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WO2015060812A1 - Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux - Google Patents

Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux Download PDF

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WO2015060812A1
WO2015060812A1 PCT/US2013/065944 US2013065944W WO2015060812A1 WO 2015060812 A1 WO2015060812 A1 WO 2015060812A1 US 2013065944 W US2013065944 W US 2013065944W WO 2015060812 A1 WO2015060812 A1 WO 2015060812A1
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Prior art keywords
drug
efflux
efflux transporter
subject
ocular
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Pradeep K. KARLA
Harpal S. Mangat
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Howard University
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Howard University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • compositions are described for the treatment of ocular diseases in humans. More particularly, the methods and compositions include efflux transporter inhibitors and ocular drugs where the drugs are effective for the treatment of ocular diseases w 7 hich include but are not limited to diabetic retinopathy, macular
  • pharmacologic compositions for the treatment of ocular diseases are topically applied to the surface of the eye in the form of eye drops, gels, ointments or suspensions.
  • the effectiveness of these pharmacologic compositions is limited, at least in part, by natural barriers present in the eye. It has been reported that bioavailability of ocular drugs within the eye is generally about 1 to 10 percent for topically administered drugs.
  • the cornea is a known primary barrier for topical ocular drug delivery to the anterior segment of the eye.
  • the primate cornea has five layers:
  • the epithelium includes tightly packed, stratified cells which form a major barrier for drug permeation. It has been found that tight junctions and an array of drug efflux transporters in the epithelium are important factors for the poor delivery of ocular drugs. Efflux transporters play an important role in conferring drug resistance by pumping out the drug compounds, such as antimicro ials, antibiotics, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogues, miotics, and
  • Efflux transporters identified in the eye or cornea include P-glycoprotein 1 (Pgp), breast cancer resistant protein (BCRP), and multidrug resistant associated proteins 1-9 (MRPs 1-9). While not wishing to be bound by theory, it is presently believed that MRPs are considered to play a significant role in drug efflux compared to Pgp and BCRP in the eye, and often, more specifically the cornea. The presence of these efflux transporters in ocular tissue and/or in or on the cornea have been found to confer drug resistance to a variety of topically applied drugs.
  • MRPs, Pgp and BCRP efflux pumps in or the eye or cornea imply the likelihood of drug resistance to a wide range of ocular drugs.
  • Ocular and/ or corneal efflux pumps can also act in an additive manner to efflux a wider range of drug molecules, forming a very strong- physical barrier to ocular drug delivery.
  • MRPs are proteins which effect drug resistance in mammalian cells.
  • they include multidrug resistant protein 2, also known as multispecific organic transporter 1 (CMOAT), which is encoded by the human ABCC2 gene; and multidrug resistant protein 4 which is encoded by the human ABCC4 gene.
  • CMOAT multispecific organic transporter 1
  • multidrug resistant protein 4 which is encoded by the human ABCC4 gene.
  • Pgp belongs to the ATP-binding cassette (ABC) family of transporters which use adenosine triphosphate (ATP) as an energy source.
  • AAC ATP-binding cassette
  • Pgp is a glycoprotein that is encoded in humans by the ABCB 1 gene and also is known as ATP-binding cassett Subfamily B member 1.
  • This efflux transporter has two transmembrane sites embedded in a lipid bilayer of a cell membrane. Each transmembrane site includes six transmembrane domains.
  • Pgp has two nucleotide binding domains which are also known as ATP binding domains.
  • MRPs appear to play a major role in drug efflux and the resulting decrease in drug efficacy. MRPs are also classified in the ABC family of transporters and require adenosine triphosphate (ATP) for efflux function.
  • ATP adenosine triphosphate
  • the major structural difference between MRPs and Pgp is the presence in MRPs of an additional transmembrane site in a lipid bilayer, which includes five transmembrane domains. Additionally, another significant difference between the two transporters is the presence in MRP of an amino terminal on the external side of cell membrane.
  • BCRP was recentl identified in human corneal epithelial cells. BCRP also primarily employs ATP for its efflux function. BCRP is referred to as a "half
  • the transporter has one transmembrane site and one ATP binding site.
  • the transmembrane site has six transmembrane domains embedded in the lipid bilayer,
  • the relative rate of efflux through the eye or corneal epithelium is governed by multiple factors, such as the drug substrate specificity with the efflux transporter and the extent of expression of a particular efflux transporter compared to other efflux transporters.
  • ocular diseases including diabetic retinopathy, macular degeneration, endopthalmitis, glaucoma, cataracts, ocular her pes and other ocular diseases which can be treated through the creation of new blood vessels in the eye through angiogenesis of new blood vessels in a subject afflicted which such diseases. It has been found that inhibition of the drug efflux transporters in ocular tissue including the corneal epithelium significantly improves bioavailability of many ocular drugs.
  • the methods and compositions provided herein include one or more efflux transporter inhibitors in combination with at least one ocular drug, where the combination of the efflux transporter inhibitor and one at least one ocular drug is not only effective for the treatment of an ocular disease, it increases the effectiveness of the drug by at least 100% when the drug is applied at the same dosage levels at the same rate to treat the same disease at the same disease stage. In other forms, the combination increases the effectiveness of the drug by at least 200%. In another aspect, a lower dosage amount of the drug may be used to achieve the same effectiveness, in this regard, 50% of a standard dose could be used to achieve the same efficacy as a regular full dose. In this aspect, an efflux transporter inhibitor can be incorporated info a treatment regimen to be used in conjunction with an ocular drug. It has not been previously demonstrated that employing drug efflux inhibition is effective to treat ophthalmic disease in humans.
  • the efflux transporter inhibitor used in the methods and compositions described herein is effective to reduce the efflux of the drug through at least one efflux transporter in ocular tissue including the cornea.
  • the efflux transporter may be selected from the group consisting of P-glycoprotein (Pgp), breast cancer resistant protein (BCRP), and multidrug resistant associated proteins 1-9 (MRP1--9),
  • a method for treating an ocular disease in a subject in need thereof by increasing the bioavailability of a drug in the subject's eye by mitigating the effects of the efflux transporters described above.
  • a drug such as antimicrobials, antibiotics, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogues, miotics, and sympthaomimetics and an efflux transporter inhibitor, such as bevacizumab, itraconazole, caroxyamidotriazole, TNP- 470, CMIOI, IFN-a, IL- 2, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic, steroids-*- heparin, cartilage-derived Angiogenesis Inhibitory Factor, matrix meta Uoproteinase inhibitors, angiostatin, endostatin, 2-met hoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, a v p3 inhibitors, linomide,
  • a drug such as antimicrobials, antibiotics, beta block
  • the amount of efflux transporter inhibitor applied is in an amount effective to reduce the efflux of the drug through the subject's ocular tissue.
  • the ratio of the drug to efflux transporter inhibitor should be in the range of from about 5:1 to about 1:5,, preferably from about 2:1 to about 1:2. In one approach, the ratio of the drug to efflux transporter inhibitor is about 1:1.
  • the drug and efflux transporter inhibitor are applied topically to the subject's eye with a pharmaceutically acceptable carrier such as an ointment or eye drops.
  • the subject is a human.
  • a method Is provided for the treatment of diabetic retinopathy, macular degeneration, and glaucoma include beta blockers such as timolol, levobunolol, betaxoloi and carteolol; carbonic anhydrase inhibitors such as dorzolamide, timolol and brinzolamide; prostaglandin analogues such as latanoprost, latanoprost plus, timolol, travoprost, bimatoprost and unoprostone; and miotics and sympthaomimetics such as pilocarpine, dipivefrine and brimonidine. Accordingly, a method is provided for treating diabetic retinopathy, macular
  • the method comprising applying a therapeutically effective amount of the drug and an efflux transporter inhibitor, the amount of efflux transporter inhibitor applied in an amount effective to reduce the efflux of the drug from the subject's ocular tissue and cells.
  • the drug and efflux transporter inhibitor are applied topically to the subject's eye with a pharmaceutically acceptable carrier such as an ointment or eye drops.
  • the efflux transporter inhibitor is Cvclosporine A (Restasis) to treat
  • the amount of efflux transporter inhibitor included in the methods and compositions described herein is effective to reduce the efflux of the drug through the subject's ocular tissue and/ or cornea to improve the therapeutic efficacy of the drug- when administered in a given quantity by at least 100%, and in some forms, at least 200%, when the drug is applied at the same dosage levels at the same rate to treat the same disease at the same disease stage.
  • the time between application of the efflux transporter inhibitor and the drug, the relative amounts of the efflux transporter inhibitor and the drug, and the ratio of the efflux transporter inhibitor to the drug are effective to increase the therapeutic efficacy of the drug for treating the ocular disease as compared to administering the same amount of the drug without the efflux transporter inhibitor.
  • the efflux transporter inhibitor is administered before administration of the drug, such as within minutes of administration of the efflux transporter inhibitor.
  • a composition for the treatment of an ocular disease in a subject is also described herein.
  • the composition comprises an efflux transporter inhibitor and at least one ocular drug effective for the treatment of, such as antimicrobials, antibiotics, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogues, miotics, and sympthaomimetics; efflux pump inhibitors such as bevacizumab, itraconazole, caroxyamidotriazole, TNP-470 (a synthetic analog of fumagillin, an antibiotic isolated from the fungus Aspergillus fumigatus fresenius with antineoplastic activity,
  • CM101 a polysaccharide tumor angiogenesis- targeting, complement activating, immune stimulating biological produced
  • naphthalenetrisulfonic acid SU5416 (C 15 H 14 N 2 O, l,3--Dihydro--3--[(3,5-dimethy!»lH-- pyrrol-2-yl)methylene]-2H-indol-2-one), thrombospondin, VEGFR (vascular endothelial growth factor receptor) antagonists, angiostatic, steroids* heparin, cartilage-derived Angiogenesis Inhibitory Factor,, matrix metalloproteinase inhibitors,, angiostatin, endostatin, 2-methoxyestradioL tecogalan, tetrathiomolybdate, thalidomide,
  • thrombospondin thrombospondin, prolactin, ⁇ ⁇ : inhibitors, linomide, tasquinimod, and cyclosporine A and a pharmaceutically suitable carrier such as an ointment or eye drops suitable for application to ocular tissue.
  • the drug is in a therapeutic amount for the treatment of the ocular disease.
  • the relative amounts of the efflux transporter inhibitor and the drug, as well as the ratio of the efflux transporter inhibitor to the drug, in the composition are effective for increasing a therapeutic efficacy of the drug for treating the ocular disease as compared to administering the same amount of the drug without the efflux transporter inhibitor.
  • the ocular disease is diabetic retinopathy, macular degeneration, endopf halmitis, glaucoma, cataracts, keratoconus, ocular herpes and other ocular diseases which can be treated through the creation of new antimicrobials.
  • the drug may be one which is effective for the treatment of the latter diseases.
  • the drugs include beta blockers, carbonic anhydrase inhibitors, prostaglandin analogues, miotics, sympthaomimetics ceftazidine,
  • the efflux transporter inhibitor is cyclosporine A.
  • the composition is effective for the treatment of endophthalmitis.
  • Endophthalmitis is an inflammation and infection of tissues in the eye, often as a result of microbial infection after surgery or eye trauma.
  • the inflammation generally affects the vitreous fluid in the center of the eye but can also affect
  • endopthalmitis Symptoms of endopthalmitis include, for example, blurred vision, eye pain, and redness. In many instances, the loss of vision is irreversible. Endophthalmitis is typically treated with intraocular antibiotics and anti-inflammatory agents. In severe endophthalmitis, blindness can occur despite treatment.
  • a method for treating an ocular disease in a subject in need thereof by increasing the bioavailability of a drug in the subject's eye comprising applying a therapeutically effective amount of a drug and an efflux transporter inhibitor to the subject's eye, the efflux transporter inhibitor applied in an amount effective to reduce the efflux of the drug through the portions of a subject's eye.
  • the drug and efflux transporter inhibitor are applied topically to the subject's eye.
  • the subject is a human.
  • the ocular disease is endophthalmitis.
  • the ocular disease is diabetic retinopathy, macular degeneration, endopthalmitis, glaucoma, cataracts, ocular herpes and other ocular diseases which can be treated to effect new blood vessels in the eye through angiogenesis of new blood vessels via medication
  • a method for treating endopthalmitis in a subject in need thereof by Increasing the bioavailability of a drug in the subject's eye comprisin applying a therapeutically effective amount of a drug and an efflux transporter inhibitor to a subject's eye, the amount of efflux transporter inhibitor applied in an amount effective to reduce the efflux of the drug through the subject's eye.
  • the drag and efflux transporter inhibitor are applied topically to the subject's eye.
  • the efflux transporter inhibitor is cyclosporine A and the drug comprises an antimicrobial, in one aspect, the subject is a human.
  • the time between application of the efflux transporter inhibitor and the drug, the relative amounts of the efflux transporter inhibitor and the drug, and the ratio of the efflux transporter inhibitor and the drug are effective to increase the therapeutic efficacy of the drug for treating the ocular disease as compared to administering the same amount of the drug without the efflux transporter inhibitor.
  • the drug and efflux transporter inhibitor are applied to the subject's eye at substantially the same time.
  • substantially the same time is meant within about 10 minutes, in another aspect within about 5 minutes, in another aspect within about 1 minute, and in another aspect within about 0,5 minutes.
  • treating refers to an intervention performed to alter the pathology of, and thereby substantially alleviate or reduce in severity, an ocular disease or condition, including one or more symptoms of such disease or condition in a subject.
  • subject includes mammals and specifically includes humans. Veterinary applications are also contemplated.
  • treating refers to both therapeutic treatment and prophylactic measures.
  • treatment refers to the act of treating a symptom, disease or condition.
  • Those in need of treatment include subjects already having an ocular disorder or ocular disease.
  • the subject is in recognized need of treatment.
  • the subject may exhibit symptoms of ocular disease, in one aspect, the subject has been diagnosed by a medical professional as having an ocular disease or displaying symptoms of an ocular disease.
  • the ocular disease is endopthalmitis.
  • the ocular disease or condition is glaucoma, cataracts, macular degeneration, ocular herpes, diabetic retinopathy, macular degeneration, and other ocular diseases which can be treated to effect new blood vessels in the eye through angiogenesis of new blood vessels via medication.
  • the terms “therapeutically effective amount” or “effective amount” refer to the amount of drug and/ or efflux transporter modulator required to confer a biological or meaningful patient benefit, such as the biological or medical response or improvement sought by a medical doctor or other medical professional.
  • the terms “therapeutically 7 effective amount” or “effective amount” are intended to mean the amount of drug and/ or efflux transporter modulator that will bring about a biologically meaningful improvement in the subject's ocular disorder, symptom, or disease. Doses that exhibit large therapeutic indices are preferred.
  • Effective amounts may vary, as recognized by those skilled in the art, depending, for example, on route of administration, dosage form, inclusion of additional active agents, as well as age, weight, sensitivity, and health of the subject.
  • the term "effflux transporter inhibitor” means a chemical compound, protein, peptide, or other molecule that is effective to stop or reduce extrusion of a drug outside the cell via at least one efflux transporter in the subject's cornea.
  • the efflux transporter inhibitor is effective to stop or reduce extrusion of a drug via at least one efflux transporter selected from the group consisting MRPs, BCRP, and Pgp of the corneal epithelium.
  • efflux transporter inhibitors include, for example, MK-571 (C ⁇ I ⁇ CIN ⁇ O ⁇ . Na; a specific MRP inhibitor sold by Biomol International L.P.
  • ketoconazole a specific Pgp inhibitor
  • GFl 20918 a specific Pgp inhibitor marketed as Eiacridar by Santa Cruz Biotechnology
  • indomethacin PGP-4008
  • bimatoprost marketed as LUMIGAN® by r Allergan
  • latanoprost marketed as XALATAN® by Pfizer
  • sulfinpyrazone a MRP5 modulator
  • cyclosporin- A a Pgp inhibitor marketed as RESTASIS® by Allergan.
  • cyclosporin- A may be used in the methods and compositions described herein as it is FDA approved for ocular use.
  • Very strong substrates for the efflux transporters can act as inhibitors. Therefore, additional efflux transporter inhibitors can be designed and identified by one of ordinary skill in the art.
  • efflux transporters such as MPR and Pgp
  • efflux transporters sometimes act in conjunction to efflux certain drugs, and the combined activity of the efflux transporters forms a strong physical barrier against ocular drug delivery.
  • use of a combination of efflux transporter inhibitors can result in an at least additive increase in uptake of drugs.
  • MRP plays a more significant role compared to Pgp in ocular drug efflux of macrolides.
  • MRP4/MRP5 transporters play a significant role in the efflux of nucleoside and nucleotide analogues. It has also been demonstrated that efflux inhibitor GF12091.8 interacts with both BCRP and Pgp.
  • the efflux transporter inhibitor should be selected in conjunction with the drug selected for the particular treatment regimen. For example, it is known that erythromycin is a good substrate for MRP efflux but not a good substrate for Pgp efflux. Therefore, an efflux transporter inhibitor would be selected that inhibits MRP efflux. Selection of an efflux transporter inhibitor that inhibits Pgp efflux but not MRP efflux would not be expected to provide the desired clinical benefit. Also, for example, MK ⁇ 571 is non-specific inhibitor for MRP1-9 but not for Pgp and BCRP. Therefore, MK-571 would be used in conjunction with a drug that is a substrate for MRP1-9 but not for Pgp and BCRP.
  • MRP2 and MRP5 are involved in acyclovir efflux so an MRP inhibitor, such as MK-571, would be appropriate for treatment with acyclovir.
  • an MRP inhibitor such as MK-571
  • two widely used, glaucoma drugs, bimatoprost and lafanoprost are both substrates for MRP5 and can suppress efflux of drugs administered therewith that are also substrates of MRP5.
  • the efflux transporter inhibitor is applied in an amount effective to reduce the efflux of the drug through the subject's eye for a period of time sufficient for the administered drug to have clinical benefit to the patient.
  • drug comprises at least one active ingredient, including, for example, compound, protein, peptide, or prodrug compound, that is effective to ameliorate or reduce one or more symptoms of an ocular disease.
  • the efficacy of the drug is substantially increased when used in conjunction with an efflux transporter inhibitor.
  • the drug is a substrate of at least one efflux transporter selected from the group consisting of MRPs, BCRP, and Pgp.
  • the active ingredient includes at least one of an antimicrobial (including, for example, antibiotic, antifungal, and antiviral compounds).
  • antimicrobials include, for example, amoxicillin, ciprofloxacin, moxifloxacin, cephalexin, vancomycin, ceftazidime, amphotericin, doxycycline, tobramycin, amikacin, gentamicin,
  • acyclovir also called acycloguanosine and marketed as ZOVIRAX® by GlaxoSmithKline LLC
  • valacyclovir valacyclovir
  • ameliorating or reducing one or more symptoms of endophthalmitis includes, for example, reducing eye redness, eye pain, and improving blurred or lost vision.
  • the methods and/or compositions described herein may further include a second active ingredient in addition to the antimicrobial active agent and efflux transporter inhibitor.
  • the second active ingredient may include, for example, a steroid or anti-inflammatory agent.
  • Steroids useful in the methods and compositions described herein include, for example, hydrocortisone, fluromethalone (FML), fluromethalone acetate (FLAREX ⁇ ), prednisolone sodium phosphate (marketed as Predsol), prednisolone actetate (PRED FORTE®), and dexamethasone (MAXIDEXTM).
  • the second active ingredient can be provided in the same or different drug as the antimicrobial active agent.
  • the drug can ingorge both an antimicrobial and a second active ingredient.
  • the antimicrobial and second active agent are provided in separate compositions and are separately applied to the eye.
  • at least two of the group consisting of antimicrobial, steroid, and an ti- inflammatory are used in combination with an efflux transporter inhibitor.
  • the drug may be applied directly to a target tissue, in one aspect the subject's eye, cornea, or to a surrounding fluid or tissue.
  • administration to the desired location may be by topical application.
  • the drug can be prepared in a variety of forms.
  • a liquid formulation can be prepared, such as, for example, in the form of a solution, emulsion, or suspension in a non-toxic, pharmaceutically-acceptable carrier.
  • the drug may be a powder or lyophilisate that is reconstituted with a solvent prior to use.
  • the formulation may be in the form of an emulsion or liquid concentrate that is suitable for dilution prior to administration.
  • pharmacetitically-acceptable carriers include saline, buffered saline, isotonic saline, Ringer's solution, dextrose, sterile w 7 ater, deionized water, glycerol, ethanol, 5% dextrose in water, and combinations thereof.
  • the drug may comprise a variety of optional ingredients.
  • the topical formulation may include ingredients such as but not limited to preservatives, lubricant, stabilizer, colorant, diluent, isotonic agent, pH modifier, buffer, excipient, and the like and additional active ingredients, if desired.
  • any additional ingredients included in the composition should not negatively impact the stability of the active ingredient(s) in the drug.
  • the treatment regimen for the ocular disease can vary depending on the particular needs of the subject.
  • the dose and frequency of administration of the drug and efflux transporter inhibitor may depend in part on the age of the subject and severity of ocular disease.
  • the combination of drug and efflux transporter inhibitor may be applied at least once daily.
  • the combination of drug and efflux transporter inhibitor may be applied at least twice a day.
  • formulation such as for at least about 3 days, in another aspect at least about 10 days.
  • a shorter or longer treatment regimen may be used, if desired.
  • the combination therapy of drug and efflux transporter inhibitor can be administered to a subject for improved ocular drug bioavailability and therapeutic efficac for the treatment of other ocular diseases, including, for example, diabetic retinopathy, macular degeneration, glaucoma, cataracts, ocular herpes and other ocular diseases which can be treated to effect new blood vessels in the eye through
  • the subject presented with opacity behind the lens.
  • the subject was non-responsive to the initial treatment regimen with no light perception.
  • the subject was treated with an aggressive treatment regimen of topical antibiotics Ceftazidime eye drops, Vancomycin eye drops and steroid Prednisolone eye drops every two hours.
  • the subject showed no improvement over the next two days (initial treatment regimen that did not prevent a drop in vision from reading
  • Cyclosporin A (sold as RESTASIS® from Allergan, Inc.) was added to the treatment regimen and was administered prior to administering the antibiotic and steroid eye drops.
  • the treatment regimen was administered with the hypothesis that it would result in inhibition of drug efflux barrier on the blood ocular barrier resulting in elevated posterior segment drug concentrations.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne des procédés et des compositions pour traiter une maladie oculaire chez un sujet qui en a besoin par l'augmentation de la biodisponibilité d'un médicament dans l'œil du sujet. Dans un aspect, la maladie oculaire est au moins l'une parmi la rétinopathie diabétique, la dégénérescence maculaire, l'endophtalmie, le glaucome, la cataracte et l'herpès oculaire. Les procédés et les compositions selon l'invention comprennent un inhibiteur des transporteurs d'efflux et un médicament efficace pour traiter la maladie oculaire. L'inhibiteur des transporteurs d'efflux est efficace pour réduire l'efflux du médicament via au moins l'une parmi la P-glycoprotéine (Pgp), la protéine de résistance du cancer du sein (BCRP) et la protéine 1-9 associée à la résistance multiple (MRP1-9).
PCT/US2013/065944 2013-10-21 2013-10-21 Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux Ceased WO2015060812A1 (fr)

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PCT/US2013/065944 WO2015060812A1 (fr) 2013-10-21 2013-10-21 Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11478465B2 (en) 2019-12-19 2022-10-25 Active Biotech Ab Compounds for treatment of eye diseases associated with excessive vascularisation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294604A (en) * 1989-12-20 1994-03-15 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method of treating ocular diseases by periocular administration of cyclosporine A or G
WO2007037849A2 (fr) * 2005-09-16 2007-04-05 Allergan, Inc. Compositions et methodes pour le transport intraoculaire d'agents therapeutiques
US20070117750A1 (en) * 2005-10-06 2007-05-24 Muhammad Abdulrazik Method for enhanced ocular drug penetration
US20080132457A1 (en) * 2004-03-17 2008-06-05 Keith Bostian Bacterial efflux pump inhibitors for the treatment of ophthalmic and otic infections
WO2010097800A1 (fr) * 2009-02-26 2010-09-02 Muhammad Abdulrazik Combinaison synergique de composés bioactifs pour diminuer la pression intraoculaire
CA2807508A1 (fr) * 2010-08-05 2012-02-09 Forsight Vision4, Inc. Implant sous-conjonctival pour une administration d'un medicament dans le segment posterieur

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294604A (en) * 1989-12-20 1994-03-15 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method of treating ocular diseases by periocular administration of cyclosporine A or G
US20080132457A1 (en) * 2004-03-17 2008-06-05 Keith Bostian Bacterial efflux pump inhibitors for the treatment of ophthalmic and otic infections
WO2007037849A2 (fr) * 2005-09-16 2007-04-05 Allergan, Inc. Compositions et methodes pour le transport intraoculaire d'agents therapeutiques
US20070117750A1 (en) * 2005-10-06 2007-05-24 Muhammad Abdulrazik Method for enhanced ocular drug penetration
WO2010097800A1 (fr) * 2009-02-26 2010-09-02 Muhammad Abdulrazik Combinaison synergique de composés bioactifs pour diminuer la pression intraoculaire
CA2807508A1 (fr) * 2010-08-05 2012-02-09 Forsight Vision4, Inc. Implant sous-conjonctival pour une administration d'un medicament dans le segment posterieur

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11478465B2 (en) 2019-12-19 2022-10-25 Active Biotech Ab Compounds for treatment of eye diseases associated with excessive vascularisation
US12208091B2 (en) 2019-12-19 2025-01-28 Active Biotech Ab Compounds for treatment of eye diseases associated with excessive vascularisation

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