KR20190110101A - Intraocular drug delivery device and related methods - Google Patents

Abstract

Devices, systems, and methods for delivering an active material from the capsular coating of the subject's eye to the posterior eye may include an intraocular active material delivery device comprising an active material dispersed within a biodegradable active material matrix. Such active substances include dexamethasone and such delivery devices may be modified to fit within the lens capsular or ciliary furrows of the eye. The delivery device may be a lens capsular or ciliary of the eye during cataract surgery or for the treatment of uveitis. It can be inserted inside the furrow.

Description

Intraocular drug delivery device and related methods

Field of invention

The present invention relates to systems, methods and devices for continuously and targeted (locally) delivering a pharmaceutically active substance to the eye of a subject. Accordingly, the present invention relates to the field of polymer chemistry, material science, polymer science, drug delivery, formulation science, pharmaceutical science, and pharmaceuticals, in particular ophthalmology.

background

Age-related macular degeneration (AMD) and glaucoma are two major causes in the United States and around the world. Current glaucoma therapies generally require multidrug therapy, where subjects are often prescribed several topical agents that must be administered to the eye at different frequencies, in some cases up to three or four times daily. These dosing regimens are often difficult for a subject to consistently follow, and many individuals require surgical treatment, such as intraocular shunts or trabeculectomy, which involves significant complications.

Subjects with macular degeneration often need a monthly intravitreal injection. Such injections are painful and can lead to retinal detachment, ophthalmitis, and other complications. Moreover, such injections are generally performed only by retinal surgeons, a small part of the ophthalmology community, creating bottlenecks and increasing costs in delivering ophthalmic care.

Postoperative surgical inflammation is associated with intraocular pressure elevation (IOP) and increases the chance of cystic macular edema (CME), adhesion formation, posterior capsular opacity (PCO), and secondary glaucoma. Patient compliance is considered in postoperative inflammation management because eye drops should be administered multiple times a day at regular intervals over several weeks. Poor compliance impairs the efficacy of topical drugs, which can be more limited and highly variable intraocular concentrations by corneal absorption during the course of treatment. Uveitis specifically refers to inflammation of the middle layer of the eye, termed “vein membrane”, but in normal use may refer to an inflammatory process associated with the interior of the eye. Uveitis is estimated to account for approximately 10% of blindness in the United States.

Postoperative cataract surgery inflammation can be well controlled by improving patient compliance. Available literature and experience shows that poor penetration of the drug after topical administration and higher higher systemic concentrations means more frequent systemic side effects. All these factors underscore the need for continuous intraocular delivery of pharmaceutically active substances to effectively control inflammation.

summary

The method of delivering the active substance to the posterior eye of the subject may include disposing the biodegradable active substance matrix inside the lens capillary of the subject to deliver such active substance to the eye posterior eye. The biodegradable active substance matrix comprises the active substance present in an amount to deliver a therapeutically effective amount of the active substance from the capsular coating to the posterior eye.

Therefore, some of the more important features of the present invention have been outlined somewhat broadly so that the detailed description of the invention that follows may be better understood, and in order that the contribution of the invention to the art may be better understood. Other features of the invention will become apparent from the following detailed description of the invention, taken in conjunction with the accompanying drawings and claims, or may be learned by practice of the invention.

Brief description of the drawings
1 is a photograph showing a bioerodible dexamethasone implant (BDI), in accordance with some examples of the present invention.
2 is a bar graph showing the amount of active agent present in various eye tissues after implantation of an intraocular device according to another aspect of the present invention.
3 is an in vitro release kinetics graph of one exemplary BDI implant. Data are presented as mean ± SD (n = 3).
4 is a time-to-concentration profile of one exemplary BDI implant using New Zealand white (NZW) rabbits' ocular (water) and 120-160 μg of dexamethasone (DXM) in vitreous fluid.
5 is a time versus concentration profile of one example BDI implant with 120-160 μg DXM in the iris / ciliary and retina / choroid of NZW rabbits.
FIG. 6 is a time versus concentration profile graph of one example BDI implant and topical eye drops in New Zealand white rabbits' ocular water resistance.
FIG. 7 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in the vitreous fluid of New Zealand white rabbits.
8 is a time versus concentration profile graph of one example BDI implant and topical eye drops in the retina / choroid of New Zealand white rabbits.
FIG. 9 is a time versus concentration profile graph of one example BDI implant and topical eye drops in the iris / ciliates of New Zealand white rabbits.
FIG. 10 is a graph showing the effect of croscarmellose concentration on drug release for some example BDI implants.
11 is an in vitro release kinetics graph of one exemplary BDI implant. Data are presented as mean ± SD (n = 3).
12 is an in vitro release kinetics graph of another exemplary BDI implant. Data are presented as mean ± SD (n = 3).
FIG. 13 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in New Zealand white rabbits with ocular water protection.
14 is a time versus concentration profile graph of one example BDI implant and topical eye drops in the vitreous fluid of New Zealand white rabbits.
15 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in the retina / choroid of New Zealand white rabbits.
FIG. 16 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in the iris / ciliates of New Zealand white rabbits.
17 is a graph of retinal thickness vs. time profile of one example BDI implant and topical eye drops compared to normal control.
FIG. 18 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in New Zealand white rabbits with ocular water protection.
19 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in vitreous fluid of New Zealand white rabbits.
20 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in the retina / choroid of New Zealand white rabbits.
FIG. 21 is a graph of time versus concentration profile of one example BDI implant and topical eye drops in iris / ciliates of New Zealand white rabbits.
22 is a graph of retinal thickness versus time profile of one example BDI implant and topical eye drops compared to normal control. These drawings are only illustrative of exemplary embodiments of the invention and are not to be considered as limiting the scope of the invention. As generally described herein and shown in the figures, it will be readily understood that the components of the present invention can be arranged, sized and designed in a wide variety of different structures.

Detailed description of the invention

Exemplary embodiments of the present invention will be described in detail below with reference to the accompanying drawings, the accompanying drawings which form part of the description, in the drawings, illustrate exemplary embodiments in which the invention may be practiced. As shown. Although those skilled in the art have described these exemplary embodiments in sufficient detail to practice the invention, other embodiments may be implemented and various changes may be made in the invention without departing from the spirit and scope of the invention. It should be understood that it can. Therefore, the following detailed description of the invention is not intended to limit the scope of the invention as claimed, but to illustrate the features and characteristics of the invention, to present the best mode of operation of the invention, and to It is provided for the purpose of illustration only and not limitation to enable those skilled in the art to fully practice the present invention. Accordingly, the scope of the invention is to be defined only by the appended claims.

As used in this specification and the appended claims, it should be noted that the singular forms “a,” “an,” and “the” include plural unless the context clearly dictates otherwise. Thus, for example, reference to “one drug” includes reference to one or more such drugs, “one excipient” includes reference to one or more such excipients, and “filling” means one or more such steps. Refer to these.

Justice

In describing the present invention and describing the claims, the following terms will be used in accordance with the definitions given below.

As used herein, “active substance,” “bioactive substance,” “pharmaceutically active substance” and “drug” are substances that have a specified or selected physiological activity that is measurable when administered to a subject in significant or effective amounts, or It may be used interchangeably to refer to a component. Such technical terms are well known in the pharmaceutical and pharmaceutical fields.

As used herein, “formulation” and “composition” can be used interchangeably herein and refer to two or more components, or combinations of components. In some embodiments the composition may comprise an active substance, excipient, or carrier to enhance delivery, depot formation, and the like.

As used herein, “effective amount” refers to an amount of ingredients sufficient to produce the intended composition or physiological effect when included in a composition. Therefore, a “therapeutically effective amount” refers to an amount of active substance that is sufficient to produce a therapeutic result that is effective but substantially nontoxic to treat or prevent a condition in which the active substance is known to be effective. It is contemplated that various biological factors may affect the ability, therefore, an “effective amount” or “therapeutically effective amount” may depend on these biological factors in some instances. It is known that qualified medical practitioners can be measured using assessment methods known in the art, but the implementation of a therapeutic effect can be determined subjectively depending on individual differences and responses to the treatment. Of skilled technicians in pharmaceutical and nutrition sciences as well as pharmaceutical sciences Fall over.

As used herein, “subject” refers to a mammal that would benefit from administration with a composition or method referred to herein. Examples of subjects include humans, and also include other animals, such as horses, pigs, cattle, dogs, cats, rabbits, marine mammals, and the like.

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

The term “ciliary sulcus” as used herein refers to the space between the ciliary body and the posterior root of the iris of the eye.

As used herein, the term “substantially” refers to a complete or nearly complete range or degree of action, property, property, condition, structure, item, or result. For example, an "substantially" closed "object would mean that the object is fully closed or almost completely closed.The exact degree of allowable deviation from absolute integrity may in some cases depend on the particular situation. Generally speaking, the proximity of completion would be such that it would have the same overall result as if it had achieved absolute and total completion.The use of “substantially” means that a certain action, property, property, state, structure, item, or result The same applies when used in a negative sense to refer to completely or almost completely, for example, a composition that is “substantially free of particles” would be completely free of particles, or almost completely free of particles. Would be the same as if the particles were completely absent, that is, the component or composition A composition that is "substantially free" of elements may still contain such items in fact, unless there is a measurable effect thereof.

The term "about" as used herein is used to provide flexibility for a range of endpoint values, provided that the given value may be "slightly above" or "slightly below" the endpoint value.

As used herein, a plurality of items, structural elements, compositional elements, and / or materials may be presented in a common list for convenience. However, these lists should be construed as though each component of the list is specified as a separate component. Therefore, each component of this list should be construed as substantially equivalent to any other component of the same list based only on what is presented in the common group, unless there is an objectionable content.

The term "at least one of" as used herein is to be similar to "one or more of". For example, “at least one of A, B, and C” explicitly includes A alone, B alone, C alone, and a combination of each.

Concentrations, amounts and other numerical data may be expressed or presented in a range format herein. This range format is used merely for convenience and brevity, so that not only does it contain numerical values explicitly stated as the limits of the range, but each individual numerical value or sub-range contained within that range is like It is to be understood that the values and sub-ranges should be interpreted flexibly as including them, as explicitly mentioned. As an example, the numerical range of "about 1 to about 5" should be construed to include the values of about 1 to about 5 explicitly mentioned, as well as to include individual values and sub-ranges within this presented range. Therefore, this range includes individual values such as 2, 3, and 4 and sub-ranges such as 1-3, 2-4, and 3-5, and the like. This same principle applies equally to the ranges referring to only one numerical value. Moreover, this interpretation should be applied irrespective of the range or the width of the properties described.

Any steps mentioned in any method or process claim may be performed in any order unless stated otherwise and are not limited to the order set forth in the claims. Means-functions or step-functions limitations may only be used for the purposes of a particular claim limitation if the following conditions are all present in that limitation: a) “Means for” or “Steps for” are clearly stated; And b) the corresponding function is clearly stated. The structures, materials or actions that underpin means-functions are clearly described in the specification. Accordingly, the scope of the present invention should be determined only by the appended claims and their legal equivalents, and not by the description and examples provided in the specification.

Intraocular drug delivery device

Intraocular drug delivery devices can provide improved ocular drug delivery by relieving the need for multiple injections or complex eye drops by providing an intraocular lens reservoir that is implantable and biodegradable, often requiring no subsequent surgery. Moreover, such devices can deliver a variety of different agents or combinations thereof.

Novel intraocular drug delivery devices, systems, and related methods for providing sustained release of ocular active substances for long periods of time are disclosed and described. One problem with many ocular diseases, such as age-related macular degeneration (AMD), is the need for subjects to receive ill ocular injections, which present a significant risk of retinal detachment, vitreous bleeding, and endophthalmitis. Intraocular drug delivery devices enable the continuous release of the active material over time, eliminating the need for frequent ocular injections.

It should be noted that angiogenesis is an important pathophysiological process in various eye diseases such as AMD, proliferative diabetic retinopathy, vascular occlusion, and radiation retinopathy. In addition, the occurrence of glaucoma is increasing worldwide. Many other disorders, including severe uveitis and lead atrophy in AMD, can be treated using such intraocular drug delivery devices. Therefore, implantable, generally unsealed drug delivery devices for placement in the anterior eye of the eye are very likely to improve the quality of life of subjects.

Such drug delivery devices can continuously deliver dexamethasone or other anti-inflammatory or therapeutic substances with near zero order kinetics for at least two weeks. Uveitis treatment requires long-term (6-8 weeks) continuous delivery of anti-inflammatory agents. The biggest drawback of topical eye drops is that negligible concentrations of the drug reach the posterior eye and especially the retina / choroid. Designed and disclosed drug delivery devices can deliver dexamethasone and / or other therapeutic agents to almost zero order kinetics to both the anterior and posterior eye of the eye to effectively control inflammation.

Therefore, there is an opportunity to improve the management of AMD, postoperative surgical inflammation and uveitis patients undergoing cataract surgery by continually releasing the pharmaceutically active substance (s). Accordingly, the present invention provides a system, apparatus and related methods for delivering active substances to the eye of a subject. In some examples, such systems, devices, and related methods may be placed in the anterior eye of the subject's eye (eg, in the capsular coat) to deliver the active material to the posterior eye of the subject's eye. Non-limiting examples of ocular zones found within the eye posterior eye may include at least one of the vitreous fluid, choroid, and retina. In addition to delivering the active substance to the posterior eye, the active substance may also be delivered to the anterior eye of the eye. The anterior eye part of the eye may include at least one of eye protection, iris, and lens capsular film. In one aspect, the intraocular device may be sutureless. A sealless device may be defined as a device or structure that can be inserted and fixed in the capsular membrane without requiring a suture to hold the device in place.

More specifically, in some aspects such a device may be implanted into the capsular film during cataract surgery, especially during “piggybacking” during cataract extraction, thus eliminating the need for additional surgical procedures. One benefit of "piggyback" during cataract extraction is the ability to deliver steroids, antibiotics, and / or various non-steroidal substances directly to the eye after surgery, thus helping to minimize complications such as cystic macular edema. . In other aspects, the device may be implanted, for example, in a surgery separate from the cataract procedure followed by an earlier cataract extraction that reopened the capsular capsule. For example, the device may be used for the treatment of macular degeneration, retinal vein or artery occlusion, diabetic retinopathy, macular edema (e.g., due to diabetes, uveitis, intraocular surgery, etc.), retinal degeneration with neuroprotective agent delivery, and the like. Can be implanted after cataract surgery.

In one embodiment, the device may be provided in the form of an implant containing the active substance in a biodegradable or bioerodible polymer matrix. The biodegradable active substance matrix may comprise the active substance present in an amount to deliver a therapeutically effective dose or therapeutically effective amount of the active substance from the capsular coat to the posterior eye. The therapeutically effective amount or therapeutically effective dose may vary depending on the particular therapeutic agent used in the biodegradable active substance matrix. In addition, the therapeutically effective amount or therapeutically effective dose may vary depending on the severity of the condition being treated. Nevertheless, these active substances may be present in an amount that facilitates the transfer of the active substance from the anterior eye part of the eye (eg, from the capsular coat) to the posterior eye part.

A therapeutically effective amount or therapeutically effective dose may typically range from about 50 micrograms (mcg) to about 10 milligrams (mg), depending on the severity of the active substance and condition utilized. In certain specific examples, the therapeutically effective amount or therapeutically effective dose may range from about 50 mcg to about 600 mcg. In still other examples, the therapeutically effective amount or therapeutically effective 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 material may typically be 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% by weight. In addition, depending on the dose requirement, one, two, or more implants may be implanted in each eye to achieve a therapeutically effective dose.

Biodegradable active substance matrices can be designed to biodegrade to provide a therapeutically effective amount of release control over a period of days, weeks, or months. In some embodiments, the therapeutically effective amount can be released over a period ranging from about 1 week to about 10 weeks. In other embodiments, the therapeutically effective amount can 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 period often can range from 2 months to 12 months, and in some cases can range from 2.5 months to 5 months. For example, bioerodible lipid polymers and / or bioerodible polycaprolactones can be used as long-term release matrix materials.

In addition to the amount of active material present in the biodegradable active material matrix, it is noted that other additional factors may affect the delivery of the active material to the eye posterior eye. For example, the intracapsular placement of the device inside the capsular coating can affect the delivery of the active substance to the posterior eye. In some examples, implant placement in the lower circumferential position relative to the intraocular lens (IOL) or into the lower circumferential capillary may suitably deliver the active material to the posterior eye. Typically, the implant may also be located at a lower portion inside the capsular membrane. For example, the implant may be oriented inside the lower perimeter, annular perimeter, surrounding the intraocular lens at least 180 degrees, and so on, unless the gaze is obstructed.

In addition, the molecular weight and molecular size of the active material can affect the delivery of the active material to the eye posterior eye. Therefore, in some examples, the active material may have a molecular weight of 250,000 Daltons (Da) or less. In still other examples, the active material may have a molecular weight of 170,000 Da or less. In further examples, the active material may have a molecular weight of 500 Da or less.

Treatment of various eye diseases such as AMD (neovascular or atrophic form), glaucoma, diabetic retinopathy, prematurity retinopathy, uveitis, corneal graft rejection, capsular fibrosis, posterior capsular opacity, retinal vessel occlusion, infection, or the like, or Numerous active substances for prevention are known. Any suitable active substance for incorporation into the biodegradable active substance matrix can be used, such as steroids, NSAIDs, antibiotics, anti-VEGF substances, PDGF-B inhibitors (Fovista® integrin antagonists, complement antagonists, and the like, or combinations thereof. Non-limiting examples of suitable active agents include dexamethasone, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis® sunitinib, pegaptanib (Macugen® moxifloxacin, gatifloxacin, bepsifloxacin, thymoloxin) Rolls, latanoprost, brimonidine, nepafenac, bromfenac, diclofenac, ketorolac, triamcinolone, difluprenate, fluorinolide, aflibercept, and the like, or combinations thereof. And may additionally include various photodynamic therapies, etc. In one particular example, the active agent may comprise dexamethasone.

The bioerodible polymer matrix may comprise one or several excipients, which may vary depending on the duration of active substance delivery. Non-limiting examples of active material matrix materials may include polymeric and non-polymeric materials. Specific non-limiting examples of suitable matrix materials include biodegradable polymers such as PLGA (different ratios of lactic acid to glycolide content and end groups such as acid or ester termination), PVA, PEG, PLA, PGA, hydroxypropylcellulose , Sodium carboxymethylcellulose, croscarmellose sodium, polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymers thereof, and the like. Certain copolymers such as polylactic-polyglycolic acid block copolymers (PLGA), polyglycolic acid-polyvinyl alcohol block copolymers (PGA / PVA), hydroxypropylmethylcellulose (HPMC), polycaprolactone- Polyethylene glycol block copolymers, croscarmellose, and the like can be particularly effective. In one aspect, the active substance matrix may be PLGA having about 45-80% PLA and 55-20% PGA, such as about 65% PLA and 35% PGA, and in one case about 50% PLA and 50% PGA have. In another alternative embodiment, the weight ratio of PLGA, dexamethasone, and croscarmellose sodium may be in the ratio 60-90 / 5-25 / 5-25 or 50-75 / 10-40 / 10-40. In another aspect, the biodegradable active substance matrix comprises low melting fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, capric acid, oleic acid, palmitoleic acid, and mixtures thereof. Including but not limited to. In one aspect, the biodegradable active substance matrix may comprise a pharmaceutically acceptable disintegrant. In one example, the disintegrant may be a strongly disintegrant. Non-limiting examples of suitable disintegrants include crosslinked celluloses (eg, croscarmellose, Ac-Di-Sol, NYMCE ZSX, PRIMELLOSE, SOLUTAB, VIVASOL), microcrystalline celluloses, alginates, crosslinked PVPs (eg, CROSSPOVIDONE, KOLLIDON, POLYPLASDONE), cross-linked starch, soy polysaccharide, calcium silicate, salts thereof, and the like.

Typically, delivery devices of the invention can be targeted for relatively short delivery periods, such as less than nine weeks. In some embodiments, the active substance has a delivery period of about 2 weeks to about 6 weeks. The delivery period can be a function of the type of polymer used in the matrix, the copolymer ratio, and other factors. Although other biodegradable polymers may be suitable, for example the polymers listed above, particularly suitable polymers are poly (lactic-co-glycolide), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol , Croscarmellose, polycaprolactone, Eudragit L100, Eudragit RS100, poly (ethylene glycol) 4000, poly (ethylene glycol) 8000 and poly (ethylene glycol) 20,000. In one example, the biodegradable active substance matrix may comprise poly (lactic-co-glycolide) having a copolymer ratio of 10/90 to 90/10 and in still other cases 52/48 to 90/10. In one particular aspect, the copolymer ratio may be about 50/50. In another specific example, the copolymer ratio is 52-78 / 48-22 and in another specific example it may be 60-90 / 40-10. The rate of degradation may be dependent on this ratio, but other alternative approaches may be useful, such as device coating, particle encapsulation, and the like.

Homogeneous delivery devices can be formed, for example, by mixing a polymeric material with a load of active material to form a matrix dispersion. The load can be chosen to correspond to the desired capacity during diffusion. The loading may be selected in consideration of the diffusion properties of the polymer and the active material, the balance of the active material, the delivery time, and the like. The matrix dispersion can then be shaped into the device shape using any suitable technique. For example, the matrix dispersion can be casting, spraying and drying, extrusion, stamping, and the like. Such structures will almost always be formed using biodegradable matrices, but non-biodegradable materials may also be used. In one alternative formulation, the device may be formed in situ from a suspension of the active substance in a biodegradable polymeric matrix precursor. Upon delivery to the target site, the biodegradable polymer matrix precursor may form the biodegradable active material matrix in situ (via sedimentation and / or polymerization).

Using this homogeneous delivery device, certain efficacy may be provided in the treatment of uveitis and postoperative cataract surgery inflammation. For example, dexamethasone can be dispersed in a biodegradable active substance matrix. Dexamethasone dosages may vary, but in general about 100 mcg to about 400 mcg may be effective for this indication. More specifically, various factors, such as age, secondary indications, existing conditions, etc., may cause some patients to be classified as low risk while others may be classified as high risk. In most cases, low risk patients may benefit from low doses of about 100 mcg to about 150 mcg. In contrast, a high risk individual may be administered a high dose of about 250 mcg to about 350 mcg. Some biodegradable implants can be specifically designed and tested for postoperative surgical inflammation treatment and deliver up to or about two weeks or more of the pharmaceutically active substance. In addition, other biodegradable implants can be designed and tested for the treatment of postoperative surgical inflammation and uveitis, and can deliver active substances up to or about 6-8 weeks or longer. Moreover, depending on the severity of inflammation, one, two, or more implants may be implanted in each eye during surgery.

The active substance delivery device may optionally include further active substances or other desired therapeutically beneficial components. In one aspect, for example, the device may comprise at least one secondary active material. If a plurality of active substances are included in the active substance delivery device, the active substance matrix may be homogeneous or non-homogeneous. In some examples, the active substance delivery device may comprise a plurality of active substances and may be homogeneous. In some examples, the active substance delivery device may comprise a plurality of active substances and may be non-homogeneous. For example, one active substance may be coated over the implant surface. In still other examples, the implant can be formulated to have predetermined zones or layers that include different active materials. Also in other examples, the implant can be formulated to have predetermined zones or layers having the same active substance but at different concentrations. For example, in some cases, the outer zone or layer of the implant has a higher concentration of active material, which extends over a period of days or weeks after delivering the active material at a higher initial dose or rapidly. It can deliver low doses. Also, in some examples, different regions of the implant can be adapted to biodegrade at different rates. Also in other examples, the material may be selectively coated over the implant to reduce the incidence of capsular fibrosis. Non-limiting examples of such substances include anti-cell proliferative substances, anti-TGF-beta substances, a5b1 integrin antagonists, rapamycin and the like.

The ocular active mass transfer device may be configured to fit within the lens capsular or ciliary furrows of the eye. The delivery device may be shaped into any geometry that allows insertion into the capsular coat or ciliary sulcus. For example, the implant can be round, square, crescent or donut shaped. However, other suitable shapes may include, but are not limited to, discs, pellets, rods, and the like. Sizes may vary, but typical sizes may range from about 0.5 mm to about 4 mm wide and from about 0.2 mm to about 1 mm thick. The total mass of the delivery device may vary, but most of the total mass may be 0.2 mg to 4 mg, or about 1.5 mg to about 2.5 mg. For example, about 2 mg total mass can provide an effective active substance volume, but can be adjusted in size to fit within the target tissue area.

In some specific examples, the implant may be molded into discs or pellets. In this case, the implant may typically have 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. In addition, in some examples, the disk- or pellet-shaped implant may typically have a thickness in the range 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. One example of a pellet or disk is shown in FIG. 1, which has a diameter of about 2 to 2.5 mm and a thickness of about 1.0-1.5 mm. In one particular example, the implant can have a rounded edge, hemispherical or semi-circular shape.

In another particular example, the implant can be molded into a rod. In this case, the implant may 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. In addition, in some examples, the rod-shaped implant may typically have a length in the range of 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.

Yet another aspect of the invention provides a method of delivering an active substance to the eye of a subject. When discussing various examples and embodiments relating to the implantable devices, systems, and methods described herein, it is noted that each of these discussions may also apply to each of the other aspects of the present invention. Thus, for example, when discussing the implantable device itself , this discussion also relates to the methods discussed herein and vice versa .

With this in mind, in some specific examples, the method may include placing the biodegradable active substance matrix described herein into the capsular coating of the subject to deliver the active substance to the posterior eye. The biodegradable active substance matrix may comprise the active substance present in an amount to deliver a therapeutically effective dose of the active substance from the capsular coating to the posterior eye.

In some examples, the method may include performing a cataract removal surgery on the subject's eye, which includes removing the existing lens from the subject's eye, inserting an artificial lens into the subject's eye, and The method may further comprise disposing the biodegradable active substance matrix into the lens coating. In some embodiments, the biodegradable active substance matrix or implant can be associated with an intraocular lens. In this case, the delivery device may be attached to or detached from the intraocular lens. The delivery device can be connected in close proximity or by real contact, while allowing the active material to diffuse effectively into the target site of the eye. Biodegradable systems can be of substantial value in minimizing or eliminating the need for a patient to use eye drops while providing short / time-limited delivery of post-operative medications in conventional cataract surgery. The lens to be removed may be the original natural lens of the eye, or it may be a lens previously inserted into the eye as a result of a previous procedure.

Numerous ways of placing the device in the eye are contemplated. For example, in one aspect, the implant may be associated with an intraocular lens prior to inserting the intraocular lens into the eye. In such cases, it may be necessary to configure the implant to meet any surgical procedure requirements. For example, cataract surgery is often performed through small incisions. One standard size incision is about 2.75 mm; Such devices may also be compatible with smaller or larger incision sizes. As such, the intraocular lens assembly may be shaped to allow insertion through these small openings. The active mass transfer device may therefore also be configured for insertion with the intraocular lens assembly, for example by the selection and / or shape of the elastic and flexible material for the implant. In addition, the active mass transfer device may also be physically coupled or detached from such an assembly prior to inserting the intraocular lens assembly into the eye. In another aspect, the implant can be placed inside the capsular membrane and optionally combined with the intraocular lens assembly after inserting the lens inside the eye. The capsular bag can be easily re-opened for patients who have previously undergone cataract surgery. Therefore, the insertion of the delivery device can be carried out in time as a separate procedure immediately before or after implantation of the intraocular lens.

Example

Example 1:

Thirty-five rabbits were subjected to standard clear-corneal phacoemulsification with Acrysof SA60AT (Alcon) implantation. At each surgery, an intraocular device containing the active substance was inserted into the capsular coating of each rabbit. Rabbits were divided into four groups according to the active substances 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, capsular fibrosis, and cataract wounds and healing of the anterior eye. Eye subgroups were taken at 1 month to assess inflammation for 4 weeks each week and to histologically evaluate encapsulation and CDR integrity.

Example 2:

Surgery and installation were repeated as described in Example 1, eye waterproof and vitreous puncture were performed every other week and analyzed for drug concentration by HPLC and / or ELISA. In each drug group, half of the eyes were taken at 1 month and the other half at 2 months. This was done as follows: Immediately after the rabbits were sacrificed and the eyes were removed, the eyes were frozen in liquid nitrogen to prevent shaking and redistribution of the drug in eye tissue. The eye was then dissected into three parts (ocular waterproof, vitreous and retinal / choroidal layers) to assess anatomical toxicity and tissue drug concentration. The intraocular device was recovered and the amount of drug remaining was measured. The dispensing profile of the intraocular device was compared with conventional 2.5 mg / 0.1 cc Avastin® intravitreal injection to directly compare different delivery methods.

At 2 and 4 months, eyes were removed from the remaining subgroups of rabbits, fixed with 10% formalin, impregnated with paraffin, step sectioned and stained with hematoxylin and eosin (H & E). And histological changes were examined.

Example 3:

Three intraocular devices were implanted into the eyes of New Zealand white rabbits under general anesthesia after lens extraction (phacoemulsification). Two devices were loaded with Avastin and one with contrast agent Galbumin. Proper intraocular device location was confirmed by MRI and clinical trials.

Rabbits were sacrificed and eyes removed and analyzed 1 week after transplantation. Avastin was detected by ELISA at a concentration of 24-48 mcg / mL in the retina and vitreous, and absent in control rabbit eyes. 5 shows the amount of Avastin analyzed for each ocular region one week after transplantation.

Example 4:

PLGA (poly (d, l-lactide-co-glycolide), MW, to confirm placement of the implant in the capsular bag and to ensure that drugs are delivered to both the front and back of the eye for short and long term . 7000-17000, acid ends], hydroxypropyl methyl cellulose (HPMC) and dexamethasone to prepare microparticles. Dexamethasone loaded PLGA microspheres were prepared using standard oil in water (o / w) emulsion-solvent extraction. 160 mg amount of PLGA was dissolved in 4 mL methylene chloride and 1 mL acetonitrile. 40 mg of dexamethasone and 10 mg of HPMC were vortexed for 5 minutes and dispersed in a PLGA solution. This organic phase was then emulsified and homogenized in 20 mL of 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, dichloromethane and acetonitrile were evaporated to form a cloudy microparticulate suspension. Microparticles were separated by centrifugation, washed twice, resuspended in deionized water and freeze-dried to obtain lyophilized particles. The prepared microparticles were characterized and pelletized using a bench top pellet press with a 2 mm die set to form an implant.

These implants were sterile and implanted into the capsular bag of rabbit eyes. Two dose groups were used (300 and 600 μg), and at 1, 2, 4 and 6 weeks, two rabbits were sacrificed from each of the low and high dose groups and various tissue samples (ocular waterproof, vitreous fluid, IOL, iris / Ciliary body and retina / choroid) and samples were analyzed by a validated LC / MS / MS method. Microspheres ranged from 6 ± 2 μM as confirmed by Zetasizer nano and SEM micrographs. The drug load in the microparticles was> 99% and the final yield was 60% (ie encapsulation efficiency). Drug load was determined as percent drug load = (weight of drug loaded / microsphere weight) × 100. Nearly zero-order dose-related pharmacokinetics were observed in rabbits for up to six weeks. In addition, dexamethasone flow was bidirectional from the intracapsular space to both the anterior and posterior chambers. There was no cell or fibrin formation in the anterior and posterior chambers of the eye. Histological examination showed that all tissues examined were normal and showed no signs of inflammation.

All study animals were released from quarantine and randomized and learned of laboratory conditions. All positive control and transplant groups received phacoemulsification and intraocular lens (IOL) insertion in both eyes. Groups III and IV received 1 and 2 implants in each eye, respectively.

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 doses of BDI implant (one implant in each eye) and up to 2 days postoperative antibiotic eye drops (b.i.d.); n = 8

Group-IV: phacoemulsification and IOL insertion; High dose BDI implants (2 implants in each eye) and up to 2 days postoperative antibiotic instillation (b.i.d.), n = 8

Results on in vitro release kinetics are presented in FIG. 10. All batches exhibited a biphasic release pattern with initial rapid release on day -1 and then slow and sustained release. The rapid release effect was slightly higher in implants containing HPMC.

A total of 16 animals (32 eyes) received the implant. Dexamethasone concentrations are shown in FIGS. 11-14. The implant slowly degraded over 4 weeks and completely disappeared by 6 weeks. The therapeutic concentration of DXM was found up to 6 weeks with minimal systemic exposure (<40 ng / mL at high doses), but higher (> 150 ng / mL for 1 week) with dexamethasone eye drops systemic exposure. Mean PK parameters for BDI-2 implants and positive control groups in ocular waterproof, vitreous fluid, retina / choroid, and iris / ciliates are shown in Tables 1 and 2.

 Intraocular pressure was normal in all groups. In addition, there were no signs of anterior or posterior chamber inflammation as assessed by biomicroscopy such as niche and confirmed by histological examination. Retinal thickness tended to increase in animals treated with dexamethasone eye drops, while retinal thickness was maintained in implants.

PLGA polymers are hydrolyzed to lactic and glycolic acids and then further to carbon dioxide and water before being removed from the body. The implant moved to the center and did not interfere with vision.

BDI-1 implants were prepared by drying the product under high vacuum for 3 days after partial solvent casting and subsequent distillation to remove residual solvent. PLGA [poly (d, l-lactide-co-glycolide), MW. 7000-17000, acid ends], hydroxypropyl methyl cellulose (HPMC), croscarmellose sodium (crosslinked sodium carboxymethylcellulose), hydroxypropyl cellulose and dexamethasone in various different compositions to prepare various implants. .

The dried particles were immediately pelleted using a bench top pellet press with a 2 mm die set to form an implant.

Selected BDI-1 implants (in vitro release study, FIG. 7) were sterile and implanted into the capsular bag of rabbit eyes. Two implants of different compositions and doses were tested in vitro in NZW rabbits to establish pharmacokinetics. Validated LC / MS / MS method by sacrificing two rabbits on Days 2, 6, 10, and 15 and taking various tissue samples (Eye Resistant, Vitreous Fluid, IOL, Iris / Ciliary and Retina / choroid) Analyzed. Near zero pharmacokinetics of pharmacokinetics were observed in rabbits for up to 15 days. In addition, dexamethasone flow was bidirectional from the intracapsular space to both the anterior and posterior chambers. There was also no cell or fibrin formation in the anterior and posterior chambers of the eye. Histological examination showed that all tissues examined were normal and showed no signs of inflammation.

In vitro release kinetics results are shown in FIG. 7. All batches exhibited a smooth release pattern-early rapid release on day -1 and then slow and sustained release. The rapid release effect was slightly higher in implants containing HPMC.

A total of eight animals (16 eyes) received an implant containing 120 μg of DXM. DXM concentrations are shown in FIGS. 8 and 9. The implant eroded slowly over 10 days and reached DXM trough concentration by day 15. Implants are expected to degrade by 80% of their mass by day 15 and fully degrade by day 20. The therapeutic concentration of DXM was found up to day 15 with minimal systemic exposure (<23 ng / mL), while it was higher with dexamethasone eye drop systemic exposure (> 150 ng / mL for 1 week, in-house data).

Example 5:

Many biodegradable implants were prepared using PLGA, croscarmellose sodium, and dexamethasone according to Table 3 below.

Drug release profiles for each of the listed agents were obtained using an in vitro drug release model. Individual drug release profiles are shown in FIG. 10. As shown in FIG. 10, an increase in the amount of croscarmellose may increase the rate of drug release from biodegradable implants compared to biodegradable implants made only of PLGA.

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 two week period. The second BDI was configured to deliver 300 mcg dexamethasone over a six week period. Drug release profiles were assessed using an in vitro drug release model. The emission profiles for the first and second BDI are shown in FIGS. 11 and 12, respectively.

In addition, these implants were sterile and implanted into the capsular bag of rabbit eyes. The implant slowly degraded over several weeks until complete disappearance. Mean PK parameters for the first BDI implant and positive control group in ocular waterproof, vitreous fluid, retina / choroid, and iris / ciliates are shown in Tables 4 and 5.

Dexamethasone concentration profiles for each eye region are shown in FIGS. 13-16. In addition, the retinal thickness for each of the test subjects was measured over time and compared with control subjects of the retinal thickness and normal retinal thickness of test subjects treated with the topical formulation. These results are shown in FIG. As shown in FIG. 17, a therapeutically effective dose can reduce retinal thickening associated with ocular conditions as compared to retinal thickening untreated with a topical formulation or compared with treatment with a topical formulation.

Mean PK parameters for the second BDI implant and positive control group in ocular waterproof, vitreous fluid, retina / choroid, and iris / ciliates are shown in Tables 6 and 7.

Dexamethasone concentration profiles for each eye region are shown in FIGS. 18-21. In addition, the retinal thickness for each of the test subjects was measured over time and compared with control subjects of the retinal thickness and normal retinal thickness of test subjects treated with the topical formulation. 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 untreated with a topical formulation or compared with treatment with a topical formulation.

It is to be understood that the above configurations are only intended to illustrate the application of the principles of the present invention. Numerous variations and alternative configurations may be devised by those skilled in the art without departing from the object and scope of the present invention. Therefore, while the present invention has been described in detail above in connection with what is presently considered to be the most practical and preferred embodiments of the invention, it includes, but is not limited to, including size, material, shape, form, operating function and manner, assembly and use ( However, it will be apparent to those skilled in the art that numerous modifications may be made without departing from the principles and concepts presented herein.

Claims (25)

A method of delivering an active substance to the posterior eye of a subject's eye, comprising the following steps:
Disposing the biodegradable active substance matrix inside the lens capillary of the subject to deliver the active substance to the posterior eye of the eye, wherein this disposing step comprises disposing the biodegradable active substance inside the lower perimeter or the annular perimeter of the capsular capsule. And wherein the biodegradable active substance matrix comprises the active substance in an amount that delivers a therapeutically effective dose of the active substance from the capsular coating to the posterior eye of the eye. The method of claim 1, wherein disposing the biodegradable active substance matrix within the capsular coating is performed during cataract surgery on the subject's eye. The method of claim 1, wherein the disposing step further comprises disposing the biodegradable active material matrix inside the lower perimeter coating. The method of claim 1, wherein the posterior eye part comprises at least one of vitreous fluid, choroid, and retina. The method of claim 1, wherein the biodegradable active matrix is poly (lactic-co-glycolide), polylactic-polyglycolic acid block copolymer (PLGA), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide- Polyvinyl alcohol, croscarmellose sodium, hydroxypropylcellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropylmethylcellulose (HPMC), and polycaprolactone -At least one of polyethylene glycol block copolymers. The low melting point of claim 1 wherein the biodegradable active substance matrix is 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. A method comprising fatty acids. The method of claim 1, wherein the biodegradable active substance matrix comprises poly (lactic-co-glycolide) having a copolymer ratio of 52/48 to 90/10. The method of claim 1, wherein the biodegradable active substance matrix comprises poly (lactic-co-glycolide) having a copolymer ratio of about 50/50. The method of claim 1 wherein the biodegradable active substance matrix comprises a disintegrant. The method of claim 9, wherein the disintegrant is croscarmellose, or a salt thereof. The method of claim 1 wherein the biodegradable active material matrix is shaped into discs, rods or pellets. The method of claim 8, wherein the disk 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 material matrix is shaped into a rod. The method of claim 10, wherein the rod has a diameter in a range from about 0.05 mm to about 2 mm and a length in a range from about 0.5 mm to about 5 mm. The method of claim 1, wherein the active substance is an ingredient selected from the group consisting of: dexamethasone, prednisolone, bevacizumab, ranibizumab, sunitinib, pegaptanib, moxifloxacin, gatifloxin, becy Phloxacin, timolol, latanoprost, brimonidine, nefafenac, bromfenac, diclofenac, ketorolac, triamcinolone, difluprenate, fluorinolide, aflibercept, and combinations thereof. The method of claim 1, wherein the active agent is at least one of dexamethasone, moxifloxacin, ketorolac, or bromfenac. The method of claim 1, wherein the active material has a molecular weight of 250,000 Daltons (Da) or less. The method of claim 1, wherein the active substance has a molecular weight of 500 Da or less. The method of claim 1, wherein the active substance is present in the biodegradable active substance matrix in an amount of about 100 mcg to about 400 mcg. The method of claim 1, wherein the active material is present in the biodegradable active material matrix in an amount of about 5% to about 25% by weight. The method of claim 1, wherein the active substance has a delivery period ranging from about 2 weeks to about 6 weeks. The method of claim 1, wherein the active substance has a delivery period ranging from 2 months to 12 months. The method of claim 1, wherein the therapeutically effective dose of the active substance is also delivered to the anterior eye of the eye. 18. The method of claim 17, wherein the anterior eye portion comprises at least one of eye waterproof and iris. The method of claim 1, wherein the therapeutically effective dose reduces retinal thickening associated with an ocular condition as compared to untreated retinal thickening.

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