(12) United States Patent
`Aberg
`
`(54) COMPOUNDS WITH COMBINED
`ANTIHISTAMINIC AND MAST CELL
`STABILIZING ACTIVITIES, INTENDED FOR
`OPHTHALMIC USE
`
`(75)
`
`Inventor: A. K. Gunnar Aberg, Sarasota, FL
`(US)
`
`(73) As.signee: Bridge Pharma, Inc., Sarasota, FL
`(US)
`
`( *) Notice:
`
`I lllll 1111111111111111 111111111111111 111111111111111 IIIII IIIIII IIII 11111111
`US006207684B1
`US 6,207,684 Bl
`Mar.27,2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`. . .. . .. . .. . .. ...................... . .. . .. . .. . .. . .. . A61K 31/445
`Int. Cl.7
`(5 1)
`(52) U.S. Cl . ............................................. 514/324; 514/912
`(58) Field of Search ...................................... 514/324, 912
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,749,786
`4,073,915
`5,399,360
`
`7/1973 Bourquin et al. .................... 424/267
`2/1978 Martin .................................. 424/267
`3/1995 Surer et al. .......................... 424/469
`Primary Examiner-Zohreh Fay
`(74) Attorney, Agent, or Firm-Nields & Lemack
`ABSTRACT
`
`(57)
`
`This invention relates to methods of treatment of ocular
`disease states, modulated by bistaminergic and inflamma(cid:173)
`tory mechanisms in a mammal using norketotifea, 10-0 H(cid:173)
`norketotifen and pharmaceutical compositions of those com(cid:173)
`pounds. More particularly, this invention relates to methods
`of treating ocular diseases (such as, seasonal allergic con(cid:173)
`junctivitis and other forms of conjunctivitis, keratitis,
`hyperemia, cellular infiltration, vascularization, fibroblastic
`proliferation, inflammatory cell degranulation), while avoid(cid:173)
`ing certain side effects, such as local irriation, using com(cid:173)
`pounds with combined antihistaminic and mast cell stabi(cid:173)
`lizing activities.
`
`7 Claims, No Drawings
`
`(21) Appl. No.:
`
`(22) PCT Filed:
`
`(86) PCT No.:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S .C. 154(b) by O days.
`09/445,118
`Jun.9, 1998
`PCT/US98/12031
`Dec. 2, 1999
`§ 371 Date:
`§ 102(e) Date: Dec. 2, 1999
`(87) PCT Pub. No.: WO98/56381
`PCT Pub. Date: Dec. 17, 1998
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 60/049,103, filed on JlUt. 9,
`1997.
`
`FRESENIUS EXHIBIT 1064
`Page 1 of 5
`
`

`

`US 6,207,684 Bl
`
`1
`COMPOUNDS WITH COMBINED
`ANTIHISTAMINIC AND MAST CELL
`STABILIZING ACTIVITIES, INTENDED FOR
`OPHTHALI\UC USE
`
`2
`in the treatment of ophthalmic disorders, such as seasonal
`conj uncti vi tis, ve rnal kerato-conj uncti vi tis, 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- 10
`minic and mast cell stabilizing compounds, having thera(cid:173)
`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,S)cyclohepta[l,2-b )thiophene, hereinafter called
`norketotifen and the I O-OH-substituted analogs thereof,
`hereinafter called 10-OH-norketotifen.
`The parent compound of norketotifen is ketotifen, which
`bas oow been found to be less active as an antihistamine,
`more sedating, more toxic and more irritating to the eye than
`norketotifen.
`
`EXAMPLE 1
`
`Binding to Histaminergic Receptors
`
`The affinities of the test compounds for the histamine
`H1-receptor are assessed using the (3 H)pyrilamine binding
`assay as de.scribed by Dini et al. (Agents and Actions, 1991,
`33: 181- 184) . Briefly, membranes from guinea pig cerebel(cid:173)
`lum are incubated with (3 H)pyrilamine and varying concen-
`15 trations of the te.st 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 exce.ss of unlabelled ligand. The results
`are expressed as percentage of specific binding in the
`20 presence of compounds. IC50 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 SigmaplotTM software.
`
`25
`
`EXAMPLE 2
`
`Binding to Muscarinic Receptors
`
`0
`
`N I
`
`H
`NORKETOTIFEN
`
`30
`
`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
`35 counter, using a commercial scintillation cocktail. The spe(cid:173)
`cific radioligand binding lo each receptor is defined as the
`difference between total binding and nonspecific binding
`determined in the presence of an excess of unlabelled ligand.
`IC50 values (concentrations required to inhibit 50% of
`40 specific binding) are determined by non linear regression
`analysis of the competition curves.
`
`EXAMPLE3
`
`Studies on Sedative Effects
`
`Norketotifen can be metaboli7.ed in the body along various
`pathways. Thus, the two isomers of 10-OH norketotifen are
`formed by reduction of the norketotifen molecule. Norke(cid:173)
`tot ifen and 10-0H norketotifen 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 45
`the ocular indications of this application. The metabolic
`pathways are different in different species and may aL50 be
`different between infants and adult humans.
`
`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.
`50 In short, physostigrnine (1.9 mg/kg s.c.) produces 100%
`lethality when given to grouped mice with 10 animals in
`each plastic cage (approx. llx26x l3 cm). Mice adminis(cid:173)
`tered a sedating antihistamine prior to physostigmine are
`protected and survive. In the present study, test agents are
`55 administered orally 60 minutes prior to physostigmine. The
`number of survivors are counted 20 minutes after physos(cid:173)
`tigmine administration.
`
`SUMMARY OF THE INVENTION
`Norketotifen has now been syntbe.sized and studied phar(cid:173)
`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 Jess local
`irritation and Jess sedative effects than ketotifen. It is con(cid:173)
`cluded that norketotifen will have clinical utility for the 60
`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
`
`65
`
`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), tbe subject matters of
`which are incorporated herein by reference.
`
`The starting compounds for these synthe.5es are obtained
`as described in Waldvogel et al.:
`
`FRESENIUS EXHIBIT 1064
`Page 2 of 5
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`

`

`US 6,207,684 Bl
`
`3
`(1) 4-( 4-piperidylidene )-9,10-dihydro-4H-benzo[ 4,5](cid:173)
`cyclohepta[ 1,2-b ]thiophene.
`(2) 4-( 4-piperidylidene )-9,10-dihydro-4H-benzo[ 4,5](cid:173)
`cyclohepta[l,2-b ]thiophene-10-one.
`Toe present invention provides the active compounds 5
`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(cid:173)
`pound of the present invention include acetic, benzene-
`su lfonic (besylate), benzoic, camphorsulfonic, citric, 15
`ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
`hydrochloric, isethionic, lactic, maleic, malic, amndelic,
`methanesulfonic, mucic, nitric, pamoic, panthothenic,
`phosphoric, p-to\uenesulfonic, succinic, sulfuric, tartaric,
`tromethamic and the like. The hydrogen fumarate is par- 20
`ticularly preferred.
`
`10
`
`Pharmaceutical Compositions
`
`4
`EXAMPLE4
`
`Tablet Formulations
`
`Ingredients
`
`Norketotifen
`Microcrystalline cellulose
`Lactose
`Calcium stearale
`FD&C Blue It! Lake
`
`per !ablet
`
`2 mg
`30 mg
`70 mg
`2 mg
`0 .03 mg
`
`per batch of
`10,000 1ablets
`
`20 g
`300 g
`700 g
`20 g
`300 mg
`
`The active ingredient (norketotifen) in tl1is example ~~ blended with the
`lactose and cellulose unti l 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 !ablets ll'ling a o/n inch (7 mm)
`shallow concave punch. Tablets of o ther strengths may be prepared by
`altering the ratio of active ingredient to the excipients o r to the final
`weig ht of the !ableL
`
`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- 30
`ceutical compositions may be specially formulated for oral,
`conjunctiva!, 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, conjunctiva!,
`sublingual, buccal, parenteral, cutaneous, transdermal,
`rectal, topical, or nasal administration, or as an oral or nasal 40
`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 45
`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(cid:173)
`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.
`
`Solid forms of capsules, dragees, granules, pills, and
`tablets can have coatings and/or shells (ex. enteric coating.s)
`known in the pharmaceutical formulating art. The compo(cid:173)
`sitions may also be designed to release the active ingredient
`(s) in a certain part of the gastrointestinal tract or in a
`25 controlled release, slow-release or in a delayed-release man-
`ner.
`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(cid:173)
`bilizing agents), emulsifiers ( ethanol, isopropyl alcohol,
`35 ethyl carbonate, ethyl acetate, benzyl alco hol, 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(cid:173)
`trointestinal tract.
`Topical Administration Forms (Including Forms for Con(cid:173)
`junctiva! Instillation)
`Compositions for topical administration of the com(cid:173)
`pounds of this invention include solutions, suspensions,
`50 droplets, sprays, ointments and powders.
`In addition to the therapeutically active ingredients, the
`composition of this invention for topical ocular or conjunc(cid:173)
`tiva! administration may further comprise various formula(cid:173)
`tory ingredients, such as antimicrobial preservatives and
`55 tonicity agents. Examples of suitable antimicrobial preser(cid:173)
`vatives include: benzalkonium chloride, thimerosal,
`chlorobutanol, methyl paraben, propyl paraben, phenylethyl
`alcohol, edetate disodium, sorbic acid, ONA.MER M and
`other agents, known to those skilled in the art. Such
`60 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
`65 and propylene glycol. Such agents, if utilized, will be
`employed in an amount of0.1 % to 10.0% by weight (wt.%).
`Various penetration-enhancing agents, such as for example
`
`FRESENIUS EXHIBIT 1064
`Page 3 of 5
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`

`

`US 6,207,684 Bl
`
`5
`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 5
`suitable for topical ophthalmic delivery, including solids,
`solutions, suspensions, emulsions, gels, and erodible solid
`ocular inserts.
`Parenteral Administration Forms
`Pharmaceutical compositions for parenteral injections 10
`include pharmaceutically acceptable sterile aquous or nona(cid:173)
`quous solutions, dispersions, suspensions, emulsions and
`sterile powders for reconstitution into sterile injectable solu(cid:173)
`tions or dispersions prior to use. Various aquous and nona(cid:173)
`quous carriers, diluents solvent5 and vehicles may be used 15
`(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.
`Toe compositions may also contain adjuvants such as
`preservatives, wetting agents, emulsifying agents, dispers(cid:173)
`ing agents, antibacterial agents, antifungal agents, isotonic
`agents, and/ or absorption-delaying agents. Absorption(cid:173)
`prolonging or absorption-delaying delaying effects may be 25
`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(cid:173)
`sulated matrices of the drug in biodegradable polymers, such 30
`as polyanhyd rides, polylact id e-polyglycoli de,
`polyorlhoesters) or by using various types of liposomes or
`microemulsions to hold the drug. Formulations for injection
`can be s terilized by various methods.
`Topical and traosdermal delivery forms are here also 35
`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, 40
`and/or gastric absorption of the drug.
`Buccal Admi nistration Forms
`Compositions for buccal administration are preferably
`toothpastes, mouthwashes, sublingual preparations, chewing
`gums, etc.
`Transdermal Administration Forms
`Compositions for transdermal administration of the com(cid:173)
`pounds of this invention include various transdermal deliv(cid:173)
`ery systems, such as for example patches, bandages etc.
`Various penetration-enhancing agents, such as for example 50
`DMSO, DMAC and hydroxypolyethoxydodecane may also
`be included.
`Rectal Administration Forms
`Compositions for rectal administration are preferably
`suppositories.
`
`45
`
`6
`fering from seasonal conjunctivitis, the concentration of the
`compounds of this invention in solutions or gels for instil(cid:173)
`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. TI1e 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 tinles per day.
`This invention provides methods for treatment and/or
`prophylaxis of all forms of ocular and conjunctiva! allergic,
`inlmunological 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(cid:173)
`tifen or 10-OH-norketotifen or pharmaceutically acceptable
`salts thereof.
`This invention also provides methods for
`20 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 agoni.sts or antagonists, antibacterial agents, anti-
`viral agents, steroids, cyclooxygenase inhibitors, leukotriene
`antagonists, lipoxygenase inhibitors and other ocular thera(cid:173)
`peutic remedies. In particular, the present invention provides
`for co-administration of oorketotifen or of 10-OH(cid:173)
`norketotifen or an isomer thereof with an ophthalmic
`decongestant, such as for example phenylephedrine, nap(cid:173)
`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 inlprove 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
`are
`those, cau.sed 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
`tbose 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
`55 effects residing in the other isomer ( distomer).
`What is clainled 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
`60 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 clainl 1, wherein said ophthalmic
`65 disorder is selected from the group consisting of allergic
`condition, an inlmunologic condition, and an inflammatory
`condition.
`
`Therapeutic Dose Levels
`Toe 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(cid:173)
`pounds of thi5 invention are used at dose levels of 0.1 mg to
`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-
`
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`

`US 6,207,684 Bl
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`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 compos1hon
`further comprises an ophthalmic decongestant.
`7. A topical ophthalmic composition comprising a thera(cid:173)
`peutically effective amount of a compound selected from the
`5 group consisting of norketotifen and 10-OH-norketotifen or
`a pharmaceutically acceptable salt thereof, together with a
`pharmaceutically acceptable topical carrier.
`
`FRESENIUS EXHIBIT 1064
`Page 5 of 5
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