. These terms are well known in the pharmaceutical and medical fields.

  As used herein, “biodegradable” and “biodegradable” can be degraded over time in the body of a target organism, particularly in the lens capsule or ciliary groove of the subject's eyeball. May be used interchangeably to refer to new materials. The biodegradable material may be a solid matrix that dissolves slowly, releasing any active agent incorporated into the biodegradable material. Ultimately, the biodegradable graft can be completely dissolved so that the graft does not need to be removed from the subject.

  As used herein, “formulation” and “composition” may be used interchangeably herein and may 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 the active agent, delivery, depot formation, etc.

  As used herein, “subject” refers to a mammal that may benefit from the performance of a composition or method, as referred to herein. Examples of subjects include humans, and can include other animals such as horses, pigs, cows, dogs, cats, rabbits, aquatic mammals, and the like.

  As used herein, the terms “reservoir” and “active agent reservoir” may be used interchangeably and may refer to an object, mass, or cavity that can contain an active agent. Thus, the reservoir can include any structure that may contain a liquid, gelatin, sponge, semi-solid, solid, or other form of active agent that is well known to those skilled in the art. In some embodiments, the reservoir can also include an active agent matrix. Such matrices are well known in the art. A reservoir does not necessarily have a physical structure that encloses another material within itself. In some cases, the reservoir can simply be a specific amount of active agent matrix without any exterior containing the structure.

  As used herein, the term “intraocular lens” refers to a lens that is utilized to replace a crystalline lens with a subject's eyeball. Such intraocular lenses may be synthetic or biological in nature. Further, in some embodiments, the term “intraocular lens” can also refer to the original natural lens that was associated with the eyeball.

  As used herein, the term “ciliary groove” refers to the gap between the dorsal root of the iris and the ciliary body of the eye.

  As used herein, the term “substantially” refers to a complete or nearly complete range or degree of an action, feature, property, state, structure, matter or result. For example, an object that is “substantially” enclosed means that the object is completely enclosed or almost completely enclosed. The exact allowable deviation from absolute completeness may in some cases depend on the specific situation. However, generally speaking, a state close to completeness is to have the same overall results as if absolute and overall integrity were obtained. Use of the term “substantially” is used in a negative sense to refer to whether an action, feature, property, state, structure, matter or result is complete or almost completely lacking The case is equally applicable. For example, a composition that is “substantially free of particles” is either completely devoid of particles or almost completely as if it were completely devoid of particles and the associated effects were the same. Is lacking. In other words, a composition that is “substantially free” of a component or element may actually contain such an item as long as its effect is not measurable.

  As used herein, the term “about” provides flexibility to the endpoints of a numerical range by providing the possibility that a value is “slightly above” or “slightly below” that endpoint. Used to provide.

  As used herein, a plurality of items, structural elements, components and / or materials may be shown in one common list for convenience. However, these lists should be construed as if each of the lists are individually recognized as separate and unique. Thus, each individual in such a list is determined solely by the fact that they are posted in one common group without the opposite indication, and in fact any other of the same list It should not be interpreted as an equivalent.

  As used herein, concentrations, totals, and other numerical data may be displayed or shown as a range format. Such range formats are merely used for convenience and simplification and thus include not only the numbers explicitly referred to as the limits of the range, but also as if each number and subrange. It should be understood that it should be construed flexibly as including all individual numerical values or sub-ranges encompassed by that range as if explicitly stated. As a specific example, a numerical range of “about 1 to about 5” not only includes explicitly stated values from about 1 to about 5, but also individual values and subranges within this indicated range. Should also be interpreted as including. Thus, this numerical range includes individual values such as 2, 3 and 4, and partial ranges such as 1-3, 2-4 and 3-5. This same principle applies to ranges that mention only one number. Furthermore, such an interpretation shall apply regardless of the breadth of the range or the characteristics being described.

  Any steps mentioned in any method or process claims may be executed in any order and are not limited to the order presented in the claims unless stated otherwise. . For a particular claim limitation, the means-plus-function or process-plus-function limitation is used only if all of the following conditions exist in the limitation: a) “means for” or “process for” are clearly described, and b) the corresponding function is clearly described. The structure, material or action that supports the means plus function is clearly described in the description herein. Accordingly, rather than by the description and examples provided herein, the scope of the present invention should be determined solely by the appended claims and their legal equivalents.

Intraocular drug delivery devices Intraocular drug delivery devices are implantable and provide a biodegradable intracapsular reservoir that is often unnecessary for subsequent surgery, allowing frequent injections or complex eye drop treatments. By reducing the need, it is possible to provide improved ocular drug delivery. In addition, the device can collect or combine different drugs.

  Novel intraocular drug delivery devices, systems, and associated methods that provide sustained release of an active agent for the eye over time are disclosed and described. One problem with many eye diseases, such as age-related macular degeneration (AMD), is that the subject constantly needs to receive a painful eye injection, which includes retinal detachment, vitreous hemorrhage and Has a significant risk of endophthalmitis. Intraocular drug delivery devices allow release of the active agent over time, thus eliminating the need for frequent eye injections.

  In some embodiments, the device is implantable during cataract surgery and is essentially “piggybacked” to cataract extraction, thereby eliminating the need for additional surgical procedures. Is possible. One advantage of "piggybacking" on cataract extraction is the ability to deliver steroids, antibiotics and various non-steroidal substances directly to the eye after surgery, and thus, such as cystic tissue macular edema Helps minimize complications. In other embodiments, the device can be implanted during a surgery that is separate from cataract surgery, such as following a previous lensectomy with reopening of the lens capsule.

  It should be noted that neovascularization is key to the pathological course in various eye diseases such as AMD, proliferative diabetic retinopathy, vaso-occlusive disease and radiation retinopathy. In addition, the incidence of glaucoma is increasing worldwide. Many other disorders, including severe uveitis and topographic atrophy in AMD, can be treated using such intraocular drug delivery devices. Thus, such an anterior segment drug delivery device has great potential to improve the quality of life of the subject.

  The drug delivery device is capable of continuously delivering dexamethasone or other anti-inflammatory agents with kinetics on the order of near zero for up to 2 weeks. Treatment of uveitis requires long-term (6-8 weeks) sustained delivery of anti-inflammatory agents. The biggest disadvantage of using topical drugs is that the drug reaches the posterior eye and in particular the retina / choroid only at very low concentrations. The drug delivery device designed and disclosed is capable of continuously delivering dexamethasone with near-zero order kinetics to both the anterior and posterior chambers, thus effectively reducing inflammation.

  Thus, there is an advantageous condition that improves the treatment of AMD, postoperative surgical inflammation and uveitis patients undergoing cataract surgery through sustained release of the pharmaceutically active agent. Accordingly, the present invention provides systems, devices and associated methods in delivering active agents to a subject's eye. In one embodiment, as shown in FIG. 1, the active agent delivery device 100 of the eye can include a biodegradable active agent matrix 110. The active agent delivery device for the eye can be sized and designed to fit within the lens capsule. In one aspect, the device can be sutureless. A device that does not require suturing can be defined as a device or structure that can be inserted and held within the capsular bag without the need for suturing to maintain the device in place. The device can stay in place without obstructing the eyes.

  The active agent delivery device can optionally include one or more additional / separate reservoirs for delivery of additional active agents or other desirable therapeutically beneficial substances. In one embodiment, for example, the device has a first active agent reservoir having a biodegradable active agent matrix containing a first active agent, and a second having a biodegradable active agent matrix containing a second active agent. Active agent reservoirs. The second active agent reservoir can occupy an area in the device, such as a layer of a biodegradable matrix disposed in the first active agent reservoir. It should be noted that the second active agent reservoir can contain the same or different active agent as the active agent contained in the first active agent reservoir. The second active agent reservoir can also have a different matrix material than the first active agent reservoir. For example, matrix materials with different dissolution rates can be used to control the rate of drug delivery from the first and second reservoirs. Individual reservoirs can be separated by a water barrier or simply by providing an adjacent drug matrix.

  In one embodiment, as shown in FIGS. 1 and 2, the active agent delivery device 100 can have an optional second active agent reservoir 120 within the device. In this particular embodiment, the device is disk-shaped with a second reservoir having a second active agent matrix in the center surrounded on the outside by the first active agent matrix. This structure can be manufactured by co-extrusion of the first and second matrix materials to form the nuclei of the second matrix material surrounded by the first matrix material. In other embodiments, the active agent delivery device can be disk-shaped as shown in FIGS. 1 and 2, except without a second reservoir in the center. Thus, all active agent delivery devices can be one homogeneous matrix material.

  Biodegradable matrices can include a variety of polymeric and non-polymeric materials. Non-limiting specific examples of suitable matrix materials include biodegradable polymers (eg, PLGA, albumin), colloidal suspensions, nanoparticles, microparticles, microspheres, nanospheres, hydrogels, pretes, polycarbophils, solids Including matrix.

  Numerous active agents are known in the treatment of various eye diseases, but AMD (angiogenic or atrophic), glaucoma, diabetic retinopathy, retinopathy of prematurity, uveitis, corneal transplant rejection, sac Some examples used in the treatment or prevention of eye diseases such as fibrosis, posterior capsule opacification, retinal vein occlusion, infection, etc. are dexamethasone, bevacizumab (Avastin®), timolol, latanoprost, brimonidine , Nepafenac and ranibizumab (Lucentis®) can be treated with non-limiting active agents. Other non-limiting examples of active agents include antibiotics, prednisolone, fluocinolide and the like. The treatment plan may further include an anti-VEGF aptamer such as pegaptanib (McGen®), an anti-VEGF Fab fragment such as ranibizumab (Lucentis®), an integrin antagonist, various photodynamic therapies, etc. Is possible.

  In yet another aspect of the invention, a method of delivering an active agent to a subject's eyeball is provided. Such methods include performing a cataract removal operation on a subject's eye, further removing an existing lens from the subject's eye, inserting an intraocular lens into the subject's eye, and intraocular lens and the present specification. Coupling with a device as described in. The delivery device may be detached from the intraocular lens. The delivery device can be bound by actual contact or sufficient proximity to effectively dissipate the active agent to the target site of the eye. The delivery device can itself be a biodegradable matrix or reservoir system. Biodegradable systems are highly useful in certain cataract surgery because they allow short-term / timed delivery of post-surgical drugs that otherwise require the use of eye drops by the patient. The lens that is removed may be the original natural lens of the eyeball, or it may be a lens that was previously inserted into the eyeball as a result of a previous surgery.

  There are many possible ways to couple the device to the eyeball. For example, in one aspect, the device can be coupled to the intraocular lens prior to inserting the intraocular lens into the eye. In such cases, it is necessary to configure the device to meet any requirements of the surgical procedure. For example, cataract surgery is often performed through a small incision. One standard incision size is approximately 2.75 mm; however, the device is compatible with smaller or larger sized incisions as well. As such, the intraocular lens assembly can be formed into a shape that can be inserted through this small opening. Thus, the active agent delivery device also needs to be configured to be inserted by the intraocular lens assembly, for example, by the shape of the device and the choice of elastic and flexible materials. In addition, the active agent delivery device can also be physically coupled or detached from the intraocular lens assembly prior to insertion of the assembly into the eyeball. In another aspect, the device can be coupled to the intraocular lens assembly after insertion of the lens into the eyeball. The sac bag can be easily reopened for patients who have previously undergone cataract surgery. Thus, insertion of the delivery device can be performed immediately before insertion of the intraocular lens or later in time as a separate operation.

  Consistent with the above principles, another optional configuration involves the use of an active agent matrix and a homogeneous delivery device that forms the active agent. The active agent delivery device for the eye can be configured to fit within the lens capsule or ciliary groove of the eyeball. The delivery device can be formed by any arrangement that allows insertion into the capsular bag or ciliary groove. The dimensions can vary, but typical dimensions can range from about 0.5 mm to about 4 mm wide and from about 0.2 mm to about 1 mm thick. While the total mass of the delivery device can be varied, in many cases the total mass can be from 0.2 mg to 4 mg. For example, there is also an overall size balance to fit within the target tissue area, but a total mass of about 2 mg can provide an effective active drug amount.

  An active agent delivery device comprising a biodegradable polymer matrix can include one or more excipients depending on the duration of delivery of the active agent. As shown in FIG. 4, the device can be of the following dimensions, for example, a diameter of 2-2.5 mm and a thickness of 1.0-1.5 mm. The placement of the device can be below the intraocular lens (IOL) and can be implanted during cataract surgery. The active agent delivery device for the eye can be configured to fit within the lens capsule or ciliary groove of the eyeball. The delivery device can be formed by any arrangement that allows insertion into the capsular bag or ciliary groove. The device can be in the shape of a disc, pellet, rod, square, crescent, donut or other shape. One or two devices can be implanted per eye according to the required dose.

  Suitable active drug matrices can include dexamethasone or those previously reported as active drug carriers. Non-limiting examples of active agent 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, HPMC, hydroxypropyl cellulose, Biodegradable polymers such as sodium carboxymethylcellulose, croscarmellose sodium, polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymer thereof and the like are included. Polylactic acid-polyglycolic acid block copolymer (PLGA), polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropylmethylcellulose (HPMC), polycaprolactone polyethylene glycol block copolymer, croscarmellose, etc. Certain copolymers such as may be particularly effective. In one embodiment, the active agent matrix can be PLGA having about 45-80% PLA and 55-20% PGA, such as about 65% PLA and 35% PGA. In another other embodiment, the ratio of PLGA, dexamethasone and croscarmellose sodium can be a ratio of 60-90 / 5-25 / 5-25 or 50-75 / 10-40 / 10-10-40 It is.

  A homogeneous delivery device can be formed, for example, by mixing a loading of active agent with a polymeric material to form a matrix dispersion. The fill volume can be selected to match the desired dose during diffusion. The loading can take into account diffusion properties such as polymer and active agent, residual active agent, delivery time. The matrix dispersion can then form the shape of the device using any suitable technique. For example, the matrix dispersion can be casting, spraying and drying, extrusion, stamping or others. Such structures are often formed using a biodegradable matrix, although non-biodegradable materials can also be used. For example, in one embodiment, the matrix dispersion can be extruded from a mold with a circular cross section, and then the extruded matrix dispersion can be sliced to create a disc-shaped implant. In another formulation, the device can be formed from a suspension of the active agent in situ in a biodegradable polymer matrix precursor. Simultaneously with delivery to the target site, the biodegradable polymer matrix precursor is capable of forming a biodegradable active agent matrix in situ (through precipitation and / or polymerization).

  With the homogeneous delivery device described above, specific efficacy can be provided for the treatment of uveitis and postoperative cataract surgical inflammation. For example, dexamethasone can be dispersed within a biodegradable active agent matrix. Dexamethasone dosage can vary, but from about 100 mcg to about 400 mcg can be effective for these indications. More specifically, some patients are classified as low risk and others are classified as high risk due to various factors such as age, secondary complications, medical history, etc. Is possible. In many cases, low-risk patients can benefit from a low dose of about 100 mcg to about 150 mcg. In contrast, high-risk patients can be administered high doses of about 250 mcg to about 350 mcg. One specific embodiment of an active agent delivery device, “BDI-1 implant”, is specifically designed and tested for the treatment of post-operative surgical inflammation and is capable of delivering pharmaceutically active agents for up to 2 weeks. is there. “BDI-2 transplants” are designed and tested for the treatment of post-operative surgical inflammation and uveitis and are capable of delivering active agents for up to 6-8 weeks. Depending on the severity of the inflammation, one or two grafts per eyeball can be implanted during surgery.

  As mentioned above, the delivery devices herein are targeted for a relatively short delivery duration, in most cases less than 8 weeks. In another, the active agent has a delivery duration of about 2 weeks to about 6 weeks. Delivery duration can be a function of the type of polymer used in the matrix, copolymer ratio, and other factors. Other biodegradable polymers may be suitable, such as those previously listed, but particularly suitable polymers are poly (lactic-co-glycolide), hydroxypropylmethylcellulose, hydroxymethylcellulose, polyglycolide-polyvinyl It may include at least one of alcohol, croscarmellose, polycaprolactone, Eudragit L100, Eudragit RS100, poly (ethylene glycol) 4000, poly (ethylene glycol) 8000 and poly (ethylene glycol) 20,000. The biodegradable active agent matrix can include poly (lactic acid-co-glycolide) having a copolymer ratio of 52/48 to 90/10. In one embodiment, the copolymer ratio can be 52-78 / 48-22, and in another embodiment, it can be 60-90 / 40-10. Although the degradation rate can depend on such ratios, yet other approaches may also be beneficial, such as device coating, particle encapsulation, and the like.

  Standard transparent corneal phacoemulsification aspiration with implantation of an intraocular lens (Acrysov SA60AT, Alcon) was given to 35 rabbits. At each surgery, an intraocular device containing the active agent was inserted into the capsular bag of each rabbit. The rabbits were divided into four groups according to 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 wounds and anterior eye healing status. Eye subgroups were evaluated once a week for inflammation for 4 weeks and collected at 1 month to assess histopathological evaluation of sac and CDR integrity.

  Aqueous puncture and vitreous puncture were performed once every two weeks, and the surgery and setup described in Example 1 were repeated, except that drug concentrations were assayed by HPLC and / or ELISA. In each drug group, one eyeball was collected at 1 month and the other eyeball was collected at 2 months. This was done as follows. Immediately after sacrifice of the rabbit and removal of the eyeball, the eyeball was frozen in liquid nitrogen to prevent drug swinging and redistribution within the eyeball tissue. The eyeball was then dissected into three sites (aqueous humor, vitreous and retina / choroid layer) to assess anatomical toxicity and tissue drug concentrations. The intraocular device was collected and the amount of remaining drug was evaluated. In order to directly compare the different delivery methods, the distribution profile of the intraocular device was compared to the conventional intravitreal injection of 2.5 mg / 0.1 cc Avastin®.

  At 2 and 4 months, the eyeballs were removed from the remaining subgroups of rabbits, fixed with 10% formalin, embedded in paraffin, sectioned in stages, and with hematoxylin and eosin (H and E). Stained and analyzed for histological changes.

  After lens extraction (lens ultrasonic emulsification suction method), three intraocular devices were inserted into the eyeballs of New Zealand white rabbits with general anesthesia. Two of the devices were filled with Avastin and one was filled with the contrast agent Galbumin as a control. Appropriate intraocular device location was confirmed by MRI and clinical examination.

  The rabbits were sacrificed and the eyeballs were removed and tested one week after transplantation. Avastin was detected by ELISA in the retina and vitreous at a concentration of 24-48 mcg / mL and was absent from the control rabbit eyeball. FIG. 3 shows the amount of Avastin analyzed for each eyeball site one week after transplantation.

  PLGA [poly (d, l-lactide-co-glycolide), MW, to confirm its placement of the implant in the sac bag and deliver the drug to both the anterior and posterior segments for a short and long period of time Microparticles were prepared using 7000-17000, acid-terminated], hydroxypropyl methylcellulose (HPMC) and dexamethasone. PLGA microspheres loaded with dexamethasone were prepared using a standard oil-in-water (o / w) emulsion-solvent extraction method. A total amount of 160 mg of PLGA was dissolved in 4 mL of methylene chloride and 1 mL of acetonitrile. A total 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 a 2.0% (w / v) PVA (MW 90 kDa) solution and stirred for 6 minutes in an ice bath. To make a suspension of turbid microparticles, the contents were stirred for 8 hours at room temperature to evaporate dichloromethane and acetonitrile. To obtain lyophilized particles, the microparticles were separated by centrifugation, washed twice, resuspended in deionized water and lyophilized. The prepared microparticles were identified and set in a 2 mm mold to form an implant and pelletized using a bench top pellet press.

  These grafts were sterilized and transplanted into rabbit eyeball sac bags. Two dose groups (300 and 600 μg) were used and two rabbits from each of the low and high dose groups were sacrificed at 1, 2, 4, 6 weeks and various tissue samples (aqueous humor, vitreous humor, IOL, iris / ciliary body and retina / choroid) were collected and samples were analyzed by a validated LC / MS / MS method. The microspheres ranged from 6 ± 2 μm as confirmed by the Zetasizer Nano and SEM micrographs. Drug loading in the microparticles was 99% or higher and the final yield (ie encapsulation efficiency) was 60%. Drug loading was measured as percent drug loading = (mass of drug loaded / mass of microspheres) x 100. Dose-dependent pharmacokinetics with near-zero order kinetics were observed in rabbits for up to 6 weeks. Furthermore, dexamethasone flow was bidirectional from the space within the sac to both the anterior and posterior chambers. No cell or fibrin formation was observed in the anterior and posterior chambers of the eyeball. Histological examination revealed that all tissues examined were normal and showed no signs of inflammation.

  All laboratory animals, once exiting quarantine, were familiar and randomized to investigate laboratory conditions. All positive control groups and transplant groups received crystal sonic emulsification and intraocular lens (IOL) insertion in both eyes. Groups III and IV received one and two grafts for each eyeball.

Group I, normal control group, n = 6
Group II, phacoemulsification and IOL insertion, DXM eye drops (up to 4 weeks with tapering) and antibiotic eye drops (up to 2 days), positive control group, n = 6
Group III, phacoemulsification and IOL insertion, low dose BDI transplantation (one implant per eyeball) and antibiotic eye drops up to 2 days (2 times daily) after surgery, n = 8
Group IV, phacoemulsification and IOL insertion, high dose BDI transplantation (2 grafts per eye) and antibiotic eye drops up to 2 days after surgery (twice daily), n = 8
The results of the release kinetics in the test tube are shown in FIG. All batches showed a biphasic release pattern with the first burst release on day 1, then slowed down and continued release. The effect of burst was slightly higher with grafts containing HPMC.

  A total of 16 animals (32 eyes) received the graft. Dexamethasone concentrations are shown in FIGS. Grafts that slowly disintegrate for 4 weeks and until week 6 had completely disappeared. The therapeutic concentration of DXM was confirmed up to week 6 with minimal systemic exposure (less than 40 ng / mL with high dose), whereas it was higher with systemic exposure to dexamethasone eye drops (150 ng / week over the first week). mL or more). Average PK parameters for BDI-2 transplantation 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, it was evaluated by slit lamp biomicroscopy and confirmed by histological examination, but there was no sign of anterior or posterior chamber inflammation. There was a tendency for retinal thickness to increase in animals treated with dexamethasone eye drops, while retinal thickness was maintained in the graft.

  PLGA polymers break down into lactic acid and glycolic acid through hydrolysis, and then break down into carbon dioxide and water before being removed from the body. The graft did not move to the center to obstruct the field of view.

  The BDI-1 implant continued to evaporate and was made using the partial solvent casting method, and the residual solvent was removed by drying the product under high vacuum for 3 days. PLGA [poly (d, l-lactide-co-glycolide) MW, 7000-17000, acid-terminated], hydroxypropylmethylcellulose (HPMC), croscarmellose sodium (cross-linked carboxymethylcellulose sodium) in several different compositions Various implants were prepared using hydroxypropylcellulose and dexamethasone.

  Dry particles were set in a 2 mm mold to form an implant and pelletized directly using a bench top pellet press.

  Selected BDI-1 grafts (from the in vitro release study of FIG. 5) were sterilized and transplanted into a rabbit eyeball sac bag. To establish pharmacokinetics, two implants with different compositions and doses were tested in vivo in NZW rabbits. Two rabbits were sacrificed on days 2, 6, 10, 15 and various tissue samples (aqueous humor, vitreous humor, IOL, iris / ciliary body and retina / choroid) were collected, and the samples were collected for effective LC / Analysis was performed by MS / MS method. Pharmacokinetics with near-zero order kinetics were observed in rabbits up to 15 days. Furthermore, dexamethasone flow was bidirectional from the space within the sac to both the anterior and posterior chambers. No cell or fibrin formation was observed in the anterior and posterior chambers of the eyeball. Histological examination revealed that all tissues examined were normal and showed no signs of inflammation.

  The results of the release kinetics in the test tube are shown in FIG. All batches showed a smooth release pattern with the first burst release on day 1, then slowed down and continued release. The effect of burst was slightly higher with grafts containing HPMC.

  A total of 8 animals (16 eyes) received grafts containing 120 μg of DXM. DXM concentrations are shown in FIGS. Grafts eroded slowly over 10 days and reached the DXM bottom concentration by day 15. The graft is expected to degrade to 80% of its mass on day 15 and fully degraded on day 20. The therapeutic concentration of DXM was confirmed by day 15 with minimal systemic exposure (<23 ng / mL), but was higher with systemic exposure to dexamethasone eye drops (> 150 ng / mL over the first week, tissue Data).

  As previously reported by our group, microparticles containing DXM were prepared with PLGA [poly (lactide-co-glycolide)] and hydroxypropylmethylcellulose (HPMC). In New Zealand White (NZW) rabbits (n = 18), after intravitreal injection of Concanavalin A (Con-A) followed by phacoemulsification aspiration, BDI was placed in the lower cap of the sac bag. All eyes were evaluated clinically using slit lamp biomicroscopy and graded according to the Draize scoring criteria. Retinal thickness measurements were also made. BDI was effective in preventing retinal thickening. Retina thickness was measured using SD-OCT (spectral domain optical coherence tomography, Heidelberg Engineering GmbH, Heidelberg, Germany). The rabbits were anesthetized and spread as described above. At least four measurements were taken from each eyeball. The measured value was recorded as an average value ± SD. Retina thickness was defined as the distance between the inner retinal boundary (vitreous fluid-retinal interface) and the outer retinal boundary (retinal-retinal pigment epithelium interface). A baseline of 23 means that the thickness of the retina was 130 ± 5 μm in all experimental rabbits as measured by SD-OCT. In the standard control group, retinal edema gradually increased and structural collapse was observed in n = 4 eyeballs by week 4 (FIG. 6). The retina thickness in the BDI group was effectively controlled and was near normal at all time points. However, in the topical eye drop group, retinal thickness was significantly (P <0.05) persistently increased from week 1 to week 6 compared to both normal control and BDI groups. The results are shown in FIG.

  It should be understood that the above preparation is merely an illustrative application of the principles of the present invention. Numerous modifications and alternative constructions may be devised by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, the present invention is described above with particularity and details regarding what is considered to be the most practical and preferred embodiment at present, but not limited thereto, size, material, shape. It will be apparent to those skilled in the art that many changes, including variations in form, function and manner of operation, assembly and use, can be made without departing from the principles and concepts described herein. Let's go.

Claims (16)

An intraocular active drug delivery device comprising:
An active agent dispersed within a biodegradable active agent matrix, the active agent comprising dexamethasone, and the delivery device configured to fit within the lens capsule or ciliary groove of an eyeball An intraocular active drug delivery device. The device of claim 1, wherein
The device wherein the active agent is present at about 100 mcg to about 400 mcg. The device of claim 1.
A device wherein the active agent is present at a low dose of about 100 mcg to about 150 mcg. The device of claim 1, wherein
The device wherein the active agent is present at a high dose of about 250 mcg to about 350 mcg. The device of claim 1, wherein
The device wherein the active agent has a delivery duration of about 2 weeks to about 6 weeks. The device of claim 1, wherein
The biodegradable active agent matrix is poly (lactic acid-co-glycolide), polylactic acid-polyglycolic acid block copolymer (PLGA), hydroxypropylmethylcellulose, hydroxymethylcellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium , Hydroxypropylcellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropylmethylcellulose (HPMC) and polycaprolactone-polyethylene glycol block copolymer Device. The device of claim 1, wherein
The device wherein the biodegradable active agent matrix comprises poly (lactic acid-co-glycolide) having a copolymer ratio of 52/48 to 90/10. The device of claim 1, wherein
The delivery device is a disc or pellet shape device. The device of claim 1, wherein
The device has a shape in which the active agent is suspended in a biodegradable polymer matrix precursor, and the biodegradable polymer matrix precursor forms the biodegradable active agent matrix in situ. Device. The device of claim 1, further comprising at least one second active agent reservoir disposed within the biodegradable active agent matrix.   The device of claim 1, wherein the delivery device has a total mass of 0.2 mg to 4 mg. A method for treating an eye disease comprising:
2. The method comprises administering the active agent to the eyeball using the delivery device of claim 1 by inserting the delivery device into a lens capsule or ciliary groove of an eyeball, wherein the eye disease is postoperative A method which is at least one of cataract surgical inflammation and uveitis.   15. The method of claim 14, wherein the insertion is performed during cataract surgery.   15. The method of claim 14, wherein the insertion is performed after cataract surgery to treat post-operative cataract surgery inflammation.   15. The method of claim 14, wherein the eye disease is uveitis. The method of claim 14, wherein
The delivery device is in the form of a suspension of the active agent in a biodegradable polymer matrix precursor, and the insertion comprises injecting the suspension into the lens capsule or ciliary groove, thereby A method wherein the biodegradable polymer matrix precursor is one that forms the biodegradable active agent matrix in situ.

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