(12) United States Patent
`Aberg
`
`USOO62O7684B1
`(10) Patent No.:
`US 6,207,684 B1
`(45) Date of Patent:
`Mar. 27, 2001
`
`(54) COMPOUNDS WITH COMBINED
`ANTHISTAMINIC AND MAST CELL
`STABILIZING ACTIVITIES, INTENDED FOR
`OPHTHALMIC USE
`
`(75) Inventor: A. K. Gunnar Aberg, Sarasota, FL
`(US)
`
`(*) Notice:
`
`(73) Assignee: Bridge Pharma, Inc., Sarasota, FL
`(US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.:
`09/445,118
`(22) PCT Filed:
`Jun. 9, 1998
`(86) PCT No.:
`PCT/US98/12031
`S371 Date:
`Dec. 2, 1999
`S 102(e) Date: Dec. 2, 1999
`(87) PCT Pub. No.: WO98/56381
`PCT Pub. Date: Dec. 17, 1998
`Related U.S. Application Data
`(60) Provisional application No. 60/049,103, filed on Jun. 9,
`1997.
`
`(51) Int. Cl." ................................................... A61K 31/445
`(52) U.S. Cl. ............................................. 514/324; 514/912
`(58) Field of Search ...................................... 514/324, 912
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`7/1973 Bourquin et al. .................... 424/267
`3,749,786
`2/1978 Martin .................................. 424/267
`4,073.915
`3/1995 Surer et al. .......................... 424/469
`5,399,360
`Primary Examiner Zohreh Fay
`(74) Attorney, Agent, or Firm Nields & Lemack
`(57)
`ABSTRACT
`
`
`
`This invention relates to methods of treatment of ocular
`disease States, modulated by histaminergic and inflamma
`tory mechanisms in a mammal using norketotifen, 10-OH
`norketotifen and pharmaceutical compositions of those com
`pounds. More particularly, this invention relates to methods
`of treating ocular diseases (such as, Seasonal allergic con
`junctivitis and other forms of conjunctivitis, keratitis,
`hyperemia, cellular infiltration, vascularization, fibroblastic
`proliferation, inflammatory cell degranulation), while avoid
`ing certain Side effects, Such as local irriation, using com
`pounds with combined antihistaminic and mast cell Stabi
`lizing activities.
`
`7 Claims, No Drawings
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1064, p. 1 of 5
`
`

`

`US 6,207,684 B1
`
`1
`COMPOUNDS WITH COMBINED
`ANTIHISTAMINIC AND MAST CELL
`STABILIZING ACTIVITIES, INTENDED FOR
`OPHTHALMIC USE
`
`2
`in the treatment of ophthalmic disorders, Such as Seasonal
`conjunctivitis, Vernal kerato-conjunctivitis, Vernal
`conjunctivitis, and Vernal keratitis. The Surprising findings
`are described in the following examples.
`
`This application is a 371 of PCT/US98/12031 Jun. 9,
`1998, which claims benefit of Provisional Application Ser.
`No. 60/049,103 filed Jun. 9, 1997.
`BACKGROUND OF THE INVENTION
`This invention relates Specifically to combined antihista
`minic and mast cell Stabilizing compounds, having thera
`peutic use in various diseases, most importantly for patients
`Suffering from ocular diseases, Such as Vernal conjunctivitis,
`keratitis, and mast cell degranulation
`The compound described in this invention 10-oxo
`4Hbenzo 4.5cyclohepta1,2-bithiophene, hereinafter called
`norketotifen and the 10-OH-substituted analogs thereof,
`hereinafter called 10-OH-norketotifen.
`The parent compound of norketotifen is ketotifen, which
`has now been found to be leSS active as an antihistamine,
`more Sedating, more toxic and more irritating to the eye than
`norketotifen.
`
`
`
`H
`NORKETOTIFEN
`
`Norketotifen can be metabolized in the body along various
`pathways. Thus, the two isomers of 10-OH norketotifen are
`formed by reduction of the norketotifen molecule. Norke
`totifen and 10-OH norke totifen can also undergo
`N-glucuronidation. Other metabolites, Such as for example
`9-OH-norketotifen and 9,10-di-OH-norketotifen may be
`formed and may as well be therapeutically active entities for
`the ocular indications of this application. The metabolic
`pathways are different in different Species and may also be
`different between infants and adult humans.
`SUMMARY OF THE INVENTION
`Norketotifen has now been synthesized and studied phar
`macologically. Surprisingly and importantly, a significant
`quantitative difference between ketotifen and norketotifen
`was found: It has now been found that norketotifen has
`potent anti-inflammatory and anti-histaminic effects and
`does not have irritating effects when applied to the eye.
`It was Surprisingly found that although norketotifen has
`more potent anti-histaminergic effects, it causes less local
`irritation and leSS Sedative effects than ketotifen. It is con
`cluded that norketotifen will have clinical utility for the
`treatment of various allergic and inflammatory ophthalmic
`conditions.
`
`DETAILED DESCRIPTION
`Pharmacological Studies of Norketotifen
`AS discussed above, it has now been possible to show that
`norketo-tifen has beneficial pharmacological effects, useful
`
`EXAMPLE 1.
`
`Binding to Histaminergic Receptors
`
`The affinities of the test compounds for the histamine
`H-receptor are assessed using the Hpyrilamine binding
`assay as described by Dini et al. (Agents and Actions, 1991,
`33: 181-184). Briefly, membranes from guinea pig cerebel
`lum are incubated with Hpyrilamine and varying concen
`trations of the test compound(s). The specific binding of the
`radioactive ligand to the receptor is defined as the difference
`between total binding and nonspecific binding, determined
`in the presence of an exceSS of unlabelled ligand. The results
`are expressed as percentage of Specific binding in the
`presence of compounds. ICso values (concentration required
`to inhibit 50% of specific binding) and Hill coefficients (nH)
`are determined by non linear regression analysis of the
`competition curves. These parameters are obtained by Hill
`equation curve fitting using Sigmaplot" Software.
`
`EXAMPLE 2
`
`Binding to Muscarinic Receptors
`The experiments are carried out on membranes prepared
`from SF9 cells infected with bacculovirus to express human
`recombinant muscarinic receptor Subtypes. After incubation
`with the test article and the proper radioligand and washing,
`bound radioactivity is determined with a liquid Scintillation
`counter, using a commercial Scintillation cocktail. The Spe
`cific radioligand binding to each receptor is defined as the
`difference between total binding and nonspecific binding
`determined in the presence of an excess of unlabelled ligand.
`ICso values (concentrations required to inhibit 50% of
`Specific binding) are determined by non linear regression
`analysis of the competition curves.
`
`EXAMPLE 3
`
`Studies on Sedative Effects
`
`The phySOStigmine-induced lethality test used in these
`tests is a modification of the Sedation test technique reported
`by COLLIER et al., in Br. J. Pharmac., 1968, 32: 295-310.
`In short, physostigmine (1.9 mg/kg. s.c.) produces 100%
`lethality when given to grouped mice with 10 animals in
`each plastic cage (approx. 11x26x13 cm). Mice adminis
`tered a Sedating antihistamine prior to phySOStigmine are
`protected and Survive. In the present Study, test agents are
`administered orally 60 minutes prior to phySoStigmine. The
`number of Survivors are counted 20 minutes after phySOS
`tigmine administration.
`
`Chemical Synthesis of the New Compounds
`The synthesis of ketotifen, norketotifen and of (RS)-10
`OH-norketotifen have been described by Waldvogel et al.
`(Helv Chem Acta, 1976, 59:866–877), the subject matters of
`which are incorporated herein by reference.
`The Starting compounds for these Syntheses are obtained
`as described in Waldvogel et al.:
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1064, p. 2 of 5
`
`

`

`3
`(1) 4-(4-piperidylidene)-9,10-dihydro-4H-benzo 4,5-
`cyclohepta1,2-bithiophene.
`(2) 4-(4-piperidylidene)-9,10-dihydro-4H-benzo 4,5-
`cyclohepta1,2-bithiophene-10-one.
`The present invention provides the active compounds
`norketotifen, racemic 10-OH-ketotifen, the optically active
`isomers of 10-OH-norketotifen, and the pharmaceutically
`acceptable Salts and Solvates thereof.
`The terms “pharmaceutically acceptable Salts' or “a phar
`maceutically acceptable Salt thereof refer to Salts prepared
`from pharmaceutically acceptable non-toxic acids. Suitable
`pharmaceutically acceptable acid addition Salts for the com
`pound of the present invention include acetic, benzene
`Sulfonic (besylate), benzoic, camphorsulfonic, citric,
`ethaneSulfonic, fumaric, gluconic, glutamic, hydrobromic,
`hydrochloric, isethionic, lactic, maleic, malic, amndelic,
`methaneSulfonic, mucic, nitric, pamoic, panthothenic,
`phosphoric, p-toluenesulfonic, Succinic, Sulfuric, tartaric,
`tromethamic and the like. The hydrogen fumarate is par
`ticularly preferred.
`
`15
`
`Pharmaceutical Compositions
`The present invention also provides pharmaceutical
`compositions, which comprise each of the compounds
`norketotifen, racemic 10-OH-norketotifen, and the topically
`active isomers of 10-OH-norketotifen, formulated with one
`or more pharmaceutically acceptable carriers. The pharma
`ceutical compositions may be specially formulated for oral,
`conjunctival, Sublingual, parenteral, transdermal, rectal,
`buccal, topical or nasal administration or for administration
`by inhalation of powder or aeroSol.
`The pharmaceutical compositions of this invention can be
`administered to humans and other mammals by various
`routes of administration, for example, by oral, conjunctival,
`Sublingual, buccal, parenteral, cutaneous, transdermal,
`rectal, topical, or nasal administration, or as an oral or nasal
`spray or aerosol. The term “parenteral” refers to but is not
`limited to intravenous, intraarterial, intramuscular,
`intraperitoneal, intracutaneous, Subcutaneous, retrobulbar
`and intraarticular administration. The term “transdermal'
`includes to but is not limited to administration by use of
`various devices ("patches' etc.) that facilitate or control the
`transport or absorption of the drug through tissues.
`Oral Administration Forms
`Pharmaceutical compositions of this invention for oral
`administration of Solid dosage forms, include tablets,
`capsules, pills, granules, and powders. In Such Solid dosage
`forms, the active compound may be mixed with one or more
`pharmaceutically acceptable excipients or carriers (ex.
`Sodium citrate, dicalcium phosphate), fillers or extenders
`(ex. Starch, lactose, Sucrose, glucose, mannitol, Silicic acid),
`binders (ex. carboxymethyl-cellulose, alginates, gelatin,
`polyvinylpyrrolidone, Sucrose, acacia), humectants (ex.
`glycerol), disintegrating agents (ex. agar-agar, calcium
`carbonate, Starch alginic acid, Silicates, Sodium carbonate),
`Solution retarding agents (ex. paraffin), absorption accelera
`tors (ex. quarternary ammonium compounds), wetting
`agents (ex.cetyl alcohol, glycerol monostearate), absorbents
`(ex. kaolin, bentonite clay), lubricating agents (ex. talk,
`calcium Stearate, magnesium Stearate, polyethylene glycols,
`Sodium lauryl Sulfate), and/or buffering agents. Regular
`tablets can be composed according to Example 4.
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`US 6,207,684 B1
`
`4
`EXAMPLE 4
`
`Tablet Formulations
`
`Ingredients
`Norketotifen
`Microcrystalline cellulose
`Lactose
`Calcium stearate
`FD&C Blue #1 Lake
`
`per tablet
`2 mg
`30 mg
`70 mg
`2 mg
`0.03 mg
`
`per batch of
`10,000 tablets
`20 g
`300 g
`700 g
`20 g
`300 mg
`
`The active ingredient (norketotifen) in this example is blended with the
`lactose and cellulose until a uniform blend is formed. The lake is added
`and further blended. Finally, the calcium stearate is blended in, and the
`resulting mixture is compressed into tablets using a 932 inch (7 mm)
`shallow concave punch. Tablets of other strengths may be prepared by
`altering the ratio of active ingredient to the excipients or to the final
`weight of the tablet.
`
`Solid forms of capsules, dragees, granules, pills, and
`tablets can have coatings and/or shells (ex. enteric coatings)
`known in the pharmaceutical formulating art. The compo
`Sitions may also be designed to release the active ingredient
`(s) in a certain part of the gastrointestinal tract or in a
`controlled release, Slow-release or in a delayed-release man
`C.
`The active compound(s) can also be micro-encapsulated
`with one or more of the above-mentioned excipients.
`Liquid dosage forms for oral administration include phar
`maceutically acceptable emulsions, Solutions, Suspensions,
`Syrups and elixirs. The liquid dosage form may also contain
`commonly known diluents (ex. water, other Solvents, Solu
`bilizing agents), emulsifiers (ethanol, isopropyl alcohol,
`ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
`benzoate, propylene glycol, butylene glycole, dimethyl
`formamide, oils, oleic acid, glycerol, tetrahydrofurfuryl
`alcohol, polyethylene glycols, Sorbitan fatty esters, and
`mixtures thereof.
`Suspensions may contain one ore more Suspending agents
`known in the pharmaceutical formulating art.
`Oral compositions may also be designed for lymphatic
`absorption of the active ingredient(s), using for example
`oleic acid to activate lymphatic absorption from the gas
`trointestinal tract.
`Topical Administration Forms (Including Forms for Con
`junctival Instillation)
`Compositions for topical administration of the com
`pounds of this invention include Solutions, Suspensions,
`droplets, Sprays, ointments and powders.
`In addition to the therapeutically active ingredients, the
`composition of this invention for topical ocular or conjunc
`tival administration may further comprise various formula
`tory ingredients, Such as antimicrobial preservatives and
`tonicity agents. Examples of Suitable antimicrobial preser
`Vatives include: benzalkonium chloride, thimerosal,
`chlorobutanol, methyl paraben, propyl paraben, phenylethyl
`alcohol, edetate disodium, Sorbic acid, ONAMER M and
`other agents, known to those skilled in the art. Such
`preservatives, if utilized, will typically be employed in an
`amount from 0.001% to 1.0% by weight (wt.%). Examples
`of Suitable agents which may be utilized to adjust the
`tonicity or oSmolality of the formulations include Sodium
`chloride, potassium chloride, mannitol, dextrose glycerine
`and propylene glycol. Such agents, if utilized, will be
`employed in an amount of 0.1% to 10.0% by weight (wt.%).
`Various penetration-enhancing agents, Such as for example
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1064, p. 3 of 5
`
`

`

`US 6,207,684 B1
`
`S
`DMSO, DMAC and hydroxypolyethoxydodecane may also
`be included. The compositions are preferably aqueous, and
`have a pH in the range of 3.5 to 8.0.
`As will be appreciated by those skilled in the art, the
`compositions may be formulated in various dosage forms
`Suitable for topical ophthalmic delivery, including Solids,
`Solutions, Suspensions, emulsions, gels, and erodible Solid
`ocular inserts.
`Parenteral Administration Forms
`Pharmaceutical compositions for parenteral injections
`include pharmaceutically acceptable Sterile aquous or nona
`quous Solutions, dispersions, Suspensions, emulsions and
`Sterile powders for reconstitution into Sterile injectable Solu
`tions or dispersions prior to use. Various aquous and nona
`quous carriers, diluents Solvents and vehicles may be used
`(ex. water, ethanol, glycerol, glycol), as well as Vegetable
`oils (ex. olive oil), and organic esters (eX ethyl oleate), or
`mixtures thereof may be used. Fluidity can be maintained by
`use of coating material Such as lecithin, by restricting
`particle size and by use of Surfactants.
`The compositions may also contain adjuvants Such as
`preservatives, wetting agents, emulsifying agents, disperS
`ing agents, antibacterial agents, antifungal agents, isotonic
`agents, and/or absorption-delaying agents. Absorption
`prolonging or absorption-delaying delaying effects may be
`achieved by injecting a crystalline or amorphous Suspension
`with low water solubility. Delayed absorption may also be
`obtained by dissolving or Suspending the drug in an oil
`vehicle or by using injectable depot forms (ex. microencap
`Sulated matrices of the drug in biodegradable polymers, Such
`as polyanhydride S, polylactide-polygly collide,
`polyorthoesters) or by using various types of liposomes or
`microemulsions to hold the drug. Formulations for injection
`can be Sterilized by various methods.
`Topical and transdermal delivery forms are here also
`embodied as parenteral administration forms.
`Oral or Nasal Spray or Droplet Administration
`Compositions for oral or nasal Sprays or droplets may be
`in the form of Solutions, Suspensions or dry powders and
`may be designed for nasal, buccal, bronchial/pulmonary,
`and/or gastric absorption of the drug.
`Buccal Administration Forms
`Compositions for buccal administration are preferably
`toothpastes, mouthwashes, Sublingual preparations, chewing
`gums, etc.
`Transdermal Administration Forms
`Compositions for transdermal administration of the com
`pounds of this invention include various transdermal deliv
`ery Systems, Such as for example patches, bandages etc.
`Various penetration-enhancing agents, Such as for example
`DMSO, DMAC and hydroxypolyethoxydodecane may also
`be included.
`Rectal Administration Forms
`Compositions for rectal administration are preferably
`Suppositories.
`
`15
`
`25
`
`35
`
`6
`fering from Seasonal conjunctivitis, the concentration of the
`compounds of this invention in Solutions or gels for instil
`lation into the conjunctival sac range from 0.01% to 5.0%,
`preferably 0.02% to 1.0%. The frequency and amount of the
`dosage will be determined by the clinician based on various
`clinical factors, Such as for example the weight and the
`severity of the disease of the patient. The use will typically
`comprise topical application of one to two drops (or an
`amount of a Solid or Semisolid dosage form) to the affected
`eye one to four times per day.
`This invention provides methods for treatment and/or
`prophylaxis of all forms of ocular and conjunctival allergic,
`immunological and inflammatory disorders in mammals,
`Such as humans, while avoiding ocular irritation, Sedation
`and other toxic manifestations of ketotifen. These methods
`comprise administering to the mammal in need of Such
`treatment and/or prophylaxis, effective amounts of norketo
`tifen or 10-OH-norketotifen or pharmaceutically acceptable
`salts thereof.
`This invention also provides methods for
`co-administration of norketotifen or 10-OH-norketotifen or
`an optically active isomer of thereof with at least one drug
`of the following classes: ocular antihypertensive agents,
`adrenergic agonists or antagonists, antibacterial agents, anti
`Viral agents, Steroids, cyclooxygenase inhibitors, leukotriene
`antagonists, lipoxygenase inhibitors and other ocular thera
`peutic remedies. In particular, the present invention provides
`for co-administration of norketotifen or of 10-OH
`norketotifen or an isomer thereof with an ophthalmic
`decongestant, Such as for example phenylephedrine, nap
`hazoline or tetrahydrozoline.
`The invention also provides methods for administration of
`norketotifen or 10-OH-norketotifen or an optically active
`isomer of thereof in conjuction with Surgical procedures to
`minimize inflammation or irritation and improve the post
`Surgical healing process.
`Equivalents
`The perSon Skilled in the art of pharmacology will realize
`that the conditions to be treated according to this invention
`C
`those, caused by the release of mediatorS Such as
`histamine, platelet aggregating factor, leukotrienes,
`thromboxanes and other arachidonate products and
`cytokines, being released form inflammatory cells Such
`as for example mast cells, eosinophils, leucocytes etc,
`the granulation of Such cells being inhibited by a “mast
`cell stabilizer”, and
`those caused by histamine binding to histamine receptors,
`which can be inhibited by a histamine receptor blocker
`and
`those caused by both inflammatory cell degranulation and
`by histamine-induced activation of target cells, tissues
`and organs.
`The person skilled in the art will realize that by using a
`single isomer (eutomer) of 10-OH-norketotifen in stead of
`racemic 10-OH-norketotifen, it is possible to avoid the side
`effects residing in the other isomer (distomer).
`What is claimed is:
`1. A method for preventing or treating ophthalmic
`disorders, which comprises administering to a mammal in
`need of Such treatment a therapeutically effective amount of
`a composition comprising a compound Selected from the
`group consisting of norketotifen and 10-OH-norketotifen or
`a pharmaceutically acceptable Salt thereof, together with a
`pharmaceutically acceptable carrier.
`2. The method of claim 1, wherein said ophthalmic
`disorder is Selected from the group consisting of allergic
`condition, an immunologic condition, and an inflammatory
`condition.
`
`40
`
`45
`
`50
`
`55
`
`Therapeutic Dose Levels
`The actual dosage levels of active ingredients in the
`pharmaceutical compositions of this inventions may be
`varied so as to obtain the desired therapeutic effect. Thus the
`amount of drug used varies and may depend on factorS Such
`as administration form, Severity of the disease, frequency of
`dosing etc. AS an example, for use as medication to patients
`Suffering from allergic conjunctivitis oral doses of the com
`pounds of this invention are used at dose levels of 0.1 mg to
`65
`about 100 mg, preferably from 0.2 mg to 10 mg once to four
`times daily to a patient weighing 60 kg. For patients Suf
`
`60
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1064, p. 4 of 5
`
`

`

`US 6,207,684 B1
`
`7
`3. The method of claim 2, wherein said ophthalmic
`disorder is Selected from the group consisting of Seasonal
`allergic conjunctivitis, Vernal keratoconjunctivitis, Vernal
`conjunctivitis, and Vernal keratitis.
`4. The method of claim 1, wherein from about 0.01 to 100
`mg is administered from one to four times daily.
`5. The method of claim 4, wherein the concentration of
`Said compound in Said composition is from about 0.01 to 2
`percent.
`
`8
`6. The method of claim 1, wherein said composition
`further comprises an ophthalmic decongestant.
`7. A topical ophthalmic composition comprising a thera
`peutically effective amount of a compound Selected from the
`group consisting of norketotifen and 10-OH-norketotifen or
`a pharmaceutically acceptable Salt thereof, together with a
`pharmaceutically acceptable topical carrier.
`
`k
`
`k
`
`k
`
`k
`
`k
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1064, p. 5 of 5
`
`