EP1976494A1 - Adenosine a3 receptor agonists for the treatment of dry eye disorders - Google Patents

Adenosine a3 receptor agonists for the treatment of dry eye disorders

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Publication number
EP1976494A1
EP1976494A1 EP06701840A EP06701840A EP1976494A1 EP 1976494 A1 EP1976494 A1 EP 1976494A1 EP 06701840 A EP06701840 A EP 06701840A EP 06701840 A EP06701840 A EP 06701840A EP 1976494 A1 EP1976494 A1 EP 1976494A1
Authority
EP
European Patent Office
Prior art keywords
dry eye
agonist
adenosine
eye
iodobenzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06701840A
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German (de)
English (en)
French (fr)
Inventor
Pnina Fishman
Tatiana Reitblat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Can Fite Biopharma Ltd
Original Assignee
Can Fite Biopharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Can Fite Biopharma Ltd filed Critical Can Fite Biopharma Ltd
Publication of EP1976494A1 publication Critical patent/EP1976494A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to compounds and methods useful in the treatment of dry eye.
  • the preocular tear film plays an important role in the maintenance of corneal integrity, the protection against infection and the preservation of visual acuity. These functions, in turn, are critically dependent upon the stability, tonicity and/or composition of the tear film structure. Alteration, deficiency or absence of the tear film may lead to undesired dryness of the corneal epithelium, ulceration and perforation of the cornea, an increased incidence of infectious disease, and ultimately, severe visual impairment and blindness.
  • Keratoconjunctivitis sicca or more commonly keratitis sicca, refers to any eye with some degree of dryness.
  • aqueous tear deficiencies which are most frequently responsible for dry eye states, originate from lacrimal gland disorders and include autoimmune disease, congenital alacrima, paralytic hyposecretion or excretory duct obstruction;
  • mucin deficiency which is observed in various conjunctival cicatrization conditions, such as Stevens-Johnson syndrome, trachoma, pemphigoid, thermal and chemical bums, as well as hypovitaminosis A;
  • lipid abnormalities which may occur during eyelid inflammation (e.g. chronic blepharitis); and
  • diminished eyelid function [Holly, FJ., Tear film physiology. Internal Ophthalmol. Clin. 27:2-6 (1987)].
  • the first line of treatment is usually eye drops, preferably preservative free, that act as artificial tears.
  • Most artificial tears are hydrogels that increase the moisture content on the eye surface and give some temporary relief. These solutions and ointments give some temporary relief, but do little to arrest or reverse any damaging conditions.
  • a recently introduced artificial tear product is based on Castor oil emulsion (Refresh Endura tears).
  • warm moist compresses applied to the skin of the closed eyelids are also used to reduce tear loss due to evaporation.
  • anti- inflammatory agents such as topical steroids (in eye drops) are sometimes prescribed.
  • topical steroids in eye drops
  • One example includes the combination of castor oil with cyclosporine (Restasis).
  • pilocarpine the active ingredient in SalagenTM or cevimeline, the active ingredient in EvoxacTM, are known to stimulate specific receptors in lacrimal gland and cause increased secretion of tears.
  • the invention provides a method for treating dry eye condition in an individual comprising administrating to said individual an amount of A 3 adenosine receptor (A 3 AR) agonist, the amount being effective to ameliorate dry eye symptoms.
  • a 3 AR adenosine receptor
  • the invention provides a method for treating dry eye syndrome in an individual, comprising administrating to said individual an A 3 adenosine receptor (A 3 AR) agonist.
  • a 3 AR A 3 adenosine receptor
  • the invention provides a pharmaceutical composition for treating dry eye syndrome comprising as active ingredient an amount of A 3 AR agonist and a physiologically acceptable carrier, the amount of said A 3 AR agonist being effective to ameliorate dry eye symptoms.
  • the present invention provides the use of an A 3 AR agonist for the preparation of a pharmaceutical composition for treating dry eye condition.
  • Dry eye syndromes encompass a constellation of diverse disease processes that produce objective clinical signs of keratoconjunctivitis sicca (KCS).
  • KCS keratoconjunctivitis sicca
  • the classic prototype of the dry eye syndrome is Sjogren's syndrome, but there are many other causes of KCS including cicatrising conjunctival d iseases such as trachoma and pemphigoid, non-cicatrising syndromes causing specific dry eye findings, and atypical syndromes such as keratomalacia in which the eye is symptomatically and objectively dry but tear production is paradoxically normal.
  • the main symptom of dry eye is usually a scratchy or sandy feeling as if something is in the eye.
  • Other symptoms may include stinging or burning of the eye; episodes of excess tearing that follow periods of very dry sensation; a stringy discharge from the eye; and pain and redness of the eye.
  • individuals with dry eye experience heaviness of the eyelids or blurred, changing, or decreased vision, although loss of vision is uncommon.
  • tears Some individuals with dry eye may have tears that run down their cheeks. This is because the eye may be producing less of the lipid and mucin layers of the tear film, which help keep tears in the eye. When this happens, tears do not stay in the eye long enough to thoroughly moisten it.
  • the present invention provides a method for treating dry eye condition, specifically dry eye syndrome, comprising providing an individual exhibiting one or more dry eye symptoms and signs with an amount Of A 3 adenosine receptor (A 3 AR) agonist, the amount being effective to treat the dry eye condition.
  • a 3 AR adenosine receptor
  • compositions comprising the A 3 AR agonist for use in said treatment.
  • dry eye condition denotes any condition or syndromewhich results in the manifestation of dry eye symptoms. It includes an already existing condition as well as pseudo dry eye conditions, i.e. conditions high predisposition of developing dry eye syndromes. Dry eye syndrome may be as a result of another underlying condition causing dry eye, for example, Sjogren's syndrome, menopause or rheumatoid arthritis. Dry eye may also be a complication of inflammation, e.g. Blepharitis or of a foreign body in the eye. Yet dry eye may be a result of infection, or a side effect of medications, or exposure to toxins, chemicals, or other substances may cause a symptom or condition of dry eye.
  • dry eye symptoms which may be used interchangeably with the term “dry eye signs” is used herein to denote any sensation or change in normal function or structure of the eye that is experienced by an individual.
  • a non-limiting list of signs which may be perceived by a subject and be indicative of an dry eye syndrome includes, dry eye feeling, sandy eye feeling, scratchy eye feeling, burning eye, stinging or itching eye, excessive tearing, eye pain, redness of the eye, blurred vision, degraded vision.
  • treating or “treatment”, and the like are used herein to refer to obtaining a desired pharmacological and physiological effect.
  • the effect may be prophylactic in terms of preventing or partially preventing a disease, symptom or condition of dry eye and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to dry eye syndrome.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing dry eye syndrome from occurring in an individual which may be predisposed to develop dry eye syndrome but has not yet been diagnosed as having it, i.e., causing the clinical symptoms of dry eye syndrome not to develop in a subject that may be predisposed to dry eye syndrome but does not yet experience or display symptoms of dry eye syndrome; (b) inhibiting dry eye syndrome, i.e., arresting or reducing the development of dry eye syndrome or its clinical symptoms; or (c) relieving dry eye syndrome, i.e., causing regression of dry eye syndrome and/or its symptoms or conditions.
  • a 3 adenosine receptor agonist in the context of the present invention refers to any molecule capable of specifically binding to the A 3 AR, thereby fully or partially activating said receptor.
  • the A 3 AR agonist is thus a molecule that exerts its prime effect through the binding and activation of the A 3 AR. This means that at the doses it is being administered it essentially binds to and activates only the A 3 AR.
  • an A 3 AR agonist has a binding affinity (Kj) to the human A 3 AR in the range of less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally less than 5 nM.
  • Particularly preferred are A 3 AR agonists that have a Kj to the human A 3 R of less than 2 nM and desirably less than 1 nM.
  • a 3 AR agonists can also interact with and activate other receptors with lower affinities (namely a higher Ki).
  • a molecule will be considered an A 3 AR agonist in the context of the invention (namely a molecule that exerts its prime effect through the binding and activation A 3 AR) if its affinity to the A 3 AR is at least 3 times (i.e. its Ki to the A 3 AR is at least 3 times lower), preferably 10 times, desirably 20 times and most preferably at least 50 times larger than the affinity to any other of the adenosine receptors (i.e. A 1 , A 2a and A 2b ).
  • the affinity of an A 3 AR agonist to the human A 3 AR as well as its relative affinity to the other human adenosine receptors can be determined by a number of assays, such as a binding assay.
  • binding assays include providing membranes containing a receptor and measuring the ability of the A 3 AR agonist to displace a bound radioactive agonist; utilizing cells that display the respective human adenosine receptor and measuring, in a functional assay, the ability of the A 3 AR agonist to activate or deactivate, as the case may be, downstream signaling events such as the effect on adenylate cyclase measured through increase or decrease of the cAMP level; etc.
  • an A 3 AR agonist is thus preferably administered at a dose such that the blood level is such so that essentially only the A 3 AR will be activated.
  • R 2 is selected from the group consisting of hydrogen, halo, Ci-Ci 0 alkyoxy, amino, C 2 -Ci 0 alkenyl, and C 2 -Ci 0 alkynyl;
  • R 5 is selected from the group consisting of R- and S-1-phenylethyl, an unsubstituted benzyl group, and a benzyl group substituted in one or more positions with a substituent selected from the group consisting of Ci-Ci 0 alkyl, amino, halo, C 1 -Ci 0 haloalkyl, nitro, hydroxy, acetamido, Ci-Ci 0 alkoxy, and sulfo.
  • R a and R b may be the same or different and are selected from the group consisting of hydrogen and Ci-Ci 0 alkyl, particularly when R 2 is hydrogen or halo, especially hydrogen.
  • Additional specific compounds are those compounds wherein R a is hydrogen and R 2 is hydrogen, particularly when R 5 is unsubstituted benzyl.
  • R b is a Ci-C 10 alkyl or C 3 -Ci 0 cycloalkyl, particularly a Ci-Ci 0 alkyl, and more particularly methyl.
  • R a is hydrogen
  • R b is C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • R 5 is R- or S-1-phenylethyl or a benzyl substituted in one or more positions with a substituent selected from the group consisting of halo, amino, acetamido, C 1 -C 10 haloalkyl, and sulfo, where the sulfo derivative is a salt, such as a triethylammonium salt.
  • R 2 is other than hydrogen, particularly those wherein R 2 is halo, C 1 -C 10 alkylamino, or C 1 -Ci 0 alkylthio, and, more preferably, when additionally R a is hydrogen, R b is a C 1 -C 10 alkyl, and/or R 5 is a substituted benzyl.
  • Such specifically disclosed compounds include 2-chloro-N 6 -(3-iodobenzyl)- 9-[5-(methylamido)-a-D-ribofuranosyl]-adenine, N 6 -(3-iodobenzyl)-2- methylamino-9-[5-(methylamido)-a-D-ribofuranosyl]-adenine, and N 6 -(3- iodobenzyl)-2-methylthio-9-[5-(methylamido)-a-D-ribofuranosyl]-adenine.
  • R 7 and R 8 may be the same or different and are selected from the group consisting of Ci-Ci 0 alkyl, R- and S-1-phenylethyl, an unsubstituted benzyl group, and a benzyl group substituted in one or more positions with a substituent selected from the group consisting of Ci-Ci 0 alkyl, amino, halo, Ci-Ci 0 haloalkyl, nitro, hydroxy, acetamido, Ci-Ci 0 alkoxy, and sulfo; and
  • R 9 is selected from the group consisting of halo, benzyl, phenyl, and C 3 -Ci 0 cycloalkyl.
  • WO 99/06053 discloses in examples 19-33 compounds selected from:
  • the A 3 AR agonist is a compound that exerts its prime effect through the binding and activation of the adenosine A 3 AR and is a purine derivative falling within the scope of the general formula (I):
  • Rn represents an alkyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or a group of the following general formula (II):
  • Y represents oxygen, sulfur or CH 2 ;
  • R e and R f may be the same or different and are selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl or are joined together to form a heterocyclic ring containing two to five carbon atoms; and
  • R 8 is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl;
  • X 12 is H, hydroxyl, alkylamino, alkylamido or hydroxyalkyl
  • R' and R" represent independently an alkyl group
  • Ri 2 is selected from the group consisting of hydrogen, halo, alkylether, amino, hydrazido, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl, thio, and alkylthio; and
  • - Ri 3 is a group of the formula -NRi S R 16 wherein
  • Ri 5 is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl-NH-C(Z)-, with Z being O, S, or NR a with R e having the above meanings; wherein when Ri 5 is hydrogen than
  • R ⁇ 6 is selected from the group consisting of R- and S-1-phenylethyl, benzyl, phenylethyl or anilide groups unsubstituted or substituted in one or more positions with a substituent selected from the group consisting of alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy, and sulfonic acid or a salt thereof; benzodioxanemethyl, fururyl, L-propylalanyl- aminobenzyl, ⁇ - alanylamino- benzyl, T-BOC- ⁇ -alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; or Ri 6 is a group of the following formula:
  • R 16 is selected from the group consisting of heteroaryl-NR a -C(Z)-, heteroaryl-C(Z)-, alkaryl-NR a -C(Z>, alkaryl- C(Z)-, aryl-NR-C(Z)- and aryl-C(Z)-; Z representing an oxygen, sulfor or amine; or a physiologically acceptable salt of the above compound.
  • the A 3 AR agonist is a nucleoside derivative of the general formula (IV):
  • non-cyclic carbohydrate groups e.g. alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamine, etc
  • the non-cyclic carbohydrate groups are either branched or unbranched, preferably containing from one or two to twelve carbon atoms.
  • physiologically acceptable salts of the compounds employed by the present invention it is meant any non-toxic alkali metal, alkaline earth metal, and ammonium salt commonly used in the pharmaceutical industry, including the sodium, potassium, lithium, calcium, magnesium, barium ammonium and protamine zinc salts, which are prepared by methods known in the art.
  • the term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid.
  • the acid addition salts are those which retain the biological effectiveness and qualitative properties of the free bases and which are not toxic or otherwise undesirable. Examples include, inter alia, acids derived from mineral acids, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric and the like.
  • Organic acids include, inter alia, tartaric, acetic, propionic, citric, malic, malonic, lactic, fumaric, benzoic, cinnamic, mandelic, glycolic, gluconic, pyruvic, succinic salicylic and arylsulphonic, e.g. p-toluenesulphonic, acids.
  • a 3 AR agonist which may be employed according to general formula (IV) of the present invention include, without being limited thereto, N 6 -2- (4-aminophenyl)ethyladenosine (APNEA), N 6 -(4-amino-3-iodobenzyl) adenosine- 5'-(N-methyluronamide) (AB-MECA), N 6 -(3-iodobenzyl)-adenosine-5'- N- methyluronamide (IB-MECA) and 2-chloro-N 6 -(3-iodobenzyl)- adenosine-5'-N- methyluronamide (Cl-IB-MECA).
  • IB-MECA is the most preferred compound in accordance with the invention.
  • the A 3 AR agonist may be an oxide derivative of adenosine, such as N ⁇ benzyladenosme-S'-N-alkyluronamide-N 1 - oxide or N ⁇ benzyladenosme-S'-N-dialkyluronamide-N ⁇ oxide, wherein the 2- purine position may be substituted with an alkoxy, amino, alkenyl, alkynyl or halogen.
  • adenosine such as N ⁇ benzyladenosme-S'-N-alkyluronamide-N 1 - oxide or N ⁇ benzyladenosme-S'-N-dialkyluronamide-N ⁇ oxide
  • an amount of A 3 AR agonist which prevents or reduces symptoms of dry eye in patients.
  • the “effective amount” can be readily determined, in accordance with the invention, by administering to a plurality of tested subjects various amounts of the A 3 AR agonist and then plotting the physiological response (for example an integrated "SS index” combining several of the therapeutically beneficial effects) as a function of the amount.
  • the effective amount may also be determined, at times, through experiments performed in appropriate animal models and then extrapolating to human beings using one of a plurality of conversion methods; or by measuring the plasma concentration or the area under the curve (AUC) of the plasma concentration over time and calculating the effective dose so as to yield a comparable plasma concentration or AUC.
  • the effective amount may depend on a variety of factors such as mode of administration (for example, oral administration may require a higher dose to achieve a given plasma level or AUC than an intravenous administration); the age, weight, body surface area, gender, health condition and genetic factors of the subject; other administered drugs; etc.
  • dosages are indicated in weight/Kg, meaning weight of administered A 3 AR agonist (e.g. IB-MECA) per kilogram of body weight of the treated subject in each administration.
  • weight/Kg and microgram/Kg denote, respectively, milligrams of administered agent and micrograms of administered agent per kilogram of body weight of the treated subject.
  • the effective amount is preferably less than about 1 mg/kg body weight, particularly less than about 500 ⁇ g/kg or even less than about 200 ⁇ g/kg body weight or at times less than about 100 ⁇ g/kg body weight or even less than about less than 50 ⁇ g/kg body weight.
  • the effective amount is preferably less than 5 mg each dose, for once daily administration (namely a dose less than about 70 ⁇ g/kg body weight, assuming an average individual weight of about 70 kg), and less than about 4 mg each dose (i.e. less than about 57 ⁇ g/kg body weight), for twice daily administration.
  • the dose of IB-MECA is more preferably less than about 2 mg each dose and typically between about 0.1-1 mg each dose, for either once or twice daily administration (the corresponding dosages in weight per body weight being about 29 ⁇ g/kg and about 1.5-15 ⁇ g/kg body weight, respectively).
  • the administration of the A 3 AR agonist to an individual may be together with a pharmaceutically acceptable carrier.
  • the carrier is one that is acceptable for oral administration.
  • the carrier is one that is acceptable for topical administration, one example being ocular administration.
  • harmaceutically acceptable carrier any one of inert, non-toxic materials, which do not react with the A 3 AR agonist and which can be added to formulations as diluents or carriers or to give form or consistency to the formulation.
  • An oral formulation may be in the form of a pill, capsule, in the form of a syrup, an aromatic powder, and other various forms.
  • the carrier is selected at times based on the desired form of the formulation.
  • the carrier may also at times have the effect of the improving the delivery or penetration of the active ingredient to the target tissue, for improving the stability of the drug, for slowing clearance rates, for imparting slow release properties, for reducing undesired side effects etc.
  • the carrier may also be a substance that stabilizes the formulation (e.g. a preservative), for providing the formulation with an edible flavor, etc.
  • the carriers may be any of those conventionally used and is limited only by chemical-physical considerations, such as solubility and lack of reactivity with the A 3 AR agonist, and by the route of administration.
  • the carrier may include additives, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • the carrier may be an adjuvant, which, by definition are substances affecting the action of the active ingredient in a predictable way.
  • Typical examples of carriers suitable for oral administration comprise (a) liquid solutions, where an effective amount of the active substance is dissolved in diluents, such as water, saline, natural juices, alcohols, syrups, etc.; (b) capsules (e.g.
  • the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers), tablets, lozenges (wherein the active substance is in a flavor, such as sucrose and acacia or tragacanth or the active substance is in an inert base, such as gelatin and glycerin), and troches, each containing a predetermined amount of the tragacanth as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; (e) suitable emulsions; (f) liposome formulation; and others.
  • a topical formulation may be in any form suitable for topical administration, including, without being limited thereto, an ophthalmic solution (e.g. eye drops), an ophthalmic gel or an ophthalmic ointment or oily lotion.
  • Topical administration of the A 3 AR agonist also comprises the use of ophthalmic patches carrying the A 3 AR agonist in a suitable drug containing layer and to be placed on top of the eyelid as well as to Ocular inserts which are devices containing the A 3 AR agonist and placed into the inferior or superior conjunctival sacs (see for example WO0059420).
  • Eye drops may be prepared by dissolving A 3 AR agonist in a sterile aqueous solution such as saline, buffering solution etc., or by combining powder compositions to be dissolved before use.
  • Other additives may be included in the eye drops such as isotonizing agents (e.g., sodium chloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (e. g., benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.), thickeners (e.
  • saccharide such as lactose, mahnitol, maltose, etc.
  • hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate, etc.
  • mucopolysaccharide such as chondroitin sulfate, etc.
  • sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, etc. e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, etc.
  • Eye ointments may be prepared by mixing A3AR agonist into a base.
  • Examples of the base for eye ointment include petrolatum, selen 50, Plastibase, macrogol, etc., but not limited thereto.
  • Some exemplary ophthalmic viscosity enhancers that can be used in the present formulation include: carboxymethyl cellulose sodium; methylcellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxyethyl cellulose; polyethylene glycol 300; polyethylene glycol 400; polyvinyl alcohol; and providone.
  • Some natural products such as veegum, alginates, xanthan gum, gelatin, acacia and tragacanth, may also be used to increase the viscosity of ophthalmic solutions.
  • a tonicity is important because hypotonic eye drops cause an edema of the cornea, and hypertonic eye drops cause deformation of the cornea.
  • the ideal tonicity is approximately 300 mOsM.
  • the tonicity can be achieved by methods described in Remington: The Science and Practice of Pharmacy, known to those versed in the art.
  • an A 3 AR agonist includes one or more compounds which are capable of specifically binding to the A 3 AR, thereby fully or partially activating said receptor.
  • compositions include the recited active agent, i.e. A 3 AR agonist, but not excluding other elements, such as physiologically acceptable carriers and excipients as well as other active agents.
  • active agent i.e. A 3 AR agonist
  • Consisting essentially of is used to define compositions which include the recited elements but exclude other elements that may have an essential significance on treatment of dry eye syndrome. "Consisting of shall thus mean excluding more than trace elements of other elements. Embodiments defined by each of these transition terms are within the scope of this invention.
  • IB-MECA improves dry eye symptoms in Rheumatoid Arthritis patients
  • the A 3 AR agonist used was a clinical grade of the compound known genetically as 1 -Deoxy- 1 - [6- [[(3 -iodopheny l)methyl] amino]-9H-purine-9-yl] -N- methyl-D-ribofuranuronamide or as N 6 -(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA), that was synthesized for Can-Fite BioPharma, under good clinical practice (GMP) by Albany Molecular Research Inc, Albany, NY 5 USA.
  • the IB-MECA was formulated in oval softgel capsules.
  • the capsules contained solutions of IB-MECA in Cremophor RH 40 and Miglyol 812.
  • the capsules contained a dose of 0.1, 1 or 4 mg of IB-MECA, the exact composition of each capsules' type is shown in the following Tabels 1-3:
  • the capsules with IB-MECA were given to patients orally twice daily. All patients had rheumatoid arthritis (RA) and were give IB-MECA within the framework of a clinical study aimed at testing the effect of IB-MECA in modifying RA disease symptoms in these patients.
  • the patients received randomly capsules of one of the above there doses.
  • the patients received the IB- MECA for a period of 12 weeks.
  • Table 1 summarizes the results of CFlOl treatment of RA patients. Specifically, four patients at the age 58 ⁇ 4 years who suffered from RA for 8 ⁇ 2 years were followed. At base line, the patients had elevated levels of rheumatoid factor, i.e., 313 ⁇ 120 IU/ml (0 ⁇ normal ⁇ 40) and had suffered from dry eyes for 5 ⁇ 1.6 years. Upon treatment with CFlOl for 6.25 ⁇ 1.1 months, an improvement in Schirmer's test from 8.5 ⁇ 1.4mm to 15.6 ⁇ 2.9mm was observed.
EP06701840A 2006-01-27 2006-02-01 Adenosine a3 receptor agonists for the treatment of dry eye disorders Withdrawn EP1976494A1 (en)

Applications Claiming Priority (2)

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US76250606P 2006-01-27 2006-01-27
PCT/IL2006/000130 WO2007086044A1 (en) 2006-01-27 2006-02-01 Adenosine a3 receptor agonists for the treatment of dry eye disorders

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EP (1) EP1976494A1 (zh)
JP (2) JP5185139B2 (zh)
KR (1) KR101037095B1 (zh)
CN (1) CN101365430B (zh)
AU (1) AU2006336834B2 (zh)
BR (1) BRPI0621052A2 (zh)
CA (1) CA2622975C (zh)
IL (1) IL191271A (zh)
WO (1) WO2007086044A1 (zh)

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HUE034474T2 (en) 2007-03-14 2018-02-28 Can Fite Biopharma Ltd Method for the synthesis of IB-meca
IL184620A0 (en) * 2007-07-15 2008-01-20 Can Fite Biopharma Ltd Composition for the treatment of inflammation
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WO2007086044A1 (en) 2007-08-02
AU2006336834A1 (en) 2007-08-02
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KR101037095B1 (ko) 2011-05-26
AU2006336834B2 (en) 2009-12-10
JP2013032396A (ja) 2013-02-14
IL191271A0 (en) 2009-08-03
CN101365430B (zh) 2011-09-21
BRPI0621052A2 (pt) 2012-07-17
JP5185139B2 (ja) 2013-04-17
JP2009524647A (ja) 2009-07-02
KR20080090517A (ko) 2008-10-08
CA2622975C (en) 2011-05-03
CA2622975A1 (en) 2007-08-02

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