WO2008144441A1 - Protection du tissu glandulaire oculaire et de sa fonction contre les effets indésirables externes ou intrinsèques dans des troubles de l'œil sec - Google Patents

Protection du tissu glandulaire oculaire et de sa fonction contre les effets indésirables externes ou intrinsèques dans des troubles de l'œil sec Download PDF

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WO2008144441A1
WO2008144441A1 PCT/US2008/063786 US2008063786W WO2008144441A1 WO 2008144441 A1 WO2008144441 A1 WO 2008144441A1 US 2008063786 W US2008063786 W US 2008063786W WO 2008144441 A1 WO2008144441 A1 WO 2008144441A1
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dry eye
formulation
metal
containing catalytic
ocular
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PCT/US2008/063786
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English (en)
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Peter Koulen
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Univ Of North Texas Health Science Center
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • 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 present invention relates generally to methods of treatment for dry eye. BACKGROUND OF THE INVENTION
  • Dry eye also known genetically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is widespread among various populations. However, it particularly affects post-menopausal women due to hormonal changes following the cessation of fertility.
  • a predominant cause of these disorders are abnormalities in tear film composition including, but not limited to dysfunctions of glands, such as the lacrimal gland and the Meibomian gland; eye lid disorders, such as, but not limited to blepharitis; and various systemic eye disorders.
  • Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water-soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Examples of such solutions are available from AlconLabs Inc of Fort Worth, Texas. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye. Another approach involves the provision of lubricating substances in lieu of artificial tears.
  • compositions directed to treatment of the dry eye condition have also been pursued. Many of these compositions use steroids that have limited utility due to concomitant increases in intraocular pressure and/or development of cataracts in the eye.
  • Porphyrines combine readily with metals, coordinating with them in the central cavity. Iron- (heme), magnesium- (chlorophyll), zinc-, copper-, nickel-, manganese-, and cobalt- containing porphyrines are known, and many other metals can be inserted. A porphyrine in which no metal is inserted in its cavity is called a free base. Commonly, iron-containing porphyrines are called hemes. Hemes and/or heme-containing proteins are found extensively in biochemistry in forms such as hemoglobin.
  • porphyrines include meso-tetraphenylporphyrin iron-(III) chloride (or ClFeTPP) as a catalyst in organic chemistry, compounds for molecular memory, inks, and/or the like.
  • ClFeTPP meso-tetraphenylporphyrin iron-(III) chloride
  • a metal containing porphyrine in the treatment of ocular disorders, such as, but not limited to a dry eye disorder. Accordingly, a treatment regimen using a porphyrine-based compound(s) for the treatment of a dry eye disorder would most likely be a novel treatment.
  • a Salen is a dianionic and tetradendate ligand in an organometallic complex. Salen is a contraction for salicylic aldehyde and ethylene diamine which are the reactants for the ligand.
  • the actual composition of the ligand depends on the various substituents. For example, and not by way of limitation, Salph is a salen ligand with a Phenyl core group from the imine forming reaction of salicylic aldehyde with o-diaminobenzene.
  • a macrocylic molecule is a cyclic macromolecule or a macromolecular cyclic portion of a molecule. It is understood in the art field that a macrocyclic molecule has donor atoms arranged in more fixed positions and thus there is less of an entropic effect in the binding energy of macrocycles than monodentate or bidentate ligands with an equal number of donor atoms.
  • Metal containing porphyrines, metal containing salens and metal containing macrocyclics can be classified as antioxidants. Antioxidants have many important biological functions. However, to date, no studies have been performed on the use of metal containing porphyrines or metal containing salens in the treatment of a dry eye disorder. Accordingly, treatments for a dry eye disorder using a at least one metal-containing catalytic antioxidant would be beneficial in therapy approaches for dry eye diseases.
  • Various embodiments of the present invention generally relate to methods of treating dry eye and/or dry eye symptoms. Methods and systems are disclosed for treating dry eye or a dry eye symptom with at least one formulation having at least one metal-containing catalytic antioxidant that provides enhanced benefits as compared to currently available treatments, including at least enhanced tissue regeneration.
  • the at least one formulation comprises a superoxide dismutase (SOD) mimetic.
  • SOD superoxide dismutase
  • the treatment approach leads to at least one of a reduction of oxidative stress, a reduction the cellular degeneration, and/or decline in the death of acinar cells induced by oxidative stress as compared to the prior art treatments.
  • Various embodiments are suitable for the treatment of at least one of congenital, autoimmune conditions, chemical damage, mechanical damage, infections, and/or the like.
  • Various embodiments of the present invention comprise a method of treating dry eye and/or dry eye symptoms, the method comprising administering an effective amount of a formulation comprising at least one metal-containing catalytic antioxidant to a patient, wherein the administered formulation treats dry eye and/or dry eye symptoms.
  • Further embodiments comprise a method of protecting ocular gland tissue in a patient suffering from a dry eye syndrome or at least one of the symptoms thereof, said method comprising the steps of administering an effective amount of a formulation comprising a at least one metal-containing catalytic antioxidant to a patient, wherein the administered formulation protects ocular gland tissue.
  • Yet further embodiments comprise a formulation comprising an ophthalmically acceptable carrier and a therapeutically effective amount of at least one metal-containing catalytic antioxidant.
  • FIG 1 shows Hematoxylin-Eosin stained adult NOD/LtJ (left panels, “NOD”) mouse lacrimal gland tissue and wildtype C57BL/6J (right panels, “Normal”) adult mouse lacrimal gland tissue.
  • Figures 2A-2D show micrographs of Hematoxylin-Eosin stained 12 ⁇ m thick cryo- sections of mouse lacrimal glands with or without manganese-porphyrin treatment.
  • Control group injected with saline (PBS)( Figure 2A) Control group injected with manganese-porphyrin ( Figure 2B), NOD mice injected with saline (PBS) ( Figure 2C), and NOD mice injected with manganese-porphyrin ( Figure 2D).
  • Figure 3 is a bar graph illustrating the blood glucose concentration for control mice (C57BL6J) injected with saline, Control mice injected with manganese-porphyrin, NOD mice injected with saline, and NOD mice injected with manganese-porphyrin.
  • Figure 4 shows histochemical staining of lacrimal gland tissue from Control mice (top two panels) treated with saline alone (vehicle treated) or with MnTE-2-PyP (MnTE-2-PyP treated control) and from NOD mice (bottom two panels) treated with saline (vehicle treated NOD mice) or withMnTE-2-PyP (MnTE-2-PyP treated NOD mice).
  • Figure 6 is a graphic representation of the histological grading of inflammatory lesions of lacrimal glands as visualized by Hematoxylin and Eosin staining in control and NOD mice untreated or treated with MnTE-2-PyP.
  • Control mice injected with saline Control
  • control mice injected with MnTE-2-PyP Control+inj
  • NOD mice injected with saline NOD
  • NOD+inj NOD mice injected with MnTE-2-PyP
  • Figures 7A-7L depict micrographs of PlO mouse primary cultures acinar cells fixed after oxidative stress insult.
  • DIC images show cells that received no treatment (Figure 7A), 100 ⁇ m of MnTMPyP (Fig. 7C), lO ⁇ m of hydrogen peroxide (Figure 7E), lO ⁇ m of hydrogen peroxide with 10 ⁇ m of MnTMPyP ( Figure 7G), lO ⁇ m of hydrogen peroxide with 50 ⁇ m of MnTMPyP ( Figure 71), lO ⁇ m of hydrogen peroxide with 100 ⁇ m of MnTMPyP ( Figure 7K).
  • Figures 7B, 7D, 7F, 7H, 7J, and 7L are the corresponding micrographs displaying DAPI counterstaining of the same samples. Scale bar shown in Figure 7L applies to Figures 7A-7L, 25 ⁇ m.
  • Figure 8 is the graphic representation of hydrogen peroxide induced cell death of lacrimal acinar cells expressed as percentage of total cell number.
  • Figure 9 is a bar graph comparing results of testing of various compounds for cytoprotection of lacrimal gland tissue in NOD mice.
  • the term “dismutation reaction” means and refers to a reaction in which two like-molecules react to produce two different products
  • dismutase means and refers to at least one catalyst for a dismutation reaction.
  • the term "effective amount” means and refers to an amount that is effective in providing at least partial relief to the condition being treated.
  • a "fluid” is a continuous, amorphous substance whose molecules move freely past one another and that has the tendency to assume the shape of its container, for example, a liquid or a gas.
  • a health care provider is known in the art and specifically includes a physician, a person with authority to prescribe a medication (whether directly or indirectly), and a veterinarian.
  • a health care provider includes an individual that provides a medication without prescription, such as in providing an over-the- counter medication.
  • identifying subjects and “diagnosing” are used interchangeably with regard to the detection of a “predisposition,” “increased propensity,” “risk,” “increased risk,” and the like.
  • intraperitoneal means and refers to the peritoneal cavity.
  • intraperitoneal injection means and refers to at least one injection into the peritoneal cavity.
  • other retinal or optic nerve disease means and refers to at least one of age-related macular degeneration, cataract, acute ischemic optic neuropathy (AION), commotio retinae, retinal detachment, retinal tears or holes, diabetic retinopathy and iatrogenic retinopathy and other ischemic retinopathies or optic neuropathies, myopia, retinitis pigmentosa, and/or the like.
  • AION acute ischemic optic neuropathy
  • commotio retinae commotio retinae
  • retinal detachment retinal tears or holes
  • diabetic retinopathy and iatrogenic retinopathy and other ischemic retinopathies or optic neuropathies myopia, retinitis pigmentosa, and/or the like.
  • administered to the subject and/or “to the subject's site” means and refers to delivery of an effective amount of the formulation and/or medicament.
  • subject or “patient” refers to any invertebrate or vertebrate species. The methods of the present invention are particularly useful in the treatment of warmblooded vertebrates. Thus, in an embodiment, the invention concerns mammals and birds.
  • SODs superoxide dismutase(s)
  • SODs means and refers to a family of metalloenzymes that catalyze the intra- and extracellular conversion of oxygen radicals (O 2 .) and H 2 into H 2 O 2 plus O 2 , and represent the first line of defense against the detrimental effects of superoxide radicals.
  • Three SODs are known and found in the human body. One is a dimeric copper- and zinc-containing enzyme (CuZn SOD) found in the cytosol of all cells. A second is a tetrameric manganese-containing SOD (Mn SOD) found within mitochondria. The third is a tetrameric, glycosylated, copper- and zinc-containing enzyme (EC-SOD) found in the extracellular fluids and bound to the extracellular matrix.
  • CuZn SOD dimeric copper- and zinc-containing enzyme
  • Mn SOD tetrameric manganese-containing SOD
  • EC-SOD tetrameric, glycosy
  • a method of treating dry eye or dry eye symptoms may include administering a formulation of an embodiment of the present invention effectively to the eye of a patient.
  • a formulation of the present invention comprises at least one metal -containing catalytic antioxidant.
  • administration of the formulation to the patient with dry eye is capable of treating the underlying cause of dry eye.
  • a formulation of the present invention comprises at least one superoxide dismutase (SOD) mimetic.
  • administration of the formulation to the patient with dry eye is capable of treating the underlying cause of dry eye.
  • methods and systems are disclosed for treating dry eye or a dry eye symptom with at least one metal-containing catalytic antioxidant that provides enhanced benefits as compared to currently available treatments, including at least enhanced tissue regeneration.
  • Various treatment approaches and/or regimens are capable of use with various embodiments of the present invention to reduce damage to ocular gland tissue and/or allow preservation of gland function.
  • such treatment regimens are referred to as a an intervention approach, wherein of embodiments of the present invention are capable of leading to at least one of a reduction of oxidative stress, a reduction of cellular degeneration, and/or a decline in the death of acinar cells induced by oxidative stress as compared to the prior art treatments.
  • various embodiments are suitable for the treatment of congenital, autoimmune conditions, chemical damage, mechanical damage, infections, and/or the like.
  • Metal-containing catalytic antioxidants appropriate for use in various embodiments of the present methods comprise methine (i.e., meso) substituted porphyrines, or pharmaceutically acceptable salts thereof (e.g., chloride or bromide salts).
  • the invention includes both metal-free and metal-bound porphyrines.
  • metal-bound porphyrines manganic derivatives of methine (meso) substituted porphyrines are preferred, however, metals other than manganese such as iron (II or III), copper (I or II), cobalt (II or III), or nickel (I or II), can also be used.
  • the metal selected can have various valence states, for example, manganese II, IH or V can be used.
  • Zinc (II) can also be used even though it does not undergo a valence change and therefore will not directly scavenge superoxide.
  • the antioxidant is a SOD mimetic, such as, but not limited to a manganese porphyrine.
  • the SOD mimetic is an iron porphyrine.
  • any metal complexed antioxidant can be used.
  • Ri and R 3 are the same and are:
  • R 2 and R 4 are the same and are:
  • Y is halogen or -CO 2 X, each X is the same or different and is an alkyl and each R 5 is the same or different (preferably the same) and is H or alkyl.
  • Rj and R 3 are the same and are:
  • R 2 and R 4 are the same and are:
  • Y is — F or -CO 2 X each X is the same or different and is an alkyl (preferably, Ci -4 alkyl, e.g., methyl or ethyl) and each R 5 is the same or different (preferably the same) and is H or alkyl (preferably, Ci -4 alkyl, e.g., -CH 3 or -CH 2 CH 3 ).
  • Ri, R 2 , R 3 and R 4 are the same and are
  • each X is the same or different and is Ci -4 alkyl, advantageously, methyl or ethyl, particularly, methyl.
  • one or more of the pyrrole rings of the porphyrin of Formula I can be substituted at any or all beta carbons, i.e.: 2, 3, 7, 8, 12, 13, 17 or 18.
  • substituents, designated P can be hydrogen or an electron withdrawing group, for example, each P can, independently, be a NO 2 group, a halogen (e.g., Cl, Br or F), a nitrile group, a vinyl group, or a formyl group.
  • substituents alter the redox potential of the porphyrin and thus enhance its ability to scavenge oxygen radicals.
  • halogen e.g., Br
  • substituents preferably, 1-4
  • the remaining P's advantageously being hydrogen.
  • P formyl
  • P NO 2
  • mimetics for use with varying embodiments of the present invention are capable of being selected by assaying for metal-containing antioxidant activity.
  • Mimetics can also be screened for their ability to inhibit lipid peroxidation or scavenge ONOO ' (as determined, for example, by the method of Szabo et al, FEBS Lett. 381 :82 (1996)).
  • Measuring SOD activity is common in the art.
  • SOD activity is capable of being measured by the presence and absence of EDTA using the method of McCord and Fridovich (J. Biol. Chem. 244:6049 (1969)).
  • various embodiments of the present invention comprise the use of formulations as herein disclosed as a cytoprotectant for treatment of dry eye disorders.
  • the formulation comprises at least two metal-containing catalytic antioxidants. In an alternate embodiment, the formulation comprises at least three metal-containing catalytic antioxidants. In an alternate embodiment, the formulation comprises at least four metal-containing catalytic antioxidants. In general, any number of compounds can be used.
  • the formulation comprises at least two SOD mimetics. In an alternate embodiment, the formulation comprises at least three SOD mimetics. In an alternate embodiment, the formulation comprises at least four SOD mimetics. In general, any number of compounds can be used.
  • formulations of the present invention comprise substantially pure at least one metal-containing catalytic antioxidant.
  • the concentration of metal-containing catalytic antioxidant is at least about 40%.
  • the concentration of metal-containing catalytic antioxidant is at least about 50%.
  • the concentration of metal-containing catalytic antioxidant is at least about 60%.
  • the concentration of metal-containing catalytic antioxidant is at least about 70%.
  • the concentration of metal-containing catalytic antioxidant is at least about 80%. In an alternate embodiment, the concentration of metal-containing catalytic antioxidant is at least about 90%. In an alternate embodiment, the concentration of metal-containing catalytic antioxidant is at least about 95%. In an alternate embodiment, the concentration of metal-containing catalytic antioxidant is at least about 99%. However, the concentration of metal-containing catalytic antioxidant can be varied as desired.
  • formulations of the present invention comprise substantially pure at least one SOD mimetic.
  • the concentration of SOD mimetic is at least about 40%. In an alternate embodiment, the concentration of SOD mimetic is at least about 50%. In an alternate embodiment, the concentration of SOD mimetic is at least about 60%. In an alternate embodiment, the concentration of SOD mimetic is at least about 70%. In an alternate embodiment, the concentration of SOD mimetic is at least about 80%. In an alternate embodiment, the concentration of SOD mimetic is at least about 90%. In an alternate embodiment, the concentration of SOD mimetic is at least about 95%. In an alternate embodiment, the concentration of SOD mimetic is at least about 99%. However, the concentration of SOD mimetic can be varied as desired.
  • a method of the present invention comprises administering a formulation comprising at least about 10% metal-containing catalytic antioxidant.
  • the metal-containing catalytic antioxidant is at least about one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, and/or 99%.
  • the various formulations of the present invention comprise a pharmaceutically effective amount of a first metal-containing catalytic antioxidant.
  • the formulation further comprises a pharmaceutically acceptable carrier, a first metal-containing catalytic antioxidant and at least one other therapeutic agent.
  • the formulation further comprises a pharmaceutically acceptable carrier, a first metal-containing catalytic antioxidant, a second metal-containing catalytic antioxidant, and at least one other therapeutic agent, and/or the like.
  • compositions and/or formulations in accordance with the present invention, broadly comprise a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a chemical structure in accordance with various embodiments of the present invention and/or having metal-containing catalytic antioxidants..
  • the mode and/or route of administration of the formulation is such that a sufficient amount of the formulation is delivered to the ocular region of the patient or subject.
  • various modes of administration suitable for use with various embodiments of the present invention include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, ocular, transscleral, transcorneal, and sublingual), vaginal, subcutaneous, or parenteral (including subcutaneous, intramuscular, intravenous, i.p., and intradermal) administration.
  • Suitable forms of administration to the ocular region of the subject include, but are not limited to topical ocular drops or ointments; slow release devices in the cul-de-sac or implanted adjacent to the sclera or within the eye; transscleral, transcorneal, periocular, conjunctival, sub-tenons, intracameral, intravitreal, or intracanalicular injections.
  • Formulations suitable for oral administration may be presented as discrete units such as pills, tablets or capsules each containing a predetermined amount of active ingredient(s); as a powder or granules; as a solution or suspension.
  • the active ingredient(s) may also be present as a bolus or paste, or may be contained within liposomes.
  • Formulations for rectal administration may be presented as a suppository or enema.
  • suitable formulations include aqueous and non-aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
  • the metal-containing catalytic antioxidant of the present invention are generally fo ⁇ nulated as between about 0.0001 to about 3.0 percent by weight (wt %) solutions in an aqueous solution buffered to a pH between 4.5 to 8.0 with a suitable buffering agent.
  • the pH is between about 7.0 and about 7.6.
  • formulations of the present invention are between about 0.0003 to about 0.3 wt %.
  • formulations of the present invention comprise between about 0.003 and about 1.0 wt % active ingredient.
  • formulations of the present invention comprise between about 0.01 and 0.1 wt % active ingredient.
  • the percentage of metal-containing catalytic antioxidant can be varied as desired and/or needed for a particular application.
  • dosage units e.g., tablets
  • conventional additives such as fillers, colorants, polymeric binders and the like
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
  • Further embodiments comprise formulations with additional therapeutic agents, such as prostanoids (also known as prostaglandin receptor agonists), beta-blockers (beta-adrenergic receptor antagonists), alpha-adrenergic receptor agonists, and/or carbonic anhydrase inhibitors.
  • the additional therapeutic agents are capable of treating at least one of ocular surface pain, uveitis, scleritis, episcleritis, keratitis, surgically-induced inflammation, endophthalmitis, crizos, ratin, ratin, ratin, ratin, ratin, ratin, ratin, ratin, ratin, ratin, ratin, fibrosis, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, fibroblasts, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, rin, r
  • the carrier for the active agent(s) is an aqueous solution buffered to physiologically acceptable pH levels with an acidic or basic pH-adjusting agent.
  • the osmolarity of the solution would be adjusted with osmolality adjusting agents, such as sodium chloride (NaCl) or potassium chloride (KCl), as is known in the art.
  • ingredients, excipients, and additives which may be desirable to use in the ophthalmic preparations of the present invention include anti-oxidants, co-solvents and viscosity building agents.
  • an appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • concentration will vary, depending on the substrate employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 6-7.5.
  • Formulations of the present invention can be packaged in a single dose form or a multiple dose form. Formulations packaged in single dose form are typically for use when formulated, therefore, not requiring long storage, i.e., no preservative. However, a preservative is capable of use with various embodiments of the present invention.
  • Formulations packaged in multidose form generally require the addition of preservatives to prevent microbial contamination during use.
  • the formulation comprises a naturally occurring or recombinant antimicrobial peptide.
  • the antimicrobial peptide typically would be employed at a concentration between about 0.001% and 1.0% by weight
  • Viscosities greater than that of aqueous solutions may be desirable in certain cases to increase ocular absorption of the active compound, to decrease physical separation of components of the formulation, to decrease inherent variability in dispensing the formulations, and/or otherwise to improve and/or enhance the Formulation.
  • viscosity building agents such as, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, and/or the like can be used. Such agents are typically employed at a concentration between about 0.01% and about 2% by weight. However, the exact concentration can vary as needed for the particular application.
  • a topical dosage form typically, a sterile solution is used.
  • the dosage range for topical (including transdermal, buccal, mocular, and sublingual) administration is between about 0.1 and 100 micrograms ( ⁇ g) per eye per day, and is most preferably between 1 and 10 ⁇ g per eye per day. While the precise regimen is left to the discretion of a health care provider, it is recommended that the resulting solution be topically applied by placing one drop in each eye one or two times a day.
  • a topical application is at least one of eye droplets, a cream, a mist, and/or the like.
  • the formulation is administered in more than one application, such that the total dose is administered in one or more discrete applications.
  • the formulation is administered in one dose.
  • compositions administered may also include various other ingredients as earners, including but not limited to surfactants, tonicity substrates, buffers, preservatives, co-solvents and viscosity building substrates.
  • tonicity substrates may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity substrate will vary, depending on the particular substrate to be added. In general, however, the compositions will have a tonicity substrate in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm/L, preferably 250-350 mOsm/L).
  • compositions formulated for the treatment of dry eye-type diseases and disorders may also comprise aqueous carriers designed to provide immediate, short-term relief of dry eye- type conditions.
  • aqueous carriers designed to provide immediate, short-term relief of dry eye- type conditions.
  • Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures of both.
  • phospholipid carrier and artificial tears carrier refer to aqueous compositions which: (i) comprise one or more phospholipids (in the case of phospholipid carriers) or other compounds, which lubricate, "wet,” approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration; and (ii) are safe.
  • artificial tears compositions useful as artificial tears carriers include, but are not limited to, commercial products, such as Tears Naturale.RTM., Tears Naturale II. RTM., Tears Naturale Free.RTM., and Bion Tears. RTM. (Alcon Laboratories, Inc., Fort Worth, Tex.).
  • phospholipid carrier formulations include those disclosed in U.S. Pat. Nos.
  • Other compounds designed to lubricate, "wet,” approximate the consistency of endogenous tears, aid in natural tear integrity, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration the eye are known in the art.
  • Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomelic polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol, hydroxypropylmethyl cellulose ("HPMC”), carboxy methylcellulose sodium, hydroxy propylcellulose (“HPC”), dextrans, such as, dextran 70; water soluble proteins, such as gelatin; and vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, such as, carbomer 934P, carbomer 941 , carbomer 940, carbomer 974P.
  • monomelic polyols such as, glycerol, propy
  • other compounds may also be added to the ophthalmic compositions to increase the viscosity or enhance the physical stability of the composition.
  • viscosity enhancing substrates include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; carboxy vinyl polymers such as carbomers (e.g., carbomer 974P); and acrylic acid polymers.
  • the phospholipid carrier or artificial tears carrier compositions will exhibit a viscosity of 1 to 400 centipoises ("cps").
  • formulations of the present invention are intended for administration to a human patient suffering from dry eye or symptoms of dry eye.
  • such compounds are administered i.p.
  • the formulations are administered topically.
  • the doses used for the above described purposes will vary, but will be in an effective amount to eliminate or improve dry eye conditions.
  • 1 -2 drops of such compositions will be administered from once to many times per day.
  • the present invention may provide a formulation and method for the treatment of dry eye that addresses the need for repair of cells and tissues contributing to tear formation. Such an approach may obviate the need for costly long term use of tear replacement formulations and other palliative therapeutics.
  • MnTE-2-PyP meso-tetrakis (N-ethyl-2-pyridyl) porphyrin pentachloride
  • PBS Phosphate Buffer saline
  • mice were sacrificed at the end of the treatment regimen.
  • the lacrimal glands were harvested, fixed in 4% phosphate buffered formaldehyde (ph 7.2), and prepared for histological evaluation. 12 ⁇ m cryosections were stained with hematoxylin and eosin (H&E) and color images were taken with color digital microscope camera.
  • H&E hematoxylin and eosin
  • the histological examination of the four experimental groups vehicle treated control ("control”); MnTE-2-PyP treated control ("control + inj”); vehicle treated NOD mice (“NOD”); MnTE-2-PyP treated NOD mice (“NOD + inj") are depicted in Figures 2A-2D. Blood glucose levels were monitored before testing to exclude the occurrence of diabetes as a complicating factor. Blood glucose levels were normal in all groups ( Figure 3).
  • MnTE-2-PyP treatment did not significantly reduce the infiltration with immune cells, but did reduce tissue damage and functional morphology of acinar cells, acini cells, and/or ducts in the lacrimal gland, as is illustrated in Figures 4 and 5.
  • mice Male NOD or C57BL/6J (control) mice were obtained from the Jackson laboratory (Bar Harbor ME) and were housed under specific pathogen-free conditions in the Department of Laboratory Animal Medicine (DLAM) of the University of North Texas Health Science Center at Fort Worth (UNTHSC). 24 of the 10 week old animals were divided equally into the following groups: vehicle (PBS) treated controls (C57BL/6J) mice, MnTE-2-PyP treated (C57BL/6J) mice, vehicle (PBS) treated NOD mice and MnTE-2-PyP treated NOD mice.
  • DLAM Department of Laboratory Animal Medicine
  • MnTE-2-PyP manganese (III) meso-tetrakis (N-ethyl-2- pyridyl) porphyrin pentachloride
  • PBS Phosphate Buffer saline
  • C57BL/6J pups postnatal 10 days were used for primary acinar cell culture.
  • the mouse lacrimal glands were carefully dissected out in Hank's balanced salt solution (HBSS) and cut into pieces.
  • HBSS Hank's balanced salt solution
  • the lacrimal gland pieces were transferred to a 15 ml conical tube with trypsin (4 glands per tube) and incubated in a 37 degrees centigrade water bath for 10 minutes.
  • the pellet was re-suspended with 2 ml of STI solution (STI, soybean trypsin inhibitor 0.2 mg/ml in 0.5% BSA-DMEM without sodium pyruvate 2.5mM EGTA) and incubated in a 37 degrees centigrade water bath for 5 minutes and centrifuged again.
  • the pellet was resuspended in collagenase solution (collagenase 0.4 mg/ml, in 0.5% BSA-DMEM without sodium pyruvate) and incubated for 10 minutes in a 37 degrees centigrade water bath.
  • a glass Pasteur pipette with a fire polished tip was used for mechanical dissociation of the glands.
  • the tissue was triturated mechanically until the solution looks cloudy and then centrifuged for 2 minutes at 500g rcf.
  • the pellet was washed with medium, centrifuged again and then resuspended with 40 ml culture media (DMEM without sodium pyruvate with 10% heat inactivated bovine growth serum (BGS) and 50U/ml penicillin and streptomycin at 37 degrees centigrade).
  • 40 ml culture media DMEM without sodium pyruvate with 10% heat inactivated bovine growth serum (BGS) and 50U/ml penicillin and streptomycin at 37 degrees centigrade.
  • 100 ⁇ l of cell suspension was plated per coverslip inside a 6-well plate and cells were allowed to attach to coverslips at 37 degrees centigrade for at least 2 hours.
  • 2 ml of culture media was added per well and the cell suspension was further incubated at 37 degrees centigrade in a CO 2 /air (1 :19) atmosphere. Media was changed twice a week.
  • Figure 9 is illustrates the results of testing of various compounds for cytoprotection of lacrimal gland tissue in NOD mice. The compounds tested included:
  • [001 18] a) Manganese(III)-5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin Pentachloride [Mn(III) meso-tetrakis(N-ethyl-2-pyridyl)porphyrin Pentachloride; MnTE-2-PyP; molecular formula: C 44 H 2 SClFeN 4 Oi 2 S 4 .
  • n-manganese complex EUK-8 molecular formula: CiOH] 4 ClMnN 2 O 2 .
  • the vehicle for EUK-8 was DMSO and for MnTE-2-PyP and the vehicle for FeTPPS was saline.
  • the respective SOD mimetic was injected i.p. at 10mg/kg every other day for two weeks.
  • Blood glucose levels were monitored before testing to exclude the occurrence of diabetes as a complicating factor. Blood glucose levels were normal in all groups. Lacrimal glands were fixed and sectioned and stained for histological analysis with standard hematoxylin- eosin staining.

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Abstract

La présente invention a pour objet des procédés et des systèmes pour traiter l'œil sec ou un symptôme d'œil sec avec au moins une formulation renfermant au moins un antioxydant catalytique contenant un métal qui procure des bénéfices amplifiés par comparaison aux traitements actuellement disponibles, y compris au moins une amplification de la régénération tissulaire. Diverses approches thérapeutiques de modes de réalisation de la présente invention réduisent les lésions du tissu glandulaire oculaire et/ou permettent la conservation de la fonction de la glande. Dans divers modes de réalisation, l'approche interventionnelle mène à une réduction du stress oxydatif, une réduction de la dégénération cellulaire et/ou le déclin de la mort des cellules acineuses induite par le stress oxydatif par comparaison aux traitements de l'art antérieur. Divers modes de réalisation sont appropriés pour le traitement d'affections congénitales, auto-immunes, de lésions chimiques, de lésions mécaniques, d'infections et/ou analogues.
PCT/US2008/063786 2007-05-15 2008-05-15 Protection du tissu glandulaire oculaire et de sa fonction contre les effets indésirables externes ou intrinsèques dans des troubles de l'œil sec WO2008144441A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013071059A1 (fr) * 2011-11-10 2013-05-16 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Mimétiques de catalase/superoxyde dismutase de synthèse et méthodes de traitement d'infections virales
KR20180126881A (ko) * 2017-05-18 2018-11-28 가톨릭대학교 산학협력단 Sod3를 함유하는 건성안의 예방 또는 치료용 조성물
WO2023128078A1 (fr) * 2021-12-27 2023-07-06 주식회사 제노포커스 Superoxyde dismutase et son utilisation pour la prévention ou le traitement du syndrome de l'œil sec

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030228299A1 (en) * 2001-06-07 2003-12-11 Marie-Therese Droy-Lefaix Use of antioxidant for treating and/or preventing surface ocular disorders
US20060149089A1 (en) * 1992-12-07 2006-07-06 Bernard Malfroy-Camine Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060149089A1 (en) * 1992-12-07 2006-07-06 Bernard Malfroy-Camine Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease
US20030228299A1 (en) * 2001-06-07 2003-12-11 Marie-Therese Droy-Lefaix Use of antioxidant for treating and/or preventing surface ocular disorders

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013071059A1 (fr) * 2011-11-10 2013-05-16 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Mimétiques de catalase/superoxyde dismutase de synthèse et méthodes de traitement d'infections virales
US20140329792A1 (en) * 2011-11-10 2014-11-06 The United State of America, as represented by the Secretary,Department of Health & Human Services Synthetic catalase/superoxide dismutase mimetics and methods for treating viral infections
US10683316B2 (en) 2011-11-10 2020-06-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synthetic catalase/superoxide dismutase mimetics and methods for treating viral infections
KR20180126881A (ko) * 2017-05-18 2018-11-28 가톨릭대학교 산학협력단 Sod3를 함유하는 건성안의 예방 또는 치료용 조성물
KR101966330B1 (ko) * 2017-05-18 2019-04-05 가톨릭대학교 산학협력단 Sod3를 함유하는 건성안의 예방 또는 치료용 조성물
WO2023128078A1 (fr) * 2021-12-27 2023-07-06 주식회사 제노포커스 Superoxyde dismutase et son utilisation pour la prévention ou le traitement du syndrome de l'œil sec

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