WO2008130591A2 - Utilisation de polypeptides en feuille de trèfle pour traiter des lésions oculaires associées aux opérations ophtalmiques - Google Patents

Utilisation de polypeptides en feuille de trèfle pour traiter des lésions oculaires associées aux opérations ophtalmiques Download PDF

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WO2008130591A2
WO2008130591A2 PCT/US2008/004950 US2008004950W WO2008130591A2 WO 2008130591 A2 WO2008130591 A2 WO 2008130591A2 US 2008004950 W US2008004950 W US 2008004950W WO 2008130591 A2 WO2008130591 A2 WO 2008130591A2
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itf
polypeptide
trefoil
procedure
patient
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PCT/US2008/004950
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WO2008130591A3 (fr
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Chee-Wai Woon
Nicholas P. Barker
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The Gi Company, Inc.
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Publication of WO2008130591A2 publication Critical patent/WO2008130591A2/fr
Publication of WO2008130591A3 publication Critical patent/WO2008130591A3/fr

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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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • 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

Definitions

  • this invention relates to the field of treatment of ophthalmic disorders.
  • Surgical procedures for ophthalmic disorders are often used to improve the refractive function of the eye as an alternative to the use of glasses or contact lenses.
  • the technologies associated with these surgical procedures have advanced over time, with laser surgery now a common procedure to treat ophthalmic disorders.
  • Photorefractive keratectomy (PRK) and laser- assisted in situ keratomileusis (LASIK) are two laser-mediated procedures often performed to correct refractive disorders of the eye, including myopia, hyperopia, or astigmatism.
  • PRK photorefractive keratectomy
  • LASIK laser- assisted in situ keratomileusis
  • Proper wound healing is critical for the success of any ophthalmic procedure.
  • surgical procedures to correct ophthalmic disorders have high rates of success in correcting the disorders, complications in the wound healing process sometimes ensue, particularly within the cornea. Many patients endure a slow and painful recovery following surgical ophthalmic procedures.
  • the invention features methods, kits, compositions, and devices for treating an ophthalmic disorder.
  • the invention is particularly useful for treating patients having a lesion of the eye caused by or associated with an ophthalmic procedure, e.g., PRK or LASIK.
  • the present invention is also useful for treating pain associated with ophthalmic disorders.
  • the invention features a method of treating a patient having a lesion of the eye caused by or associated with an ophthalmic procedure performed on the patient, wherein the method includes administering to the patient, within fourteen days of the procedure, a pharmaceutical composition that includes trefoil polypeptide in an amount sufficient to treat the lesion.
  • the trefoil polypeptide-containing pharmaceutical composition described herein may also be used to treat pain associated with an ophthalmic procedure.
  • the procedure and treatment occur simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or fourteen days of each other. Treatment may even begin prior to the ophthalmic procedure.
  • the trefoil polypeptide may also be used for the preparation of a medicament that is used to treat a patient having a lesion of the eye caused by or associated with an ophthalmic procedure. Furthermore, the trefoil polypeptide may be used for the preparation of a medicament that is used to treat pain caused by or associated with an ophthalmic procedure.
  • the pharmaceutical composition described herein may also be administered through the use of an ophthalmic device that is suitable for ophthalmic contact.
  • the device may be an ophthalmic surgical instrument (e.g., a microkeratome), an intraocular lens implant, an intracorneal ring implant, a suture, or a therapeutic contact lens (e.g., a bandage contact lens).
  • the device may be coated or impregnated with the trefoil polypeptide.
  • the trefoil polypeptide of the device may also be formulated for sustained release.
  • the invention further features a kit that includes: (i) a pharmaceutical composition that includes a trefoil polypeptide; and (ii) instructions for administering the trefoil polypeptide to a patient having a lesion of the eye caused by or associated with an ophthalmic procedure performed on the patient.
  • the kit further includes an eye dropper.
  • the instructions state that the administering is to occur within fourteen days of the procedure.
  • the trefoil polypeptide of the kit e.g., ITF 15-73 or ITF 21-73 , or another trefoil polypeptide described herein, can be at a concentration of, e.g., 15 mg/ml to 100 mg/ml, e.g., about 20 mg/ml.
  • the kit further includes an additional therapeutic agent, e.g., any therapeutic agent described herein.
  • the ophthalmic procedure that causes, or is associated with, the lesion of the eye can be, e.g., radial keratotomy, astigmatic or arcuate keratotomy, laser thermokeratoplasty, conductive keratoplasty, photorefractive keratectomy (PRK), phototherapeutic keratectomy, photoastigmatic refractive keratectomy, hyperopic photorefractive keratectomy, presbyopic photorefractive keratectomy, laser-assisted in situ keratomileusis (LASIK), hyperopic-LASIK, epi-LAS ⁇ C, intra-LASIK, wavefront-LASIK, laser-assisted subepithelial keratomileusis, phakic intraocular lens implant, intraocular contact lens implant, refractive lens exchange, cataract extraction and intraocular lens implant, intracorneal ring implant, scleral expansion, or limbal relaxing incision.
  • the procedure is PRK or LASIK,
  • the pharmaceutical composition used to treat a patient or the pain associated with the ophthalmic procedure is administered directly to the eye in the form of an eye drop or ointment.
  • the trefoil polypeptide of the pharmaceutical composition may be present in the composition at a concentration of, e.g., 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 mg/ml, or any concentration between these values.
  • Trefoil polypeptides prepared in particular concentration ranges e.g., 15-100 mg/ml, 20-40 mg/ml, or other suitable ranges, may be useful in the methods, compositions, devices, and kits described herein.
  • the trefoil polypeptide may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the pharmaceutical composition contains an iso-osmotic saline solution.
  • the pharmaceutical composition may also contain a mucoadhesive agent.
  • the pharmaceutical composition can include a second therapeutic agent, e.g., an antimicrobial agent, an anti-inflammatory agent, an antibiotic agent, an antiviral agent, an antifungal agent, an analgesic, an anesthetic, a sedative, a lubricant, an immunomodulatory agent, or a 5 -aminosalicylate derivative, as described herein.
  • the second therapeutic agent may be administered independent of the pharmaceutical composition.
  • the pharmaceutical composition described herein may be administered in, e.g., 10, 20, 30, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100, 150, or 200 ⁇ l aliquots once, twice, three times, four times, or five times each day, or in other quantities and frequencies.
  • multiple aliquots are administered to a patient at one time; for example, two, three, four, five, or more drops of, e.g., about 45 ⁇ l, can be administered to the eye of a patient at one time, and this procedure can be repeated multiple times, e.g., two times, three times, four times, five times, or more per day.
  • the lesion caused by or associated with any ophthalmic procedure described herein may be any size, e.g., at least 4, 6, 8, 10, or 12 millimeters in one dimension. In some instances, the size of the lesion is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90% within seven days subsequent to treatment. Likewise, the methods described herein reduce pain, e.g., within seven days subsequent to the treatment described herein.
  • the trefoil polypeptide described herein may be selected, e.g., from intestinal trefoil factor (ITF; SEQ ID NO.: 1), pS2 (SEQ ID NO: 2), and spasmolytic peptide (SP; SEQ ID NO: 3), or any biologically active fragments of these polypeptides.
  • the trefoil polypeptide is selected from the group consisting Of ITFj -72 , ITF 15-72 , ITF 15-73 , ITF 21-62 , ITF 21-72 , ITF 21- 73 , ITF 22-62 , ITF 22-70 , ITF 22-72 , ITF 22-73 , ITF 25 .
  • the trefoil polypeptide described herein can be substantially identical to SEQ ID NO.: 1, SEQ ID NO.: 2, or SEQ ID NO.: 3 over at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 contiguous residues.
  • the degree of sequence identity can be, e.g., 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or even 100%.
  • Trefoil polypeptides may be administered according to any of the methods described herein as a monomer, a dimer, or in another multimeric form.
  • administering is meant a method of giving a dosage of a pharmaceutical composition to a patient.
  • the compositions utilized in the methods described herein can be administered by ocular administration, or alternatively by a route selected from, e.g., inhalation, parenteral, dermal, transdermal, buccal, rectal, sublingual, periungual, nasal, topical administration, and oral administration.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, and intramuscular administration.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the composition being administered and the severity of the condition being treated.
  • an amount sufficient to treat is meant the amount of a compound required to improve, inhibit, or ameliorate a condition of a patient, or a symptom of a disease, in a clinically relevant manner. Any improvement in the patient is considered sufficient to achieve treatment.
  • a sufficient amount of an active compound used to practice the present invention for the treatment of ophthalmic disorders varies depending upon the manner of administration and the age, body weight, and general health of the patient. Ultimately, the prescribers or researchers will decide the appropriate amount and dosage regimen.
  • a “high dosage” is meant at least 5% more (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • a high dosage of a trefoil polypeptide formulated for ocular administration may differ from a high dosage of the same agent formulated for intravenous administration.
  • immunomodulatory agent an agent that can elicit or suppress an immune response.
  • immunomodulatory agents include, e.g., non-steroidal immunophilin-dependent immunosuppressants, e.g., cyclosporine (e.g., Restasis), and steroids, e.g., dexamethasone, rimexolone, fluorometholone, medrysone, and loteprednol etabonate.
  • lesion of the eye is meant any abnormality of the epithelium of the eye, e.g., any injury or alteration to the epithelium of the eye caused by or associated with an ophthalmic procedure, e.g., PRK or LASIK.
  • a lesion of the eye can include, for example, an incision caused by a blade or laser.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • non-steroidal immunophilin-dependent immunosuppressant or “NsIDI” is meant any non-steroidal agent that decreases proinflammatory cytokine production or secretion, binds an immunophilin, or causes a down regulation of the proinflammatory reaction.
  • NsIDIs include calcineurin inhibitors, such as cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other agents (peptides, peptide fragments, chemically modified peptides, or peptide mimetics) that inhibit the phosphatase activity of calcineurin.
  • NsIDIs also include rapamycin (sirolimus) and everolimus, which bind to an FK506- binding protein, FKBP- 12, and block antigen- induced proliferation of white blood cells and cytokine secretion.
  • ophthalmic disorder any disturbance, defect, or abnormality in eye function or structure (e.g., a procedure resulting in a disruption of the epithelium of the eye, e.g., the corneal epithelium).
  • An ophthalmic disorder as defined herein can be congenital or hereditary, or can be the result of a trauma such as a physical injury, an illness, inflammation, an autoimmune disease, a virus (e.g., adenoviruses, herpes simplex virus), a blepharitis, a keratitis sicca, a trachoma, a corneal foreign body, ultraviolet light exposure (e.g., welding arcs, sunlamps), contact lens overwear, a systemic drug (e.g., adenine arabinoside), a topical drug, or invasion by a microbe.
  • a trauma such as a physical injury, an illness, inflammation, an autoimmune disease, a virus (e.g., adenovirus
  • Ophthalmic disorders can include refractive disorders of the eye, including, e.g., myopia, hyperopia, and astigmatism.
  • the ophthalmic disorder can be caused by or associated with any ophthalmic procedure, e.g., PRK or LASIK.
  • the ophthalmic disorder can include a lesion caused by or associated with the ophthalmic procedure, e.g., an incision by a blade or laser.
  • ophthalmic procedure is meant a procedure to treat an ophthalmic disorder.
  • the ophthalmic procedure can be selected, e.g., from radial keratotomy, astigmatic or arcuate keratotomy, laser thermokeratoplasty, conductive keratoplasty, photorefractive keratectomy (PRK), phototherapeutic keratectomy, photoastigmatic refractive keratectomy, hyperopic photorefractive keratectomy, presbyopic photorefractive keratectomy, laser- assisted in situ keratomileusis (LASIK), hyperopic-LASIK, epi-LASIK, intra- LASIK, wavefront-LASIK, laser-assisted subepithelial keratomileusis, phakic intraocular lens implant, intraocular contact lens implant, refractive lens exchange, cataract extraction and intraocular lens implant, intracorneal ring implant, scleral expansion, and limbal relaxing incision.
  • PRK photore
  • patient is meant any animal, e.g., mammal (e.g., a human).
  • a patient who is being treated for an ophthalmic disorder e.g., a lesion of the eye
  • Diagnosis may be performed by any suitable means.
  • a patient in whom the development of an ophthalmic disorder is being prevented may or may not have received such a diagnosis.
  • patients described herein may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age or a family history of ophthalmic disorders.
  • composition any composition that contains at least one therapeutically or biologically active agent and is suitable for administration to a patient.
  • pharmaceutical compositions suitable for delivering a therapeutic can include, e.g., eye drops, tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. Any of these formulations can be prepared by well known and accepted methods of art. See, for example, Remington: The Science and Practice of Pharmacy (21 st ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2005, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick, Informa Healthcare, 2006, each of which is hereby incorporated by reference.
  • polypeptide and “peptide” are used interchangeably and refer to any chain of more than two natural or unnatural amino acids, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally-occurring or non-naturally occurring polypeptide or peptide, as is described herein.
  • post-translational modification e.g., glycosylation or phosphorylation
  • a natural amino acid is a natural ⁇ -amino acid having the L-configuration, such as those normally occurring in natural proteins.
  • Unnatural amino acid refers to an amino acid, which normally does not occur in proteins, e.g., an epimer of a natural ⁇ -amino acid having the L configuration, that is to say an amino acid having the unnatural D- configuration; or a (D,L)-isomeric mixture thereof; or a homologue of such an amino acid, for example, a ⁇ -amino acid, an ⁇ , ⁇ -disubstituted amino acid, or an ⁇ -amino acid wherein the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms, such as an ⁇ - amino alkanoic acid with 5 up to and including 10 carbon atoms in a linear chain, an unsubstituted or substituted aromatic ( ⁇ -aryl or ⁇ -aryl lower alkyl), for example, a substituted
  • substantially identical is meant a polypeptide or nucleic acid exhibiting at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or even 100% identity to a reference amino acid or nucleic acid sequence over at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 contiguous residues or bases.
  • the trefoil polypeptide fragment amino acid sequences GLSANQCAVPAKDRVDCGYP and GLSPSQCMAPTNVRVDCNYP share 60% identity over 20 residues.
  • Sequence identity is typically measured using a sequence analysis program (e.g., BLAST 2; Tatusova et al., FEMS Microbiol Lett. 174:247-250, 1999) with the default parameters specified therein.
  • Conservative substitutions typically include substitutions within the following groups: glycine, alanine, valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine and tyrosine.
  • treating is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • Prophylactic treatment may be administered, for example, to a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disorder, e.g., an eye disorder, e.g., a lesion of the eye.
  • Therapeutic treatment may be administered, for example, to a subject already suffering from a disorder in order to improve or stabilize the subject's condition.
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • treatment may ameliorate a disorder or a symptom thereof, such as pain, by, e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • treating can result in both the inhibition of the formation of lesions and the healing of lesions already formed.
  • Trefoil polypeptides e.g., ITF 15-73 and ITF 21-73 , that promote healing of eye lesions or inhibit the formation of eye lesions, are useful in the methods described herein.
  • trefoil polypeptide is meant a biologically active polypeptide that is substantially identical, e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or even 100% identical, to intestinal trefoil factor (ITF; SEQ ID NO.: 1), pS2 (SEQ ID NO: 2), or spasmolytic peptide (SP; SEQ ID NO: 3) over at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 contiguous residues.
  • ITF intestinal trefoil factor
  • SP spasmolytic peptide
  • a trefoil polypeptide is biologically active if it exhibits a biological activity of a naturally-occurring trefoil polypeptide, e.g., the ability to alter gastrointestinal motility in a mammal or the ability to enhance corneal epithelial wound healing.
  • exemplary trefoil polypeptides useful in the invention are ITF 15-73 and ITF 21-73 .
  • trefoil polypeptides useful in the invention include ITFj -72 , ITFi 5-72 , ITF 2I-62 , ITF 21-72 , ITF 22-62 , ITF 22-70 , ITF 22-72 , ITF 22-73 , ITF 25-62 , ITF 25-70 , ITF 25-72 , and ITF 25-73 , wherein the subscripts delineate the bounds of each polypeptide according to SEQ ID NO.: 1.
  • Trefoil polypeptides may occur as monomers, dimers, or other multimeric forms.
  • FIGURE 1 shows the amino acid sequence (Accession No. BAA95531 ; SEQ ID NO.: 1) of human intestinal trefoil factor.
  • FIGURE 2 shows the amino acid sequence (Accession No. NP 003216;
  • SEQ ID NO.: 2 of human pS2 protein.
  • FIGURE 3 shows the amino acid sequence (Accession No. 1909187 A; SEQ ID NO.: 3) of human spasmolytic polypeptide (SP). DETAILED DESCRIPTION OF THE INVENTION
  • the present invention features methods, kits, compositions, and devices for treating a patient having a lesion of the eye caused by or associated with an ophthalmic procedure.
  • the invention further features methods and devices for treating pain associated with a lesion caused by or associated with an ophthalmic procedure.
  • Lesions can be treated, e.g., using a pharmaceutical composition containing a trefoil polypeptide.
  • Diagnosis and Treatment of Ophthalmic Disorders are useful for treating any patient that has undergone, or may undergo, an ophthalmic procedure concurrently or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or fourteen days of the treatment.
  • an ophthalmic disorder which is being treated by performing the ophthalmic procedure.
  • a patient may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • Diagnosis of ophthalmic disorders may be performed using any standard method known in the art, such as those described herein. Methods for diagnosing such disorders are described, for example, in U.S. Patent Nos. 4,842,401, 5,502,520, 6,890,076, and 7,140,730, hereby incorporated by reference, and in, e.g., Romano, P.E., Pediatrician 17(3): 134-41, 1990, hereby incorporated by reference. Diagnosis of an ophthalmic disorder may be made upon an external examination of the eye. Visual acuity disorders may be measured, e.g., using a Snellen chart. Direct and indirect ophthalmoscopy allow for the observation of the retina and other tissue at the back of the eye.
  • Retinal structures may also be examined using electroretinography or gonioscopy. Inspection of the eye with a slit lamp may also be used to detect ophthalmic diseases. The addition of fluorescein to the eye prior to a slit lamp examination allows for the detection of corneal abrasions or certain viral infections.
  • a binocular slit-lamp examination provides a detailed view of ophthalmic structures.
  • a tonometer may be used to measure intraocular pressure, and is a useful measurement to diagnose, e.g., glaucoma.
  • An Amsler grid tests the central field of vision, and may be used to diagnose retinal disorders. Pupil disorders may be diagnosed through a swinging flashlight test.
  • Optical coherence tomography is an imaging technique used for noninvasive retinal imaging for the early diagnosis of ophthalmic disorders, e.g., glaucoma.
  • An ophthalmic disorder may affect any part of the eye, e.g., the cornea, the sclera, the retina, the conjunctiva, the ciliary body, the posterior chamber, or the anterior chamber.
  • the ophthalmic disorder affects the cornea, e.g., the corneal epithelium, or the conjunctiva.
  • Ophthalmic disorders include, e.g., superficial punctate keratitis, corneal ulcer, herpes simplex keratoconjunctivitis, ophthalmic herpes zoster, phlyctenular keratoconjunctivitis, keratoconus, conjunctiva, keratoconjunctivitis sicca (dry eyes), ocular inflammation, corneal ulcers and cicatricial pemphigoid.
  • Ophthalmic disorders can be caused by viruses (e.g., adenoviruses or herpes simplex virus), blepharitis, keratitis sicca, trachoma, corneal foreign bodies, ultraviolet light exposure (e.g., welding arcs or sunlamps), contact lens overwear, systemic drugs (e.g., adenine arabinoside), topical drugs, bacteria, protozoa, fungi, or by a hypersensensitive reaction to a known or unknown antigen.
  • viruses e.g., adenoviruses or herpes simplex virus
  • blepharitis e.g., keratitis sicca, trachoma
  • corneal foreign bodies e.g., corneal foreign bodies
  • ultraviolet light exposure e.g., welding arcs or sunlamps
  • contact lens overwear e.g., systemic drugs (e.g., adenine arabinoside), topical drugs, bacteria, protozoa, fung
  • Physical eye trauma can also result in an ophthalmic disorder.
  • Physical trauma to the eye includes an abrasion to the cornea (e.g., caused by a foreign body), perforation of the cornea (e.g., caused by a blunt injury that disrupts the continuity of the cornea), chemical bums to the cornea (e.g., exposure to NaOH), or through surgical procedures (e.g., corneal transplants and intraocular injections).
  • the ophthalmic disorder generally results in damage and disruption of eye function or structure.
  • the disorder may cause the corneal epithelium to tear, may cause necrosis of the cornea, may cause corneal ulcers, or may damage the conjunctiva. Any of the ophthalmic disorders listed herein can be treated with trefoil polypeptide therapy.
  • Ophthalmic procedures may result in a lesion of the eye requiring treatment, e.g,. prophylactic or therapeutic treatment, before or after the procedure. Any of the methods known to those skilled in the art may be used to diagnosis the lesion resulting from the ophthalmic procedure and to determine an appropriate course of therapy. Lesions resulting from an ophthalmic procedure may be treated with trefoil polypeptide therapy.
  • Lesions treated by the methods of the present invention may be caused by or associated with an ophthalmic procedure performed to correct vision.
  • ophthalmic procedures may be incisional, thermal, lamellar, or ocular in nature. Examples of this procedure can include, e.g., radial keratotomy, astigmatic or arcuate keratotomy, laser thermokeratoplasty, conductive keratoplasty, photorefractive keratectomy (PRK), phototherapeutic keratectomy, photoastigmatic refractive keratectomy, hyperopic photorefractive keratectomy, presbyopic photorefractive keratectomy, laser- assisted in situ keratomileusis (LASIK), hyperopic-LASIK, epi-LASIK, intra- LASIK, wavefront-LASIK, laser-assisted subepithelial keratomileusis, phakic intraocular lens implant, intraocular contact lens implant, refractive lens exchange, cataract extraction and intra
  • Radial keratotomy is a procedure performed to correct myopia.
  • the procedure uses radial or spoke-shaped incisions to make a number of microscopic corneal incisions, allowing the outer cornea to relax so that the central cornea flattens.
  • the new shape of the cornea is permanently retained as the cornea heals.
  • Astigmatic or arcuate keratotomy (AK) is similar to radial keratotomy, but single or paired arcuate incisions are made on the cornea concentric to the visual axis. Incisions made during the AK procedure flatten the cornea to correct astigmatism.
  • Laser thermal keratoplasty a procedure for the correction of low hyperopia, is performed with a non-contact laser, wherein symmetrical, radial spots are placed outside the visual axis. The laser heats the cornea, resulting in stromal collagen shrinkage, and modifying the curvature of the cornea.
  • conductive keratoplasty CK is thermal keratoplasty performed with a high-frequency electric probe rather than a laser. CK is used to correct low hyperopia and keratoconus.
  • Photorefractive keratectomy is a lamellar refractive surgery that corrects low, moderate, and high myopia. PRK reshapes the cornea by destroying microscopic amounts of tissue from the outer corneal surface using an excimer laser to restore visual acuity.
  • Photoastigmatic refractive keratectomy is a surgery similar to PRK, but the ablation profile is specific for astigmatism.
  • Phototherapeutic keratectomy (PTK) unlike PRK, does not correct refractive errors of the cornea. Instead, PTK is used to treat visual impairment or irritative symptoms relating to corneal diseases.
  • Hyperopic photorefractive keratectomy is similar to myopic PRK, wherein an excimer laser is used to remove small amounts of corneal stroma. However, instead of flattening the central cornea, the H-PRK surgical procedure serves to "steepen" the cornea by ablating tissue in the cornea's peripheral regions. Presbyopic photorefractive keratectomy corrects presbyopia. Like PRK, the surgery utilizes an excimer laser, which is used to ablate a semilunar-shaped zone within the cornea, steepening the corneal curvature.
  • LASIK Laser-assisted in situ keratomileusis
  • LASIK a lamellar procedure that combines photoablation and intrastromal surgery, maintains the integrity of the outer layer of the cornea.
  • a flap of corneal tissue is cut with a microkeratome, exposing the underlying corneal stroma.
  • An excimer laser is then used to ablate a precise amount of corneal stroma, and the flap is placed back in its original position.
  • Intra-LASIK is similar to LASIK, except that the corneal flap is created with a femtosecond-laser microkeratome rather than with a mechanical, steel-bladed microkeratome.
  • Wavefront-guided LASIK, or custom LASIK is a variation of LASIK surgery, wherein measurements from a wavefront sensor guide a computer-controlled excimer laser to achieve a more optically perfect eye.
  • Laser-assisted sub-epithelium keratomileusis is a procedure, wherein a corneal epithelial flap is created using diluted alcohol placed on the cornea. An excimer laser is then used to ablate portions of the corneal stroma. After the ablation, the epithelial flap is reflected back onto the cornea.
  • Epi- LASIK is similar to LASEK. However, in the epi-LASIK procedure, an epi- keratome slides just underneath the epithelial cell layer of the cornea, creating the corneal flap.
  • Intraocular contact lens implants are surgically-implanted, corrective lenses placed in behind the iris of the eye and in front of the lens to correct moderate and high myopia and hyperopia.
  • a phakic intraocular lens is an implantable lens used to correct moderate and high myopia and hyperopia.
  • PIOLs are surgically implanted into the anterior or posterior chamber of the eye, or may be attached to the iris. The natural lens of the eye is not removed.
  • refractive lens exchange RLE, and also known as clear lens exchange, refractive lensectomy, or presbyopic lens exchange
  • the natural, crystalline lens of the eye is removed and an implantable lens is inserted, correcting moderate and high myopia and hyperopia. Removal of cataracts and implantation of an intraocular lens may also be used to correct moderate and high myopia and hyperopia.
  • An intrastromal corneal ring is a removal device used correct low degrees of myopia and keratoconus.
  • the ring placed into the periphery of the cornea, causes the cornea to flatten, correcting the refractive error.
  • Scleral expansion used to correct presbyopia, involves the implantation of a plastic ring in the sclera of the eye surrounding the ciliary body. The surgery increases the space between the ciliary body and the lens equator.
  • Limbal relaxing incisions are a modification of astigmatic keratotomy (AK), a procedure that corrects astigmatism. Incisions are made on the far periphery of the corneal limbus, creating a more rounded cornea and correcting the astigmatism.
  • the pharmaceutical composition containing the trefoil polypeptide is administered concurrently or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or fourteen days of the ophthalmic procedure.
  • Treatment may be performed alone or in conjunction with another therapy, and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the therapy depends on the age and condition of the patient, the severity of the patient's lesion, and how the patient responds to the treatment.
  • Methods for monitoring corneal lesion size can include, but are not limited to, slit lamp examination using fluorescein dye, slit lamp examination using reticle grids, comparing corneal lesions with standardized photographs of corneal lesions, scanning confocal microscopy, and high-frequency ultrasound.
  • a pain measurement index may be used.
  • Indices that may be useful in the methods and compositions described herein include a visual analog scale (VAS) or a Likert scale, each of which is well known in the art. Such indices may be used to measure pain, tenderness, light sensitivity, itchiness, burning sensations, eye-pain sensations, or other variables.
  • a visual analog scale provides a measure of a one-dimensional quantity.
  • a VAS generally utilizes a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., ten 1- cm intervals. For example, a patient can be asked to rank a sensation of pain by choosing the spot on the line that best corresponds to the sensation of pain, where one end of the line corresponds to "no pain" (score of 0 cm) and the other end of the line corresponds to "unbearable pain” (score of 10 cm). This procedure provides a simple and rapid approach to obtaining quantitative information about how the patient is experiencing pain.
  • VAS scales and their use are described, e.g., in U.S. Patent Nos. 6,709,406 and 6,432,937.
  • a Likert scale similarly provides a measure of a one-dimensional quantity.
  • a Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain).
  • a patient experiencing pain is asked to choose a number between the low value and the high value to represent the degree of pain experienced.
  • Likert scales and their use are described, e.g., in U.S. Patent No. 6,623,040 and U.S. Patent No. 6,766,319.
  • compositions described herein are prepared in a manner known to those skilled in the art, for example, by means of conventional dissolving, lyophilizing, mixing, granulating, or confectioning processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy (21 st ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2005, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick, Informa Healthcare, 2006, each of which is hereby incorporated by reference. Administration of compositions described herein may be by any suitable means that results in a compound concentration that is effective for treating or inhibiting (e.g., by delaying) the development of an ophthalmic disorder.
  • the compound is admixed with a suitable carrier substance, e.g., a pharmaceutically acceptable excipient that preserves the therapeutic properties of the compound with which it is administered.
  • a suitable carrier substance e.g., a pharmaceutically acceptable excipient that preserves the therapeutic properties of the compound with which it is administered.
  • One exemplary pharmaceutically acceptable excipient is physiological saline.
  • the suitable carrier substance is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition described herein can contain a mucoadhesive agent.
  • a mucoadhesive excipient can be added to the pharmaceutical composition.
  • the mucoadhesive formulations coat the lesioned area, resulting in retention of the intestinal trefoil peptide at the lesion site, providing protection, inhibiting irritation, and accelerating healing of inflamed or damaged tissue.
  • Mucoadhesive formulations suitable for use in these pharmaceutical preparations are well known in the art (e.g., U.S. Patent No. 5,458,879).
  • Particularly useful mucoadhesives are hydrogels composed of about 0.05-20% of a water-soluble polymer, e.g., poly(ethylene oxide), poly(ethylene glycol), poly(vinyl alcohol), poly(vinyl pyrrolidine), poly(acrylic acid), poly(hydroxy ethyl methacrylate), hydroxyethyl ethyl cellulose, hydroxy ethyl cellulose, chitosan, and mixtures thereof.
  • These polymeric formulations can also contain a dispersant such as sodium carboxymethyl cellulose (0.5-5.0%).
  • compositions are ones that allow the composition to be administered as a flowable liquid, but will cause the composition to gel in the lumenal milieu or upon contact with extracellular fluids or secretions, thereby providing a bioadhesive effect which acts to hold the therapeutic agents at the lesion site for an extended period of time.
  • the anionic polysaccharides pectin and gellan are examples of materials which, when formulated into a suitable composition, will form a gel in the lumenal fluid.
  • the liquid compositions containing pectin or gellan will typically consist of 0.01-20% w/v of the pectin or gellan in water or an aqueous buffer system.
  • compositions that promote mucoadhesion and prolonged therapeutic retention in surface epithelia are colloidal dispersions containing 2- 50% colloidal particles such as silica or titanium dioxide.
  • colloidal dispersions containing 2- 50% colloidal particles such as silica or titanium dioxide.
  • Such formulations form a flowable liquid with low viscosity suitable as an enema; however, the particles interact with glycoprotein, especially mucin, transforming the liquid into a viscous gel, providing effective mucoadhesion (e.g., U.S. Patent Nos. 5,993,846 and 6,319,513).
  • composition may be provided in a dosage form that is suitable for ocular administration, or alternatively by a route selected from, e.g., inhalation, parenteral, dermal, transdermal, buccal, rectal, sublingual, perilingual, nasal, topical administration, and oral administration.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, and intramuscular administration.
  • the composition may be in form of, e.g., eye drops, tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the composition is in the form of an eye drop or ointment.
  • the trefoil peptide used in the methods and compositions described herein should be provided in therapeutically effective amounts.
  • concentration of the trefoil peptide in the pharmaceutical composition can be, e.g., 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 mg/ml.
  • the pharmaceutical composition also comprises an iso- osmotic saline solution with a pH between 7.2 and 7.6.
  • compositions according to the invention may be formulated to release the active compound immediately upon administration, or at any predetermined time period after administration, using controlled release formulations.
  • Administration of compounds in controlled release formulations is useful where the compound, either alone or in combination, has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )); ( ⁇ ) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain a therapeutic level.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings.
  • suitable formulations are known to those of skill in the art. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • the pharmaceutical composition may be administered in 10, 20, 30, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100, 150, or 200 ⁇ l aliquots once, twice, three times, four times, or five times each day, or in other quantities and frequencies.
  • the pharmaceutical composition may be administered once per week, twice per week, three times per week, four times per week, five times per week, or six times per week.
  • Trefoil polypeptide therapy can continue until the eye lesion has healed.
  • the duration of therapy can be, e.g., one week to one month; alternatively, the pharmaceutical composition can be administered for a shorter or a longer duration. Continuous daily dosing with compounds used in the methods described herein may not be required.
  • a therapeutic regimen may require cycles, during which time a drug is not administered, or therapy may be provided on an as-needed basis.
  • Appropriate dosages of compounds used in the methods described herein depend on several factors, including the administration method, the severity of the ophthalmic disorder, and the age, weight, and health of the patient to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.
  • Trefoil Polypeptides the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic
  • Trefoil polypeptides are described extensively in the literature (see, e.g., Sands et al., Ann. Rev. Physiol. 58: 253-273, 1996, hereby incorporated by reference).
  • Naturally-occurring trefoil polypeptides are expressed, e.g., in the gastrointestinal tract and have a three-loop structure formed by intrachain disulfide bonds between conserved cysteine residues.
  • Fragments that retain the trefoil structure (i.e., the three loop structure) or that lie within regions of the protein that are highly conserved are particularly useful in the invention.
  • fragments can, e.g., encompass portions of ITF from about the first cysteine residue involved in a disulfide bond of the three loop structure to about the last cysteine residue involved in a disulfide bond of the three loop structure.
  • Trefoil polypeptides useful in the methods and devices described herein can include, e.g., fragments; allelic variations; homologs from other species, e.g., rat or mouse homologs; natural mutants; induced mutants; proteins encoded by DNA that hybridizes under high or low stringency conditions to ITF-, pS2-, or SP-encoding nucleic acids retrieved from naturally occurring material; and polypeptides retrieved by antisera to or SP.
  • Trefoil polypeptides can also include chimeric polypeptides that include a trefoil polypeptide domain as defined herein, fused to another domain, e.g., with a separate activity or characteristic.
  • Trefoil polypeptides useful in the methods and devices described herein can include modifications, e.g., in vivo or in vitro chemical derivatization of polypeptides, e.g., acetylation or carboxylation. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps, e.g., by exposing the polypeptide to enzymes that affect glycosylation derived from cells that normally provide such processing, e.g., mammalian glycosylation enzymes.
  • Trefoil polypeptides can differ from naturally-occurring ITF, pS2, or SP by alterations of their primary sequence. These include genetic variants, both natural and induced. Induced mutants may be derived by various techniques, including random mutagenesis of the encoding nucleic acids using irradiation or exposure to ethanemethylsulfate (EMS), or may incorporate changes produced by site- specific mutagenesis or other techniques of molecular biology.
  • EMS ethanemethylsulfate
  • trefoil polypeptides that include residues other than naturally-occurring L-amino acids, e.g., D-amino acids or non-naturally occurring or synthetic amino acids, e.g., ⁇ or ⁇ amino acids.
  • Trefoil polypeptides useful in the present invention are described, e.g., in U.S. Patent Nos. 6,063,755, and 6,221,840; U.S. Publication Nos.
  • Trefoil polypeptides or fragments thereof can be produced by any method known in the art for expression of recombinant proteins.
  • methods for producing trefoil polypeptides are well-known in the art; see, e.g., U.S. Publication No. 2004-0171544.
  • nucleic acids that encode the desired polypeptide may be introduced into various cell types or cell-free systems for expression thereby allowing small-, large-, and commercial-scale production, purification, and patient therapy.
  • Eukaryotic and prokaryotic expression systems may be generated in which a trefoil polypeptide sequence is introduced into a plasmid or other vector, which is then used to transform living cells.
  • trefoil polypeptide cDNA contains the entire open reading frame, or biologically active fragment thereof, are inserted in the correct orientation into an expression plasmid and may be used for protein expression.
  • Prokaryotic and eukaryotic expression systems allow for the expression and recovery of fusion proteins in which the trefoil polypeptide is covalently linked to a tag molecule on either the amino terminal or carboxy terminal side, which facilitates identification and/or purification.
  • tags that can be used include hexahistidine, HA, FLAG, and c-myc epitope tags.
  • An enzymatic or chemical cleavage site can be engineered between the trefoil polypeptide and the tag molecule so that the tag can be removed following purification.
  • Typical expression vectors contain promoters that direct the synthesis of large amounts of mRNA corresponding to the inserted intestinal trefoil polypeptide nucleic acid in the plasmid-bearing cells. They may also include a eukaryotic or prokaryotic origin of replication sequence allowing for their autonomous replication within the host organism, sequences that encode genetic traits that allow vector-containing cells to be selected for in the presence of otherwise toxic drugs, and sequences that increase the efficiency with which the synthesized mRNA is translated. Stable long-term vectors may be maintained as freely replicating entities by using regulatory elements of, for example, viruses (e.g., the oriP sequences from the Epstein-Barr virus genome).
  • viruses e.g., the oriP sequences from the Epstein-Barr virus genome
  • Cell lines may also be produced that have integrated the vector into the genomic DNA, and in this manner, the gene product is produced on a continuous basis.
  • a stable cell line expressing a trefoil polypeptide may have a single integrated copy of the vector containing the desired nucleic acid sequences or multiply integrated copies.
  • Nucleic acid sequences encoding trefoil polypeptides can be amplified in situ by various methods known in the art, for example, by methotrexate selection.
  • plasmid vectors contain several elements required for the propagation of the plasmid in bacteria, and for expression of the DNA inserted into the plasmid. Propagation of only plasmid-bearing bacteria is achieved by introducing selectable marker-encoding sequences into the plasmid that allow plasmid-bearing bacteria to grow in the presence of otherwise toxic drugs.
  • the plasmid also contains a transcriptional promoter capable of producing large amounts of mRNA from the cloned gene. Such promoters may be, e.g., inducible promoters that initiate transcription upon induction.
  • the plasmid also preferably contains a polylinker to simplify insertion of the gene in the correct orientation within the vector.
  • bacterial species may also be used to propagate and/or express intestinal trefoil polypeptides and fragments in a manner similar to using E. coli.
  • Lactobacilli species may be used to express the trefoil polypeptides or fragments either as soluble cytoplasmic proteins or by creating chimeric fusion proteins in which signal peptides would direct the expressed proteins into the periplasmic regions, to the outer surface of the bacteria, or as a secreted product out of the cell.
  • Mammalian cells can also be used to express a trefoil polypeptide.
  • Stable or transient cell line clones can be made using intestinal trefoil peptide expression vectors to produce the trefoil peptide in a soluble (truncated and tagged) form.
  • Appropriate cell lines include, for example, COS, HEK293T, CHO, and NIH cell lines such as NIH-3T3.
  • the appropriate expression vectors are constructed, they are introduced into an appropriate host cell by transformation techniques, e.g., calcium phosphate transfection, DEAE-dextran transfection, electrop oration, bombardment, microinjection, protoplast fusion, dendrimer-mediated transfection, or liposome-mediated transfection.
  • transformation techniques e.g., calcium phosphate transfection, DEAE-dextran transfection, electrop oration, bombardment, microinjection, protoplast fusion, dendrimer-mediated transfection, or liposome-mediated transfection.
  • the host cells that are transfected with the vectors of this invention may include, e.g., E. coli or other bacteria, yeast, fungi, insect cells (using, for example, baculoviral vectors for expression in SF9 insect cells), or cells derived from murine, human, or other animals.
  • trefoil polypeptides, fusions, or polypeptide fragments encoded by cloned DNA may also be used.
  • Those skilled in the art of molecular biology will understand that a wide variety of expression systems and purification systems may be used to produce recombinant trefoil polypeptides and fragments thereof.
  • cell-free wheat germ extracts, rabbit reticulocyte extracts, HeLa cell extracts, Kreb's extracts, and E. coli extracts are commonly used in the art for cell-free in vitro translation. Some of these systems are described, for example, in Ausubel et al. ⁇ Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY 2000).
  • Transgenic plants, plant cells, and algae are also particularly useful for generating recombinant trefoil polypeptides and trefoil polypeptide fragments for use in the methods described herein.
  • transgenic tobacco plants or cultured transgenic tobacco plant cells expressing a trefoil polypeptide can be created using techniques known in the art (see, for example, U.S. Patent Nos. 5,202,422 and 6,140,075).
  • Transgenic algae expression systems can also be used to produce recombinant proteins (see, for example, Chen et al., Curr. Genet. 39:365-370, 2001).
  • Trefoil polypeptides and fragments may be expressed in yeast, e.g., Saccaromyces cereviseae, Schizosaccaromyces pombe, or P ichia pastor is.
  • Pichia pastoris is capable of utilizing methanol as a carbon source.
  • trefoil polypeptide and trefoil polypeptide fragment nucleic acid sequences are introduced into a Pichia expression vector comprising the 5' and 3' promoter and regulatory sequences of the methanol inducible, alcohol oxidase (AOXl) gene, which provides for both targeted integration into the Pichia genome, and for high level of methanol-induced protein production.
  • AOXl alcohol oxidase
  • Polypeptides can be expressed as soluble cytoplasmic proteins or preferably fused in-frame with a secretory signal peptide and expressed as a secreted recombinant polypeptide.
  • the secretory signal is based on either the A or ⁇ -factor secretory signal.
  • recombinant chimeric proteins bearing the A or ⁇ -factor secretory signal will be exported out of the cell and can be collected from the media for further purification (see, for example, U.S. Patent Nos. 4,808,537, 4,837,148, 4,879,231, 4,882,279, 4,818,700, 4,895,800, and 4,812,405, 5,032,516, 5,122,465, 5,268,273; hereby incorporated by reference).
  • ITF 21-72 The optimal yield of the ITF 21-72 and ITF 21-73 occurs at a pH of approximately 5, whereas the optimal yield of the ITF 1S-72 an d ITFi S-73 occurs at pH 6.0-6.5. As the pi of ITF 1S-73 an d ITF 2J-72 is 5.1 and 6.9 respectively, separation of the two products can be achieved by ion-exchange chromatography.
  • trefoil polypeptides such as ITF 25-62 , ITF 22-62 , ITF 2 i_ 62 , ITF 25-73 , ITF 22-73 , and ITF 21-73 can be attained by fusing the corresponding nucleic acid sequence immediately following an initiator methionine (AUG). Translation of the resulting mRNA in any prokaryotic or eukaryotic host would lead to the cleavage of the initiator methionine by a methionine aminopeptidase (MetAP).
  • AUG initiator methionine
  • MetAPs have been extensively studied and have been shown to cleave the initiator methionine residue if the amino acid at position 2 (i.e., following the methionine) is glycine, alanine, serine, threonine, proline, cysteine, or valine (Arfine et al., Proc. Natl. Acad. Sci. USA, 92:7714-7718, 1995; Bradshaw et al., Trends Biochem. Sci., 23:263-267, 1998; Lowther and Matthews, Biochim. Biophys. Acta, 1477:157-167, 2000).
  • Dipeptide addition does not significantly affect the biological active of the trefoil polypeptide. Most commonly, a glutamate-alanine (EA)-N-terminal addition is observed and arises from an alternative processing site in the signal sequence of the Pichia yeast expression system. An EA-N-terminal addition occurs in the production OfITF 15-73 , resulting in a 61 amino acid product (EA-ITF 15-73 ) which has been detected as a monomer, homomeric dimer, and heteromeric dimer in combination with ITF 15-73 .
  • EA-ITF 15-73 a glutamate-alanine
  • trefoil polypeptides and trefoil peptide fragments in eukaryotic expression systems has the added benefit of being post-translationally processed in the appropriate cellular organelle(s). For instance, glycosylation of trefoil polypeptides can be facilitated in the endoplasmic reticulum or Golgi apparatus prior to secretion.
  • Secreted proteins can be processed by proteolytic processing by proteases residing at the extracellular face of the cell, such as the proprotein convertases (PCs).
  • PCs proprotein convertases
  • a recombinant protein Once a recombinant protein is expressed, it can be isolated from cell lysates if expressed as a cytoplasmic protein, or from the media if expressed as a secreted protein. Protein purification techniques such as ion-exchange, gel- filtration, and affinity chromatography can be utilized to isolate trefoil polypeptides from unwanted cellular proteins. Once isolated, the recombinant protein can, if desired, be purified further by high performance liquid chromatography (HPLC; e.g., see Fisher, Laboratory Techniques In Biochemistry And Molecular Biology, Work and Burdon, Eds., Elsevier, 1980).
  • HPLC high performance liquid chromatography
  • Trefoil polypeptides and trefoil polypeptide fragments as described herein can also be produced by chemical synthesis using, for example, Merrifield solid phase synthesis, solution phase synthesis, or a combination of both (see, for example, the methods described in Solid Phase Peptide Synthesis, 2nd ed., 1984, The Pierce Chemical Co., Rockford, IL). Trefoil polypeptides may then be condensed by standard peptide assembly chemistry.
  • trefoil polypeptides may be produced in any appropriate manner, e.g., as a pre-prodrug, prodrug, or a precursor molecule encompassing a trefoil polypeptide region. It is envisioned that such a molecule upon introduction into the body can undergo further processing once inside the host. For example, a trefoil polypeptide or fragment carrying further amino acid sequences at the amino or carboxy terminus can undergo proteolytic cleavage to produce the active species used for trefoil therapy. This may be facilitated by endogenous proteases, for example, chymotrypsin, pepsin, and trypsin.
  • endogenous proteases for example, chymotrypsin, pepsin, and trypsin.
  • therapeutic agents may be administered with the trefoil polypeptide described herein at concentrations known to be effective for such therapeutic agents.
  • Particularly useful agents include, e.g., antimicrobial agents, anti-inflammatory agents, antiviral agents, antifungal agents, analgesics, anesthetics, sedatives, lubricants, immunomodulatory agents, and 5- aminosalicylate derivatives.
  • therapeutic agents may be delivered separately or may be admixed into a single formulation. When agents are present in different pharmaceutical compositions, different routes of administration may be employed.
  • Routes of administration include, e.g., ocular, inhalation, parenteral, dermal, transdermal, buccal, rectal, sublingual, periungual, nasal, topical administration, or oral administration.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, and intramuscular administration.
  • the trefoil polypeptide and additional therapeutic agents are administered at least one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or fourteen days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently. For example, one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents described herein may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a patient.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds, described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve other therapies, including modification to the lifestyle of the patient being treated.
  • treatment of the lesion or pain associated with the ophthalmic procedure with the trefoil peptide may further include coadministration with a second therapy, e.g., an antimicrobial agent, an antiinflammatory agent, an antibiotic agent, an antiviral agent, an antifungal agent, an analgesic, an anesthetic, a sedative, a lubricant, an immunomodulatory agent, or a 5-aminosalicylate derivative.
  • a second therapy e.g., an antimicrobial agent, an antiinflammatory agent, an antibiotic agent, an antiviral agent, an antifungal agent, an analgesic, an anesthetic, a sedative, a lubricant, an immunomodulatory agent, or a 5-aminosalicylate derivative.
  • Suitable anti-inflammatory agents include, e.g., non-steroidal anti-inflammatory drugs (e.g., ibuprofen or tacrolimus), cyclooxygenase-2-specif ⁇ c inhibitors such as rofecoxib (Vioxx®) and celecoxib (Celebrex®), topical glucocorticoid agents, and specific cytokines directed at T lymphocyte function.
  • Suitable anti-inflammatory agents include flubiprofen, diclofenac, and ketarolac. Antiinflammatory concentrations known to be effective can be used.
  • ibuprofen may be present in the composition at concentrations sufficient to deliver between 25-800 mg per day to the lesion.
  • exemplary antiinflammatory agents are listed in, e.g., U.S. Patent Nos. 7,112,578 and 7,199,119.
  • Antimicrobial agents include antibacterials, antifungals, and antivirals.
  • antibacterial agents examples include penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, moxifloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, cycloserine, isoniazid, rif
  • Antiviral agents are substances capable of destroying or suppressing the replication of viruses.
  • antiviral agents include 1- ⁇ -D- ribofuranosyl-l,2,4-triazole-3 carboxamide (ribavirin), 9-2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, adenine arabinoside, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.
  • Exemplary antiviral agents are listed in, e.g., U.S. Patent Nos. 6,093,550 and 6,894,033.
  • Antifungal agents include both fungicidal and fungistatic agents, e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole. Exemplary antifungal agents are listed in, e.g., U.S. Patent Nos. 5,627,153 and 7,125,842.
  • Dacryocystitis an infection to the lacrimal sac
  • hordeolum and blephartis infections to the eyelids
  • conjunctivitis and keratitis are most commonly caused by infections by microbial pathogens, for example, herpes virus, herpes zoster virus, adenovirus, Staphylococcus aureus, Streptococccus pneumoniae, Haemophilus and Neisseria spp.
  • Topical ophthalmologic-grade antibiotic and antifungal solutions and ointments are prepared, typically between 0.1-5% (w/v) in solution for treating bacterial pathogens.
  • Antiviral solutions of idoxuridine, trifluridine, and vidarabine ointments or solutions are prepared at 0.1-1% w/v, while foscarnet, acyclovir, gancyclovir, formivirsen, and cidoforvir are administered orally, intravenously, topically to the eye, or through intravital implant.
  • Analgesics and Anesthetics are prepared, typically between 0.1-5% (w/v) in solution for treating bacterial pathogens.
  • Antiviral solutions of idoxuridine, trifluridine, and vidarabine ointments or solutions are prepared at 0.1-1% w/v, while foscarnet, acyclovir, gancyclovir, formivirsen, and cidoforvir are administered orally, intraven
  • any of the commonly used topical analgesics and anesthetics can be used in the invention.
  • useful anesthetics include procaine, lidocaine, tetracaine, dibucaine, benzocaine, p-buthylaminobenzoic acid 2- (diethylamino) ethyl ester HCl, mepivacaine, piperocaine, and dyclonine.
  • Exemplary anesthetics are listed in, e.g., U.S. Patent Nos. 6,562,363 and 6,569,839.
  • Analgesics include opioids such as, for example, morphine, codeine, hydrocodone, and oxycodone. Any of these analgesics may also be co- formulated with other compounds having analgesic or anti-inflammatory properties, such as acetaminophen, aspirin, codeine, naproxen, and ibuprofen. Exemplary analgesics are listed in, e.g., U.S. Patent Nos. 6,869,974 and 7,202,259.
  • Sedatives are agents that suppress the central nervous system. Any of the commonly used sedatives can be used in the invention. Examples of useful sedatives include alprazolam, clonazepam, diazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, and triazolam. Exemplary sedatives are listed in, e.g., U.S. Patent No. 5,589,475.
  • Ophthalmic lubricants can be used in, e.g., eye drops, to treat lesions caused by or associated with ophthalmic procedures.
  • useful lubricants include sodium hyaluronate, proteoglycans, chondroitin sulfate, cellulose derivatives, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, collagen, viscosifiers, polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers.
  • Exemplary lubricants are listed in, e.g., U.S. Patent No. 7,037,469. Immunomodulatory Agents
  • Immunomodulatory agents are agents that can elicit or suppress an immune response. Any of the commonly used immunomodulatory agents can be used to treat lesions caused by or associated with ophthalmic procedures. Examples of useful immunomodulatory agents include, e.g., non-steroidal immunophilin-dependent immunosuppressants, e.g., ascomycin, cyclosporine (e.g., Restasis), everolimus, pimecrolimus, rapamycin, and tacrolimus.
  • non-steroidal immunophilin-dependent immunosuppressants e.g., ascomycin, cyclosporine (e.g., Restasis), everolimus, pimecrolimus, rapamycin, and tacrolimus.
  • steroids e.g., beclomethasone, budesonide, dexamethasone, fluorometholone, fluticasone, hydrocortisone, loteprednol etabonate, medrysone, rimexolone, and triamcinolone.
  • steroids e.g., beclomethasone, budesonide, dexamethasone, fluorometholone, fluticasone, hydrocortisone, loteprednol etabonate, medrysone, rimexolone, and triamcinolone.
  • steroids e.g., beclomethasone, budesonide, dexamethasone, fluorometholone, fluticasone, hydrocortisone, loteprednol etabonate, medrysone, rimexolone, and triamcinolone.
  • Exemplary steroids are listed in, e.g., U.S. Patent Nos
  • 5 -Aminosalicylate Derivatives 5 -Aminosalicylate (5-ASA) derivatives, e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide, may be administered as second therapeutic agents.
  • exemplary 5-ASA derivatives are listed in, e.g., U.S. Patent Nos. 6,326,364 and 7,119,119.
  • Suture materials, sterile wound dressings (occlusive and semi-occlusive, e.g., gauze pads), topical patches, adhesive films, and tissue adhesives can be impregnated or coated with the trefoil peptides of the present invention and used at an incision site to promote dermal and epidermal healing.
  • Any of the suture materials, wound dressings, topical patches, adhesive films, and tissue adhesives may also contain bioerodable polymers and alginates containing trefoil polypeptides.
  • sutures made from monofilaments can be impregnated by loading the polymer solution with a trefoil peptide, prior to extrusion.
  • Suture material can also be impregnated by repeated soaking/drying cycles using a trefoil peptide-containing solution. The number of cycles depends on the concentration of trefoil peptide in the soaking solution and the final amount of peptide to be contained in the suture. Soaking is a particularly effective impregnation or coating method for braided suture materials because the trefoil peptide is retained by the surface contours.
  • Sterile dressings and gauzes for wounds and burns, impregnated or coated with a trefoil peptide can also be prepared by standard methods.
  • the trefoil peptide will be present in a viscous gel (e.g., hydrogel), separated from the dermal lesion by a permeable fabric that does not adhere to the wound.
  • the pharmaceutical composition may also be administered through the use of an ophthalmic device that is suitable for ophthalmic contact.
  • the device may be an ophthalmic surgical instrument (e.g., a microkeratome), an intraocular lens implant, an intracorneal ring implant, a suture, or a therapeutic contact lens (e.g., a bandage contact lens).
  • the device may be coated or impregnated with the trefoil polypeptide.
  • a bandage contact lens may be used to administer the pharmaceutical composition described herein.
  • the trefoil polypeptide may be, e.g., embedded in the bandage contact lens or may coat the surface of the contact lens.
  • the bandage contact lens may be purchased from, e.g., Bausch & Lomb, CIBA Vision, Gelflex Laboratories, CooperVision, UltraVision CLPL, United Contact Lens, or Vistakon/Johnson & Johnson.
  • the bandage contact lens may be made of any suitable material, e.g., poly-2-hydroxyethyl methacrylate (poly- HEMA), polyvinyl pyrolidone (PVP), flexible plastics, fluorosilicone acrylates, cellulose acetate butyrate, polymethyl methacrylate (PMMA), silicones, siloxane methacrylates, polymacon, or silicone hydrogels (e.g., lotraf ⁇ lcon A, lotrafilcon B, galyfilcon A, senofilcon A, alfafilcon A, omafilcon A, nelfilcon A, hilafilcon A, hilafilcon B, phemfilcon A, tefilcon, tetrafilcon A, crofilcon, balafilcon A, etafilcon A, ocufilcon D, methafilcon A, and vilfilcon A).
  • poly- HEMA poly-2-hydroxyethyl methacrylate
  • Exemplary materials for the bandage contact lens are described in, e.g., U.S. Patent No. 5,958,194.
  • Chronic eye disease such as cataracts, glaucoma, uveitis, keratoconus, or dry-eye syndrome
  • ⁇ Ocular surface conditions that might be a contraindication for PRK, including keratoconjunctivitis sicca, severe meibomian gland disease, or active anterior blepharitis
  • the active study drug was recombinant human ITF in an iso-osmotic, pH neutral (pH 7.2-7.6), aqueous solution containing ITF at a concentration of 20 mg/ml.
  • the placebo drops consisted of 0.9% w/v sodium chloride solution, adjusted to approximately neutral pH.
  • the drop volume for the study drug and placebo was approximately 45 ⁇ l.
  • Each subject had one eye treated with the drug substance and the other with placebo in accordance with this scheme.
  • the ITF eye drops were administered from a specialized ophthalmic dropper bottle containing 1 ml of solution, kept frozen until the day of use. Dropper bottles were removed from the freezer at least one half hour before intended use and allowed to come to ambient temperature.
  • the study medication and placebo were dosed at four drops per day at approximately the following time points: 8, 12, 16, and 20 hours. Drops were administered on Days 1-7 of the study. Other concomitant eye drop medications were not given at the same time as the study medications. Drops were administered by the investigator or a dedicated study nurse, and were instilled directly into the conjunctival sac. The ITF and placebo eye drops were of the same color and indistinguishable in appearance. Allocation of the two study treatments was random and double-blinded. Efficacy of the ITF eye drops was assessed by comparing the response observed between the ITF-treated eyes and placebo-treated eyes. The primary assessment of efficacy was to monitor the size of the PRK-resultant corneal epithelial defect.
  • the size of the defect was assessed by first applying fluorescein dye to the surface of the eye, which stains the corneal defect.
  • a slit lamp fitted with an eyepiece reticle was used to measure the degree of fluorescein staining. Measurements of the size of the corneal epithelial defect began on Day 1 of the study (i.e., the day of surgery) and continued daily through Day 7. The size of the defect was again measured on Day 21 and Day 92 of the study. Time to healing was defined as the interval of time between Day 1 and the day on which the measured area of the corneal epithelial defect, determined by corneal staining, became zero.
  • rTFF3 rat intestinal trefoil factor peptide
  • Transepithelial excimer laser ablations (2 mm optical zone; 42-44 micron ablation depth, phototherapeutic keratoectomy mode) were made using an Esiris Excimer Laser (Schwind, Aillesburg, Germany).
  • Ophthalmic drops containing BSA 1.0 mg/mL were applied topically to the corneal wounds of five BALB/c mice three times a day for three days.
  • ophthalmic drops containing rTFF3 (0.1 and 10.0 mg/mL) in PBS were applied topically to the corneal wounds of five BALB/c mice three times a day for three days.
  • the extent of the epithelial defects in each treatment group was documented photographically to monitor the healing process.
  • the corneal defects present on the photographs were evaluated by using a grading system.
  • Each cornea was graded (blinded) for defect intensity (grade 1-5), conjunctival hyperaemia (grade 1-5), and light reflection (grade 1-5), and categorized into three groups by adding the grade numbers to arrive at an overall score, wherein a score of 11-15 indicated a healed cornea, a score of 6-10 indicated a moderately healed cornea, and a score of 3-5 indicated that the defect was still present.
  • Defect intensity included wound extent and depth.
  • Conjunctival hyperaemia was assessed to determine inflammation of surrounding cells.
  • Bandage contact lenses containing trefoil polypeptide may be used to reduce pain associated with ophthalmic disorders and may also be used to promote healing of ophthalmic lesions.
  • a bandage contact lens is obtained, and trefoil polypeptide, e.g., ITFi 5-73 or ITF 21-73 , is either embedded within the bandage contact lens or is used to coat the contact lens surface.
  • the bandage contact lens can be purchased from, e.g., Bausch & Lomb, CIBA Vision, Gelflex Laboratories, Cooper Vision, UltraVision CLPL, United Contact Lens, or Vistakon/Johnson & Johnson.
  • the bandage contact lens is made of any suitable material, including, e.g., poly-2-hydroxyethyl methacrylate (poly-HEMA), polyvinyl pyrolidone (PVP), flexible plastics, fluorosilicone acrylates, cellulose acetate butyrate, polymethyl methacrylate (PMMA), silicones, siloxane methacrylates, polymacon, or silicone hydrogels (e.g., lotrafilcon A, lotrafilcon B, galyf ⁇ lcon A, senofilcon A, alfafilcon A, omafilcon A, nelfilcon A, hilafilcon A, hilafilcon B, phemf ⁇ lcon A, tefilcon, tetrafilcon A, crofilcon, balafilcon A, etafilcon A, ocufilcon D, methafilcon A, and vilfilcon A).
  • poly-HEMA poly-2-hydroxyethyl me
  • the particular material of the lens can be chosen based on the intended use. For example, for lenses intended for use with patients with a tear deficiency, e.g., dry eye, a higher water content lens may be used, whereas a lower water content lens may be appropriate for patients with an evaporative disorder.
  • Other characteristics of the bandage lenses may be varied as well, e.g., thickness, permeability, oxygen content, tightness of fit, and disposability .
  • the bandage contact lens may contain one or more other therapeutic agents as described herein.
  • a bandage contact lens may be impregnated with a trefoil polypeptide and an antibiotic, e.g., moxifloxacin.
  • an antibiotic e.g., moxifloxacin.
  • the particular therapeutic agent or agents chosen and the characteristics of the bandage contact lens may be tailored to the intended use, based, for example, on the nature of the eye lesion being treated.
  • Suitable ITF-containing bandage contact lenses may be used, e.g., to speed healing of epithelial lesions and provide pain relief.
  • compositions containing highly concentrated trefo H polypeptide A pharmaceutical composition may be prepared by combining a high- concentration solution of trefoil polypeptide with a pharmaceutically acceptable excipient as described herein.
  • a pharmaceutical composition may be prepared in the form of eye drops and may contain as much as 100 mg/ml of trefoil polypeptide.
  • pharmaceutical compositions containing about 20 mg/ml of trefoil polypeptide may be prepared.
  • Trefoil polypeptides e.g., ITF 15-73
  • Trefoil polypeptides have extremely high solubility and have relatively low viscosity even at high concentrations, characteristics which allow trefoil polypeptide-containing eye drops to deliver milligram quantities of trefoil polypeptide per drop without being excessively viscous.
  • Other therapeutic agents e.g., as described herein, may also be included in the trefoil polypeptide-containing pharmaceutical composition.
  • the composition may be packaged together with an eye dropper or other device for administering the composition to a patient's eye.

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Abstract

La présente invention porte sur des procédés de traitement d'un patient ayant une lésion de l'œil provoquée par, ou associée à, une opération ophtalmique. La présente invention porte en outre sur des procédés de traitement de la douleur associée à des lésions provoquées par, ou associées à, une opération ophtalmique. Les lésions peuvent être traitées à l'aide d'une composition pharmaceutique contenant un polypeptide en feuille de trèfle. L'invention porte en outre sur des dispositifs ophtalmiques et des trousses comprenant des polypeptides en feuille de trèfle.
PCT/US2008/004950 2007-04-18 2008-04-17 Utilisation de polypeptides en feuille de trèfle pour traiter des lésions oculaires associées aux opérations ophtalmiques WO2008130591A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9867810B1 (en) 2016-08-19 2018-01-16 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
WO2023285878A1 (fr) * 2021-07-13 2023-01-19 Aviation-Ophthalmology Procédés de détection, de traitement et de prévention de maladies, troubles et états oculaires induits par gpr68

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030186886A1 (en) * 1996-04-12 2003-10-02 Podolsky Daniel K. Treating eye disorders using intestinal trefoil proteins
US20070042951A1 (en) * 2003-10-08 2007-02-22 Allergan, Inc. Pharmaceutical compositions comprising alpha-2-adrenergics and trefoil factor family peptides

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US20030186886A1 (en) * 1996-04-12 2003-10-02 Podolsky Daniel K. Treating eye disorders using intestinal trefoil proteins
US20070042951A1 (en) * 2003-10-08 2007-02-22 Allergan, Inc. Pharmaceutical compositions comprising alpha-2-adrenergics and trefoil factor family peptides

Non-Patent Citations (1)

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Title
GOKE ET AL.: 'Trefoil peptides promote restitution of wounded corneal epithelial cells' EXP. CELL RES., [Online] vol. 264, no. 2, 01 April 2001, pages 337 - 344 Retrieved from the Internet: <URL:http://www.sciencedirect.com/science> *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9867810B1 (en) 2016-08-19 2018-01-16 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US10639297B2 (en) 2016-08-19 2020-05-05 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US11129812B2 (en) 2016-08-19 2021-09-28 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US11974986B2 (en) 2016-08-19 2024-05-07 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
WO2023285878A1 (fr) * 2021-07-13 2023-01-19 Aviation-Ophthalmology Procédés de détection, de traitement et de prévention de maladies, troubles et états oculaires induits par gpr68

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