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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
  • A61K9/0051—Ocular inserts, ocular implants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• This invention relates to the use of methotrexate, e.g., repeated dosing or sustained-release formulations of methotrexate, for reducing risk of proliferative vitreoretinopathy (PVR) or epiretinal membranes (ERM) after surgical vitrectomy and/or scleral buckle to treat retinal detachment.
• methotrexate e.g., repeated dosing or sustained-release formulations of methotrexate
• RD Retinal detachment
• a retinal detachment is defined as the separation of the neurosensory retina from the retinal pigment epithelium (RPE).
• RPE retinal pigment epithelium
• the retinal pigment epithelium is a continuous epithelial monolayer occluded by tight junctions, which maintain a strict separation of the underlying choroidal capillary beds from the photoreceptors of the sensory retina, thus forming the outer blood-retina barrier. Its functions include the nourishment of photoreceptors, elimination of waste products, and reabsorption of subretinal fluid.
• the definitive treatment of retinal detachment is surgical repair. Multiple operative techniques are available to the treating retinologist, but the principles underlying treatment of retinal detachment remain the same: removal of fluid from the subretinal space, relief of any existing traction, and treatment and prophylaxis against the underlying cause for the ingression of fluid, whether it be due to a retinal break or an exudative process.
• Proliferative vitreoretinopathy is the most common cause for failure of retinal detachment surgery, a complication which occurs in 5- 10% of all retinal detachment surgeries. PVR can also occur spontaneously in the absence of surgery. PVR is most likely to develop following repeated surgical instrumentation of the eye, following significant physiologic insult to the eye such as in trauma, as well as in retinal detachments complicated by multiple tears, giant tears, vitreous hemorrhage, or in eyes with uveitis.
• ERM epiretinal membrane
• the present invention is based, at least in part, on the development of methods to treat and to reduce the risk of developing PVR or ERM.
• the invention provides methods for treating or reducing the risk of proliferative vitreoretinopathy (PVR) or epiretinal membranes (ERM) in a subject.
• the methods include administering a plurality, e.g., ten or more, intravitreal injections of methotrexate over a period of at least one, two, three, or more months, given no more frequently than weekly.
• each injection provides a dose of 400 meg in 0.1 ml methotrexate.
• the methotrexate is administered posterior to the limbus.
• the subject is undergoing an ocular surgical procedure that increases the subject's risk of developing ERM or PVR, e.g., a pars plana vitrectomy (PPV), Retinal Detachment (RD) surgery; ERM surgery; scleral buckle surgery; or a procedure in the other eye.
• ERM or PVR e.g., a pars plana vitrectomy (PPV), Retinal Detachment (RD) surgery; ERM surgery; scleral buckle surgery; or a procedure in the other eye.
• the subject requires a PPV to treat a rhegmatagenous retinal detachment secondary to trauma; preexisting proliferative vitreoretinopathy (e.g., grade C or higher); or for other indications associated with high risk condition for PVR development, e.g., giant retinal tears (giant retinal tears are defined as tears involving 90° or more of the circumference of the globe), retinal breaks larger than 3 disc areas, long-standing retinal detachments, or detachments associated with hemorrhage.
• a PPV to treat a rhegmatagenous retinal detachment secondary to trauma; preexisting proliferative vitreoretinopathy (e.g., grade C or higher); or for other indications associated with high risk condition for PVR development, e.g., giant retinal tears (giant retinal tears are defined as tears involving 90° or more of the circumference of the globe), retinal breaks larger than 3 disc areas, long-standing retinal detachments,
• a first injection is given at conclusion of the surgical procedure; eight weekly injections are given until postoperative month two; and a final tenth injection is given at postoperative month three.
• the methods include administering nine consecutive weekly injections, and a tenth injection three months after the first injection.
• the methods include administering additional injections monthly after the final, e.g., tenth, injection.
• the methods include administering one, two, three, four, five, six, seven, eight, or nine additional injections, e.g., monthly, after the tenth injection.
• the invention provides methods for treating or reducing the risk of PVR or ERM in a subject.
• the methods include intravitreally administering a sustained release formulation of methotrexate over at least a three-month period.
• the sustained release formulation is or comprises a lipid-encapsulated formulation; multivesicular liposome (MVL) formulations of methotrexate (MTX); nano- or microparticles; polyion complex (PIC) micelles; or bioadhesive polymers.
• the bioadhesive polymers comprise one or more of hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polyacrylic acid (PAA), or hyaluronic acid (HA).
• the invention provides methods for treating or reducing the risk of PVR or ERM in a subject.
• the methods include implanting a device for sustained release of methotrexate over at least a three-month period into the eye of the subject.
• the device is non-biodegradable.
• the subject does not have cancer, e.g., does not have an ocular cancer, e.g., does not have ocular or B cell lymphoma. In some embodiments, the subject does not have uveitis. In some embodiments, the methods include determining that a subject has or is at risk of developing PVR or ERM, or is about to undergo a procedure with a high risk of PVR or ERM as a side effect, and selecting the subject.
• FIG. 1 is a flowchart showing an exemplary treatment protocol using the present methods.
• FIGs. 2A-2C are each sets of nine images of human PVR cells plated into 12 wells with 30,000 cells per well showing that methotrexate inhibited proliferation of human proliferative vitreoretinopathy (PVR) cells in culture.
• the cells were treated with 100 ⁇ , 200 ⁇ , or 400 ⁇ Methotrexate (MTX) as indicated, and the images were taken after 72 hours (2A), 1 week (2B) or 2 weeks (2C).
• MTX Methotrexate
• the photomicrograph showed similar epithelioid morphology and limited confluence across the control plates (top row), as well as the three methotrexate concentrations (rows 2-4).
• control plates (row 1) showed a uniform, confluent cellular sheet whereas rows 2-4, which were exposed to methotrexate 400, 200, and 100 respectively, showed growth inhibition and lack of confluency, and were less epithelioid in appearance.
• the control plates (row 1) continued to be a uniform, confluent cellular sheet, whereas rows 2-4, exposed to methotrexate 400, 200, and 100 respectively, continued to have inhibited growth and lack of confluency.
• PVR Proliferative vitreoretinopathy
• Epiretinal membranes are caused by an abnormal proliferation of cells, e.g., retinal pigment epithelial (RPE) cells, glial cells, fibroblasts, and macrophages, on the surface of the retina, typically in response to ocular disease; the membranes tend to contract and cause puckering and thus distortion of the macula.
• RPE retinal pigment epithelial
• glial cells e.g., glial cells, fibroblasts, and macrophages
• PVR is an abnormal wound healing response of the vitreous and retina, a clinical syndrome where cells with proliferative capacity, driven by inflammatory mediators, multiply on the retinal surface, contract, and eventually cause recurrent retinal detachment (RD).
• the pathogenesis of PVR begins with the introduction of RPE cells into the vitreous cavity. These cells may be introduced at the time of the retinal tear itself or may be introduced iatrogenically such as through the use of cryotherapy or retinectomy. Studies from monkey eyes with PVR have also postulated that the introduction of Miiller cells, as well as potentially fibrocytes, occur as well.
• VEGF vascular endothelial growth factor
• PDGF platelet-derived growth factor
• TGF- ⁇ transforming growth factor-beta
• a pharmacologic adjuvant to prevent PVR has been an elusive goal in ophthalmology.
• a general pharmacologic strategy employed in prior PVR studies has been the single intravitreal, intraoperative administration of a variety of agents, such as duanoribicin, 5-fluorouracil (5-FU), triamcinolone, low-molecular weight heparin, and naproxen. 10"15
• the clearance of vitreally delivered drugs is dependent on a number of factors including the molecular weight of the drug, the status of the blood-retina barriers, contents of the vitreous cavity, etc., it is likely that those drugs used in these prior PVR studies were cleared from the eye within days after their administration. In contrast, PVR does not become a clinically appreciable, pathologic entity until at least 6-8 weeks after surgery.
• Methotrexate is a non-naturally occurring chemically also known as N-[4- [[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid.
• a folate analog, methotrexate is thought to act as an anti-proliferative agent by reversibly inhibiting dihydrofolate reductase, which prevents dihydrofolate from being reduced to tetrahydrofolate, which is used in the synthesis of purine nucleotides.
• Mechanisms of anti- inflammatory action are less clear, although mechanisms that have been proposed include its ability to enhance the extracellular concentration of adenosine, suppression of pro-inflammatory cytokines, inducement of apoptosis of activated T cells, and suppression of intracellular adhesion by activated T cells.
• the methotrexate is formulated for repeated injection, e.g., in Balanced Salt Solution from 25 mg vials to a sterile, single-use dose of 400 mcg/0.1 ml.
• the methotrexate is formulated for sustained release.
• sustained release formulations of methotrexate are known in the art, including but not limited to biodegradable implants such as lipid-encapsulated formulations, e.g., Depo/Methotrexate, as described in Bonetti et al., Cancer
• MDL multivesicular liposome
• MTX methotrexate
• nano- or micropartricules e.g., alpha- lactalbumin microparticles, e.g., as described in Vijayaragavan et al., Int J Pharm Res 3(l):39-44 (2011) or nanoparticles of conjugated methotrexate-human serum albumin as described in Taheri et al., J Nanomaterials 2011 (dx.doi.org/10.1155/2011/768201); polyion complex (PIC) micelles; bioadhesive polymers such as hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) and polyacrylic acid (PAA) derivatives, as well as hyaluronic
• HPMC hydroxypropyl methylcellulose
• CMC carboxymethylcellulose
• PAA polyacrylic acid
• sustained release can be achieved using a sustained-release device such as intravitreal implants, e.g., as described in Palakurthi et al., Current Eye Research, 35(12): 1105-1115 (2010) or similar to the Retisert
• the methods described herein can be used to prevent (reduce the risk of) PVR or ERM in patients, e.g., in patients requiring pars plana vitrectomy (PPV), e.g., for rhegmatagenous retinal detachment secondary to trauma; for patients requiring PPV for preexisting proliferative vitreoretinopathy grade C or higher; and/or for patients with retinal detachments requiring PPV for other indications associated with high risk condition for PVR development, e.g., giant retinal tears (giant retinal tears are defined as tears involving 90° or more of the circumference of the globe), retinal breaks larger than 3 disc areas, long-standing retinal detachments, or detachments associated with hemorrhage.
• PPV pars plana vitrectomy
• sustained methotrexate in the eye in addition to PVR include the following:
• EPvMs can develop spontaneously, which then requires surgery. If a subject developed an ERM in one eye, implanting a device to prevent ERMs in the other eye could prevent development in that eye.
• the methods described herein can include identifying and/or selecting a subject who is in need of treatment to prevent the development of PVR or ERM as a result of a condition listed above (e.g., selecting the subject on the basis of the need of treatment as a result of a condition listed above, e.g., an increased risk of developing PVR or ERM as a result of a condition listed above).
• the subjects treated with a method described herein do not have ocular cancers, e.g., do not have lymphoma (e.g., B cell lymphoma), and/or do not have uveitis.
• PVR clinically encompasses a wide phenotype.
• PVR can vary from a mild cellular haze (Grade A) to thick, fibrous membranes that cause the characteristic stiffened funnel of the detached retina (Grade D).
• GAA mild cellular haze
• G D fibrous membranes that cause the characteristic stiffened funnel of the detached retina
• a number of grading systems are in use, see, e.g., Ryan, Retina, 5 th ed (Elsevier 2013); Retina Society Terminology Committee. The classification of retinal detachment with proliferative vitreoretinopathy. Ophthalmology 1983;90: 121-5 (1983); Machemer R, Aaberg TM, Freeman HM, et al.
• the methods include identifying, selecting, and/or treating a subject who has a low grade (e.g., Grade A or Grade 1) PVR, or who has ERM.
• the methods include monitoring the subject for early signs of the development of PVR or ERM, i.e., the presence of a "vitreous haze" indicating a cellular proliferation (which may eventually develop into an organized sheet), and administering one or more doses of MTX as described herein.
• a low grade e.g., Grade A or Grade 1
• the methods include monitoring the subject for early signs of the development of PVR or ERM, i.e., the presence of a "vitreous haze" indicating a cellular proliferation (which may eventually develop into an organized sheet), and administering one or more doses of MTX as described herein.
• ERMs will cause a mild traction on the macula resulting in metamorphopsia but will not cause detachment of the retina, whereas untreated PVR will cause detachment and eventually result in a tunneled, atrophic retina.
• the methods can also be used to treat subjects without present signs of PVR but who are at risk for PVR or ERMs. Methods of Treating or Reducing Risk of PVR or ERM
• the methods described herein include the use of methotrexate in subjects who are at risk of developing a first or recurring PVR or ERM, e.g., a subject who is undergoing RD surgery or ERM surgery, as described above, and in subjects who have PVR or ERM or who are at risk for developing PVR or ERMs.
• the methods described herein include the use of methotrexate in subjects who have undergone, are undergoing, or will undergo a pars plana vitrectomy (PPV) or scleral buckle (SB).
• the methods include performing a PPV, RD surgery, or ERM surgery.
• PPV PPV is performed under local or general anesthesia using three, 23 or 20 gauge sclerotomy ports.
• Any present epiretinal membranes can be dissected, e.g., using a membrane pick and forceps.
• Intraoperative tissue staining, perfluorocarbons, cryopexy, endolaser, scleral buckling, and lensectomy can also be performed as needed.
• Standard tamponading agents can be used, e.g., silicone oil or gas.
• an effective amount of methotrexate is an amount sufficient to effect beneficial or desired results, e.g., the desired therapeutic effect (i.e., a prophylactically effective amount that reduces the risk of developing PVR or ERM).
• An effective amount can be administered in one or more administrations, applications or dosages.
• a therapeutically effective amount of methotrexate can be, e.g., 40C ⁇ g/0.1 ml per injection, e.g., with at least ten injections, giving a cumulative dose of 4,000 ⁇ g over ten injections; in some embodiments, the methods include giving more than ten injections, for a cumulative dose of more than 4,000 ⁇ g.
• the methods include giving fewer than ten injections, for a cumulative does of less than 4,000 ug.
• the compositions can be administered one from one or more times per day to one or more times per week to one or more times per month; including once every other day.
• certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
• intravitreal methotrexate injections are performed aseptically after the topical application of anaesthesia and an antiseptic agent, e.g., 5% povidone iodine, to the conjunctival sac.
• an antiseptic agent e.g., 5% povidone iodine
• each subject receives an intravitreal injection of methotrexate, e.g., 400 mcg/0.1 ml methotrexate, 3.0 to 3.5 mm posterior to the limbus, depending on lens status, with a 30-gauge needle.
• the subjects receive multiple intravitreal injections of methotrexate during their post-operative period.
• the first injection can be administered intraoperatively; subsequently, injections can be administered on postoperative (post-op) weeks 1, 2, 3, 4, 5, 6, 7, and 8, and on post-op month 3, for a total of 10 injections. See, e.g., Figure 1.
• the methods include administering the methotrexate in ten doses, or ten or more doses, or less than ten doses, over a three-month period or longer, and injections would be given no more frequently than weekly.
• the methods include additional doses at weekly, biweekly, or monthly frequency thereafter for an additional one, two, three, four, five, six, seven, eight, nine, ten, 11, or 12 months thereafter. In some embodiments the methods include ten doses over three months as shown in Fig. 1, with an optional additional one or more doses at monthly intervals thereafter for an additional one, three, six, or more months thereafter.
• the subjects receive a sustained release implant, e.g., as described above, that will release MTX over time, e.g., over a week, two weeks, a month, two months, three months, six months, or a year.
• the methods include administering subsequent implants to provide MTX administration for at least six months, one year, two years, or more.
• Example 1 Sustained methotrexate in the silicone filled postoperative eye at high risk for proliferative vitreoretinopathy
• Glaant retinal tears are defined as tears involving 90° or more of the circumference of the globe
• retinal breaks larger than 3 disc areas long-standing retinal detachments, detachments associated with hemorrhage.
• the PPV was performed under local or general anesthesia using three, 23 or 20 gauge sclerotomy ports. Any present epiretinal membranes were dissected using a membrane pick and/or forceps. Intraoperative tissue staining, perfluorocarbons, cryopexy, endolaser, scleral buckling, and lensectomy were performed as needed. Either silicone oil or gas was used as the tamponading agent.
• Routine post-operative visits which involve a dilated funduscopic examination, occured on post-operative day 1, 7, month 1, month 2, and month 3.
• the first injection was administered intraoperatively and subsequently was injected on post-op week 1,2,3,4,5,6,7,8 and on post-op month 3, for a total of 10 injections.
• Intravitreal methotrexate injections were performed aseptically after the topical application of anaesthesia and 5% povidone iodine to the conjunctival sac.
• Patient MTX08M ended the study with NLP vision. He had a history in the operative eye of pathological myopia, staphyloma, atrophy, lattice, and pave stoning. One month after his surgery (his third intravitreal surgery in that eye and the study surgery date), disc pallor was noted. Optical coherence tomographic pictures of that retina before and after had noted disorganized laminae, secondary to his underlying retinal disease. His vision at this was noted to be LP. He continued to receive injection with limited improvement in his vision and noted to be NLP at the final visit.
• PVR membranectomy was performed in patients undergoing retinal detachment repair secondary to PVR.
• cellular constituents of the PVR membranes were separated from the extracellular matrix membranes.
• 30,000 cells per well were placed into a standard 12 welled plate. All 12 wells received endothelial cell growth medium with supplemental growth factors.
• Four arms were designated consisting of three wells each. The first arm served as a control receiving the standard growth medium but no other intervention. The remaining wells were designated as treatment arms.
• the second arm of three wells served as the first treatment arm and exposed the cells to 400 micrograms of methotrexate.
• the third and fourth arms of three wells each exposed the cultured cells to 200 and 100 micrograms, respectively, of methotrexate.

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