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WO2019161378A1 - Cyclophosphamide pour le traitement de l'inflammation ophtalmique - Google Patents

Cyclophosphamide pour le traitement de l'inflammation ophtalmique Download PDF

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Publication number
WO2019161378A1
WO2019161378A1 PCT/US2019/018554 US2019018554W WO2019161378A1 WO 2019161378 A1 WO2019161378 A1 WO 2019161378A1 US 2019018554 W US2019018554 W US 2019018554W WO 2019161378 A1 WO2019161378 A1 WO 2019161378A1
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WO
WIPO (PCT)
Prior art keywords
corneal
cyclophosphamide
inflammation
formulation
ptcy
Prior art date
Application number
PCT/US2019/018554
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English (en)
Inventor
Robert B. LEVY
Victor Perez
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University Of Miami
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2019161378A1 publication Critical patent/WO2019161378A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the disclosure provides formulations comprising cyclophosphamide (Cy) and
  • Ophthalmic inflammation is a common condition that causes discomfort, affects vision, and can lead to significant complications in the eye. Inflammation is associated with a variety of ailments including, but not limited to, conjunctivitis, uveitis, cyclitis, scleritis, episcleritis, neuritis, keratitis, blepharitis, corneal and/or conjunctival ulcer, infection, and also can result from deficient tear production, allergies, abrasions, and surgical operations.
  • Ocular inflammation is also an important mechanism in many diseases which lead to loss of vision and blindness.
  • An example of this process is corneal transplantation, which is well characterized and involves an immune mediated rejection process that is initiated at the moment of surgery and transplantation.
  • Corneal transplantation is the most common form of solid organ transplant performed in the United States.
  • patients with vascularized beds prior to transplantation have a dismal rate of success (10-30%).
  • dismal rate of success 10-30%).
  • about 40,000 patients per year receive a corneal transplant for vision rehabilitation and of these 40,000, between about 4,000 and 6,000 are considered high risk. This number is likely and underestimate because many patients with high risk corneal beds are not considered surgical candidates due to the lack of effective treatments to prevent immune rejection.
  • compositions comprising cyclophosphamide (Cy).
  • Cy compositions formulated for ophthalmic delivery The disclosure further provides a method of treating or preventing ophthalmic inflammation in a subject in need thereof.
  • the disclosure further provides a method of treating or preventing host patient rejection of a corneal transplant. The method comprises locally administering (e.g., topically or subconjunctival) the formulation to an eye of the subject.
  • the disclosure provides a composition comprising cyclophosphamide (Cy).
  • the disclosure provides an ophthalmic formulation comprising
  • the disclosure provides a method of treating or preventing ophthalmic inflammation in a subject in need thereof, the method comprising locally administering the formulation of any one of claim 2 to the eye of the subject.
  • the disclosure provides a method of treating or preventing corneal transplant rejection in a subject in need thereof, the method comprising locally administering an ophthalmic formulation comprising cyclophosphamide (Cy).
  • the method includes a step of topically administering the Cy formulation to the surface of the eye.
  • the method may include subretinally administering the Cy formulation to the eye.
  • FIG. 1 is a diagrammatic overview showing graft rejection of a corneal transplant
  • FIG. 2 is a graph showing that administration of cyclophosphamide post-transplant may delay rejection of complete MHC-disparate cornea allografts
  • FIG. 3 is a graph showing that post orthotopic corneal allograft treatment with
  • cyclophosphamide (“PTCy”) significantly delays B6- BALB/c MHC-mismatched graft rejection;
  • FIG. 4 is a graph showing that administration of cyclophosphamide post-transplant significantly delays rejection of complete MHC-disparate cornea allografts;
  • FIG. 5 shows corneal transplants and an analysis of neo-vascularization after transplant of MHC-mismatched corneas in untreated and PTCy treated recipients;
  • FIG. 6 shows treated and untreated corneal transplants showing that neo-vascularization is minimal /absent in surviving corneal allografts treated with PTCy 60 days post-transplant;
  • FIG. 7 is a diagram showing the relationship between allo-reactive T-cells, neo- vascularization, and graft rejection and an inhibitory effect of PTCy on allo-reactive T-cells;
  • FIG. 8 is a diagram showing the relationship between allo-reactive T-cells, neo
  • FIG. 9 is a timeline showing effect of Cyclophosphamide on Allogeneic Corneal Transplant Survival
  • FIG. 10 depicts two bar graphs showing that TL1 A-Ig+IL-2 systemic administration induces strong Treg expansion following corneal transplant and PTCy treatment;
  • FIG. 11 is a timeline showing effect of Cyclophosphamide on Allogeneic Corneal
  • FIG. 12 is a graph showing transient expansion of Treg cells increases the survival time of complete MHC-mismatched corneal transplants treated with PTCy;
  • FIG. 13 shows schedules indicating that Local ophthalmic compartment restricted Treg expansion can be rapidly accomplished via a‘2-pathway’ targeting of TNFRSF25 and CD25;
  • FIG. 14 is a graph showing that periorbital administration of TLlA-Ig + IL-2 induces marked augmentation of Treg cells in the conjunctiva;
  • FIG. 15 depicts two graphs showing that local delivery effectively augments Treg levels in the conjunctiva systemic delivery can also increase Treg levels in the conjunctiva;
  • FIG. 16 depicts two graphs showing that periorbital vs. systemic administration of TLlA-Ig + low dose IL-2: Local delivery induces a greater elevation of conjunctival Treg cells;
  • FIG. 17 depicts two graphs showing that periorbital administered TL1 A-Ig and IL-2 expand conjunctival Tregs as assessed by frequency and Treg cell numbers;
  • FIG. 18 depicts four graphs showing that local periorbital administration of TLlA-Ig + IL-2 increases Treg cells in the Ipsilateral - but not- contralateral draining (cervical) nodes 1 week post infusion;
  • FIG. 19 depicts two graphs showing that local periorbital administration of TLlA-Ig + IL-2 increases Treg cells in the Local draining lymph node but not distal nodes 1 week post-infusion;
  • FIG. 20 is a diagram showing the relationship between allo-reactive T-cells, neo- vascularization, and graft rejection and an inhibitory effect of PTCy and Treg local on both allo- reactive T-cells and neo-vascularization.
  • cyclophosphamide may be used to treat ophthalmic inflammation and corneal transplant rejection.
  • Ocular inflammation is an important mechanism in many diseases which lead to loss of vision and blindness.
  • An example of this process is corneal transplantation, which is well characterized involving an immune mediated rejection process which is initiated at the moment of surgery and transplantation.
  • This model has enabled us to understand how enhancing the balance of T effector cells and Tregulatory cells can be regulated to control immune response in a positive manner minimizing ocular tissue damage.
  • Corneal transplantation is the most common form of solid organ transplant performed in the United States. However, patients with vascularized beds prior to transplantation have a dismal rate of success (10-30%). In fact, in the US, 40,000 patients per year receive a corneal transplant for vision rehabilitation and of these 4,000 to 6,000 are considered high risk.
  • the present disclosure provides a bench to bedside to bench translational basic science immunology project that will directly apply the disclosed pre-clinical experimental findings to induce long term tolerance in recipients of human corneal high-risk transplants.
  • CY cyclophosphamide
  • HSCT hematopoietic stem cell transplantation
  • cyclophosphamide provides an excellent platform to subsequently exploit expansion of Treg cells enabling the use of the disclosed novel”two-pathway” strategy.
  • HRVCT corneal transplantation
  • HSCT hematopoietic stem cell transplantation
  • cyclophosphamide given after bone marrow transplants (BMT), i.e. post-transplant Cy (PTCy) has shown very promising results in clinical allogeneic BMT patients. It has been demonstrated that deletion of allo-reactive T cells together with maintenance of Treg cells underlie the effectiveness of this strategy. In the present disclosure, it was assessed if PTCy would also be effective after solid tissue allografts, including high-risk corneal transplant.
  • ophthalmologic inflammation including, e.g., dry eye disease (keratoconjunctivitis sicca), ocular surface inflammation, inflammation resulting from allergies, keratitis, conjunctivitis, uveitis, inflammation associated with diabetic retinopathy, inflammation associated with age related macular degeneration, cyclitis, scleritis, episcleritis, blepharitis, inflammation associated with comeal and/or conjunctival ulcer, inflammation associated with abrasion or wound to the eye, inflammation associated with ophthalmic graft versus host disease (GVHD), or inflammation associated with ophthalmologic surgery.
  • GVHD ophthalmic graft versus host disease
  • Formulations for instance, must comprise a sufficient concentration of therapeutic to provide a beneficial effect in an extremely small volume of solution, disperse along the ocular surface to maximize delivery in topical applications, and absorb into adjacent tissues, as well as minimize impact on vision and intraocular pressure.
  • Anti inflammatories and formulation components that may be suitable for other areas of the body may not be suitable for use in the eye.
  • a method of treating or preventing ophthalmic inflammation in a subject in need thereof.
  • the method comprises locally administering the formulation described herein to the eye of the subject.
  • the ophthalmic inflammation is optionally
  • keratoconjunctivitis sicca ocular surface inflammation, inflammation resulting from allergies, keratitis, conjunctivitis, uveitis, inflammation associated with diabetic retinopathy,
  • inflammation associated with age related macular degeneration inflammation associated with nondiabetic macular edema, cyclitis, scleritis, choroiditis, episcleritis, blepharitis, inflammation associated with corneal and/or conjunctival ulcer, inflammation associated with infection (e.g., bacterial or viral infection), inflammation associated with abrasion or wound to the eye, inflammation associated with ophthalmic GVHD, or inflammation associated with
  • ophthalmologic surgery e.g., corneal transplant surgery, cataract surgery, retinal surgery, refractive surgery, or corneal surgery.
  • the formulation is locally administered to the eye.
  • Local administration refers to direct application to the eye, not systemic delivery.
  • Systemic delivery is contemplated in various aspects, which are distinct from local administration.
  • the formulation is administered topically, subconjunctivally, retrobulbarly, periocularly, subretinally,
  • the cyclophosphamide formulation may be administered in an amount effective to achieve a beneficial response in a clinically reasonable amount of time.
  • the formulation is administered in an amount effective to ameliorate ocular
  • inflammation or symptoms thereof in whole or in part, and/or protect, in whole or in part, against ocular inflammation or symptoms thereof (e.g., protect against increased severity of the inflammation).
  • Inflammation is diagnosed and monitored using a variety of techniques, including general eye exams, slit lamp examination, dilated fundus examination, corneal topography, lipid layer analysis, objective red eye scaling, corneal haze examination, staining, and the like.
  • the formulation will be administered as soon as inflammation or infection is detected or ocular surgery is completed.
  • the formulation also may be administered before inflammation or infection is detected or before or during ocular surgery.
  • the formulation is administered in an amount effective to treat or prevent corneal transplant rejection or symptoms thereof, in whole or in part, and/or protect, in whole or in part, against ocular transplant host rejection.
  • Dosage will depend upon a variety of factors, including the strength of the particular bromodomain inhibitor employed, the condition or disease state to be treated, and the amount and location of inflammation.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular bromodomain inhibitor and the desired physiological effect.
  • the formulation may be packaged in eye drop bottles and administered as drops.
  • a single administration (i.e., a single dose) of the formulation may include a single drop, two drops, three drops or more into the eyes of the subject.
  • the dose of bromodomain inhibitor is about 0.5% to about 5% provided in drop form, although intraocular injection also is contemplated.
  • the dose of the Bromodomain inhibitor is about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%.
  • ophthalmic cyclophosphamide formulation is administered at predetermined time intervals over an extended period of time.
  • ophthalmic formulation is administered once a day, twice a day, three times per day, four times per day, or more.
  • the ophthalmic formulation is administered every other day.
  • the ophthalmic formulation is administered over a treatment period of one week, two weeks, three weeks, one month, two months, three months, six months, nine months, twelve months, 18 months, or more.
  • the ophthalmic formulation is administered for a more extended period of time, including throughout the duration of the subject’s life.
  • the formulation is administered for a period of time then temporarily suspended before further treatment (i.e., a dosing holiday).
  • an initial therapeutic dose may be any initial therapeutic dose.
  • a maintenance dose typically lower than the therapeutic dose
  • the dosage and/or the frequency of administration is optionally reduced to a regimen that maintains the inflammation or symptoms thereof at an acceptable level.
  • the formulation is provided in a sustained-release delivery system or device.
  • Implants and devices are disclosed in, e.g., U.S. Pat. Nos. 5,443,505, 4,853,224,
  • An implantable device e.g., a mechanical reservoir, an intraocular device or an extraocular device with an intraocular conduit (e.g., 100 pm -1 mm in diameter) can be used.
  • Matrix -type delivery systems also are suitable for delivering the formulation. See e.g., Ueno et al., "Ocular Pharmacology of Drug Release
  • matrix-type delivery systems include soft contact lenses impregnated or soaked with the bromodomain inhibitor composition, as well as biodegradable implants comprising, e.g., poly(vinyl alcohol), polymers and
  • copolymers of polyacrylamide, ethyl acrylate, vinylpyrrolidone, polypeptides, polysaccharides, and/or crosslinked hyaluronic acid are examples of polyacrylamide, ethyl acrylate, vinylpyrrolidone, polypeptides, polysaccharides, and/or crosslinked hyaluronic acid.
  • the method optionally further comprises co-administration of other pharmaceutically active agents.
  • co-administration is meant administration before, concurrently with, e.g., in combination with the bromodomain inhibitor in the same formulation or in separate
  • corticosteroids prednisone, dexamethasone, or triamcinalone acetinide, or noncorticosteroid anti-inflammatory compounds, such as ibuprofen, can be co-administered.
  • Example 1 Murine orthotopic corneal allo-transplants were employed using B6 cornea donors and MHC-mismatched B ALB/c recipients which typically result in graft rejection rates of
  • FIG. 2 shows CT #8 PTC#l3 and the effect of Cyclophosphamide on Allogeneic Corneal Transplant Survival C57BL/6— > BALB/c.
  • FIG. 3 shows post orthotopic corneal allograft treatment with 70 mgs/kg cyclophosphamide (“PTCy”) significantly delays B6- BALB/c MHC-mismatched graft rejection.
  • PTCy post-transplant cyclophosphamide
  • FIGS. 5-6 Photographic and slit lamp analyses demonstrated markedly diminished overall number, size and location of vessels in PTCy treated CT recipients. Notably, within PTCy treated mice, long-term acceptors-but not rejectors-demonstrated minimal / no corneal neo-vascularization. In total, the findings illustrate that PTCy can effectively and significantly prolong CT.
  • FIG. 10 shows CT#8-PTC#l0 Treg expansion in peripheral blood after PTC treatment following B6 corneal allografts in BALB/c recipients.
  • TLlA-Ig+IL-2 induces Treg expansion following post-corneal transplant administration of PTCy.
  • Recipient mice were injected with TL1 A-Ig +IL-2 as in FIG. 10. beginning D.10 post-CT. Mice were bled on D.16 and stained for CD4 and FoxP3.
  • the techniques herein provide a method of use in which a strategy to limit / i.e. restrict the expansion of regulatory T cells (CD4 + FoxP3 + T cells) is implemented within the ocular compartment.
  • regulatory T cells CD4 + FoxP3 + T cells
  • periorbital delivery of these proteins results in dramatic and local Treg expansion within the ocular adnexa and draining cervical lymph nodes. In total, this enables the unique opportunity to develop and employ a combinatorial mechanism (Treg cells + PTCy) for the establishment of allograft tolerance to maintain permanent corneal graft survival.
  • An experiment was performed in which the above strategy was used to expand Tregs after cyclophosphamide and although the final treatment with IL-2 was 16 days after transplant, the survival of the allograft was significantly prolonged as shown in FIGS. 11-12.
  • the techniques herein further provide a strategy to expand Tregs by administering a“two pathway” strategy via local injection as shown in FIGS. 13-15.
  • a“two pathway” strategy via local injection as shown in FIGS. 13-15.
  • marked elevation of Treg cells in the conjunctiva was also observed when the strategy was employed systemically, Tregs were in fact elevated as well in the conjunctiva - however a one log greater level of TLlA-Ig fusion protein was employed as shown in FIG. 14.
  • FIGS. 15-16 The dosing is being optimized, which has led to identification of a potent level to locally expand conjunctival Treg cells as shown in FIG. 17.
  • the techniques herein provide that use of current anti-TNFRSF25 reagents - including evolving compounds following the use of cyclophosphamide or independently provides a powerful combinatorial strategy of deletion and expansion resulting in a balance of Teffector / Tregulatory cells which will promote long-term survival of corneal allografts as shown in FIG.
  • deletion / expansion strategy developed herein can be employed to treat a number of ocular inflammatory disorders including dry eye, uveitis, scleritis and mucous membrane pemphigoid as well as posterior segment diseases.
  • formulations are described as including components or materials, it is contemplated that the formulations can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise.
  • methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise.
  • the invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Ophthalmology & Optometry (AREA)
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  • Pain & Pain Management (AREA)
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Abstract

L'invention concerne des compositions comprenant du cyclophosphamide (Cy). Selon divers modes de réalisation, les compositions de Cy selon l'invention sont formulées pour une administration ophtalmique. L'invention concerne en outre une méthode de traitement ou de prévention de l'inflammation ophtalmique chez le patient le nécessitant. L'invention concerne en outre une méthode de traitement ou de prévention du rejet d'une greffe de cornée chez le patient hôte. L'invention concerne des méthodes permettant d'administrer localement (par exemple par voie topique ou sous-conjonctivale) les formulations de Cy au niveau de l'œil du patient.
PCT/US2019/018554 2018-02-19 2019-02-19 Cyclophosphamide pour le traitement de l'inflammation ophtalmique WO2019161378A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4853224A (en) 1987-12-22 1989-08-01 Visionex Biodegradable ocular implants
US4863457A (en) 1986-11-24 1989-09-05 Lee David A Drug delivery device
US4997652A (en) 1987-12-22 1991-03-05 Visionex Biodegradable ocular implants
US5098443A (en) 1989-03-23 1992-03-24 University Of Miami Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents
US5443505A (en) 1993-11-15 1995-08-22 Oculex Pharmaceuticals, Inc. Biocompatible ocular implants
US5554187A (en) 1995-08-18 1996-09-10 Rizzo, Iii; Joseph Medication dispensing intra-ocular lens system
US5725493A (en) 1994-12-12 1998-03-10 Avery; Robert Logan Intravitreal medicine delivery
BRPI1001466A2 (pt) * 2010-05-14 2012-01-03 Carlos Gilberto Almodin soluÇço oftalmologica de ciclofosfamida
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US4863457A (en) 1986-11-24 1989-09-05 Lee David A Drug delivery device
US4853224A (en) 1987-12-22 1989-08-01 Visionex Biodegradable ocular implants
US4997652A (en) 1987-12-22 1991-03-05 Visionex Biodegradable ocular implants
US5098443A (en) 1989-03-23 1992-03-24 University Of Miami Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents
US5443505A (en) 1993-11-15 1995-08-22 Oculex Pharmaceuticals, Inc. Biocompatible ocular implants
US5725493A (en) 1994-12-12 1998-03-10 Avery; Robert Logan Intravitreal medicine delivery
US5554187A (en) 1995-08-18 1996-09-10 Rizzo, Iii; Joseph Medication dispensing intra-ocular lens system
BRPI1001466A2 (pt) * 2010-05-14 2012-01-03 Carlos Gilberto Almodin soluÇço oftalmologica de ciclofosfamida
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JIFI-BAHLOOL H ET AL: "Peripheral ulcerative keratitis in the setting of rheumatoid arthritis: Treatment with immunosuppressive therapy", SEMINARS IN ARTHRITIS AND RHEUMAT, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 1, 1 August 1995 (1995-08-01), pages 67 - 73, XP004680727, ISSN: 0049-0172, DOI: 10.1016/S0049-0172(95)80019-0 *
PUJARI S S ET AL: "Cyclophosphamide for Ocular Inflammatory Diseases", OPHTHALMOLOGY, J. B. LIPPINCOTT CO., PHILADELPHIA, PA, US, vol. 117, no. 2, 1 February 2010 (2010-02-01), pages 356 - 365, XP027044160, ISSN: 0161-6420, [retrieved on 20091206] *
ROBERT LEVY ET AL: "Use of Post-Transplant Cyclophosphamide Therapy in High Risk Corneal Graft Transplantation: A New Strategy to Prolong Corneal Allograft Survival", INVESTIGATIVE OPHTHALMOLOGY AND VISUAL SCIENCE, vol. 59, no. 9, 29 April 2018 (2018-04-29), pages 3311, XP055581444 *
UENO ET AL.: "Controlled Drug Delivery", vol. II, 1983, CRC PRESS INC., article "Ocular Pharmacology of Drug Release Devices"

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