(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`19w ldI
`’
`°'
`
`‘
`'
`0
`1P
`“§.?£f§:12?...1'‘.;‘’.°.2E.’..’g“'‘“‘‘"°’‘
`
`‘
`
`g
`
`,
`
`,
`
`llllllllllllllllIllllllllll||||||lll||||||lllllllllllllllI||||l||||||lI||ll|||||
`
`(43) International Publication Date
`28 December 2000 (28.12.2000)
`
`(10) International Publication Number
`
`(51) International Patent Classification7:
`
`A61P
`
`(74) Agents: RYAN, Patrick M. et al.; R & D Counsel, Q-I48,
`6201 South Freeway, Fort Worth, TX 76134-2099 (US).
`
`(21) International Application Number:
`
`PCT/US00/06890
`
`(22) International Filing Date:
`
`16 March 2000 (16.03.2000)
`
`(25) Filing Language,
`
`t‘
`26 P bl’
`)
`u lea ion
`
`(
`
`L
`
`anguage
`
`:
`
`English
`
`E 1i h
`ng s
`
`(30) Priority Data:
`60/139,945
`60/158,177
`
`18 June 1999 (18.06.1999)
`7 October 1999 (07.10.1999)
`
`US
`US
`
`(7]) Applicant: ALCON LABORATORIES’ INC‘ [US/US];
`R & D Counsel, Q—l48, 6201 South Freeway, Fort Worth,
`TX 76134-2099 (US).
`
`(72) Inventors: GRAFF, Gustav; 6500 County Road 809, Cle-
`bume, TX 76031 (US). YANNI, John M.; 2821 Donny-
`brook Drive, Burleson, TX 76028 (US).
`
`(81) Designated States (national): AU, CA, JP.
`
`(84) Designated States (regional): European patent (AT, BE,
`
`CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE).
`
`Published:
`— Without international Search report and to be republished
`upon receipt ofthat report.
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`00/78396A2
`
`(54) Title: TOPICAL OPHTHALMIC MAST CELL STABILIZERS FOR TREATING ALLERGIC EYE DISEASES
`
`O (57) Abstract: Topical ophthalmic anti—aJ1ergy drugs are identified by the extent of their interaction with a phospholipid model
`membrane. Disclosed are topically administr-able ophthalmic formulations containing amphipathic anti-allergy compounds at con-
`W
`centrations such that the drugs have Surface Activity Ratings from about 2-11.
`
`APOTEX EX1023
`
`Page 1
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`TOPICAL OPHTHALMIC MAST CELL STABILIZERS FOR
`
`TREATING ALLERGIC EYE DISEASES
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`10
`
`The present invention relates to topical ophthalmic formulations used
`
`for treating allergic eye diseases, such as allergic conjunctivitis, vernal
`
`conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis.
`
`More particularly, the present invention relates to therapeutic and prophylactic
`
`topical use of mast cell stabilizers for treating and/or preventing allergic eye
`
`15
`
`diseases.
`
`Description of the Related Art
`
`20
`
`25
`
`30
`
`Conventional antihistamine drugs are known to exhibit biphasic effects
`
`on mast cells. At lower concentrations, antihistamines promote an inhibition
`
`of histamine release from mast cells. As concentrations of antihistamines are
`
`increased there is a spontaneous release of histamine from mast cells, which
`
`is associated with an apparent loss of mast cell membrane stability. See, for
`
`example, Mota et al., Brit. J. Pharmacol. 15:396-404. This biphasic behavior
`
`has been demonstrated for the anti—allergy drug ketotifen (4,9—dihydro-4-(1-
`
`methyI—4—piperidinyI—idene)- 1 0H—benzo[4,5]cyc/ohepta—[1,2—b]thiophen-1 0-one)
`
`in purified preparations of human conjunctival mast cells.
`
`Yanni et al., J.
`
`Ocular Pharmaco/., 122389-400 (1996).
`
`First generation mast cell stabilizer drugs without antihistaminic activity,
`
`such as cromolyn sodium, also exhibit biphasic behavior.
`
`Johnson et al.,
`
`Monogr. Allergy, 141299-306 (1979).
`
`Page 2
`
`Page 2
`
`

`
`wo 00/78396
`
`PCT/US00/06890
`
`U.S. Patent Nos. 4,871,865 and 4,923,892, both assigned to
`
`Burroughs Wellcome Co.
`
`("the Burroughs Wellcome Patents"), describes
`
`certain
`
`carboxylic
`
`acid
`
`derivatives
`
`of
`
`doxepin,
`
`including
`
`11—(3-
`
`5
`
`dimethylaminopropylidene)—6,11-dihydrodibenz[b,e]oxepine-2-carboxylic acid
`
`and
`
`11—(3—dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine—2(E)-
`
`acrylic acid, as mast cell stabilizers with antihistaminic action.
`
`These
`
`compounds inhibit the release of autacoids (i.e., histamine, serotonin, and the
`
`like) from mast cells and inhibit directly histamine's effects on target tissues.
`
`10
`
`The Burroughs Wellcome Patents teach various pharmaceutical formulations
`
`containing the carboxylic acid derivatives of doxepin; Example 8 (I) in both of
`
`the patents discloses an ophthalmic solution formulation.
`
`U.S. Patent 5,641,805 discloses topical ophthalmic formulations for
`
`15
`
`treating allergic eye diseases. The topical formulations contain acetic acid
`
`derivatives of doxepin and,
`
`in particular, Z-11-(3—dimethylaminopropylidene)—
`
`6,11—dihydrodibenz[b,ejoxepin-2-acetic acid (i.e., olopatadine), which is the
`
`cis form of the compound having the formula :
`
`CH2CH2N(CH3)2
`
`CHZCOOH
`
`’
`
`O
`
`m
`
`Unlike other antihistamine or mast cell stabilizer anti-allergy drugs,
`
`olopatadine does not provoke a release of histamine from mast cells at
`
`25
`
`concentrations higher than those for which antihistaminic activity is observed.
`
`Other topical ocular anti-allergy drugs that maintain mast cell membrane
`
`Page 3
`
`Page 3
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`stability and prevent histamine release from mast cells over a drug
`
`concentration range of 0.01 - 0.5 % (w/v) are desired.
`
`Summam of the Invention
`
`The present invention provides a method for selecting anti—allergy drug
`
`concentrations that are suitable for use in the topical treatment of allergic eye
`
`diseases. According to the present method, an amphipathic anti—allergy
`
`compound’s Surface Activity Rating is determined as described below. For
`
`topically administrable ophthalmic anti—allergy products, the anti-allergy drug
`
`concentration is chosen so that the drug has a Surface Activity Rating (in
`
`units of mN/m) from about 2 — 11.
`
`The present invention is also directed toward topically administrable
`
`ophthalmic
`
`anti-allergy
`
`pharmaceutical
`
`drug
`
`products
`
`comprising
`
`an
`
`amphipathic anti—allergy drug at a concentration such that the drug has a
`
`Surface Activity Rating from about 2 — 11.
`
`Among other factors, the present invention is based on the finding that
`
`amphipathic anti-allergy compounds formulated at concentrations at which
`
`they have a Surface Activity Rating of greater than 11 are likely to cause mast
`
`cell membrane instability and leakage of autocoids, including histamine, from
`
`human conjunctiva! mast cells.
`
`Brief Description of the Drawing
`
`Fig.
`
`1
`
`shows
`
`the
`
`effect
`
`of olopatadine
`
`and
`
`ketotifen
`
`drug
`
`concentrations on the surface pressure of 1-stearoyl-2—o|eoyl-sn-g|ycero-3-
`
`phosphocholine (SOPC) monolayers spread at an initial surface pressure of
`
`30 mN/m.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 4
`
`Page 4
`
`

`
`WO 00/78396
`
`PCT/USO0/06890
`
`Detailed Description of the Invention
`
`According to the present invention, topically administrable ophthalmic
`
`anti-allergy pharmaceutical drug products comprise an amphipathic anti-
`
`allergy drug at a concentration such that the drug has a Surface Activity
`
`Rating from about 2 — 11, and preferably from about 4 — 11.
`
`The drug
`
`products of the present invention contain an amphipathic anti-allergy drug at a
`
`concentration of about 20 mM or less.
`
`10
`
`15
`
`The Surface Activity Rating is obtained by determining the interaction
`
`of an amphipathic anti-allergy drug (“test compound”) in buffer alone with a
`
`phospholipid monolayer. Test compound/mast cell membrane interaction is
`
`mimicked in a phospholipid monolayer spread onto an aqueous buffer in a
`
`modified Langmuir
`
`trough.
`
`In
`
`this system,
`
`test compound—membrane
`
`interaction is quantified by determining the change in surface pressure (Arc in
`
`mN/m)
`
`of
`
`a monomolecular
`
`film of
`
`1-stearoyl—2-oleoyl-sn-glycero-3-
`
`phosphocholine (SOPC) spread at an initial surface pressure of 28 — 32
`
`mN/m on an aqueous buffer sub—phase. The initial surface pressure of 28 —
`
`32 mN/m is chosen because this pressure mimics that of most mammalian
`
`20
`
`cell membranes.
`
`Surface pressure changes are measured at 24°C, while progressively
`
`increasing the concentration of test compound in the buffer sub—phase from O
`
`to at least 5 mM (or to the compound’s solubility limit if less than 5 mM), and
`
`preferably to at least 20 mM (or the compound’s solubility limit if less than 20
`
`mM). Test compound is added to the sub—phase by continuous sub—phase
`
`exchange (keeping the total volume of the sub—phase constant) at a rate slow
`
`enough to avoid disturbing the SOPC monolayer (0.4 ml/min., for example).
`
`Surface pressure is measured using an automated interfacial monitor-
`
`controller built around a Cahn 27 electrobalance equipped with a 24 ga.
`
`25
`
`30
`
`Page 5
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`nichrome wire Wilhelmy probe. [See Tsujita et al, Regulation of carboxylester
`
`lipase adsorption to surfaces. 1. Chemical specificity. Biochemistry 2618423-
`
`8429 (1987) and Momsen et al., The suitability of nichrome for measurement
`
`of gas-liquid interfacial tension by the Wilhelmy method. J. Colloid Interface
`
`Sci. 135:547-552 (1990).]
`
`The two aqueous compartments (circular and
`
`rectangular) of the keyhole-shaped Teflon trough are disconnected; only the
`
`circular compartment (area = 25.5 cm2, volume = 24.4 ml)
`
`is used for
`
`monolayer formation. Temperature in both compartments is maintained at 24
`
`°C using a thermostated base plate controlled by a precision water bath.
`
`Precise positioning of the Wilhelmy probe in the aqueous phase, correction
`
`for probe buoyancy due to immersion, sub-phase stirring, and data collection
`
`are controlled by microprocessor (Tsujita et al, id.).
`
`The effect of test compound on surface pressure is determined by a
`
`continuous exchange of the aqueous phase with a concentrated solution of
`
`the test compound in buffer. Although the identity of the buffer is not critical
`
`as long as the aqueous sub-phase is maintained at a physiological pH, the
`
`preferred buffer is 10mM HEPES/100 mM NaCl with the pH adjusted to 7.5.
`
`The concentration of test compound in the aqueous phase is determined from
`
`the fraction of sub-phase volume exchanged and the concentration of the
`
`solute in the concentrated solution. The continuous exchange is necessary to
`
`avoid disturbing the SOPC monolayer, and is accomplished by a side or
`
`bottom injection/withdrawal ports.
`
`The amphipathic anti-allergy drugs of the present invention preferably
`
`possess antihistamine activity, such as tricyclic H1-receptor antagonists
`
`exhibiting an in vitro binding affinity (k;) in the range of 0.1 — 100 nM for the
`
`H1-receptor. The amphipathic anti-allergy drugs of the present
`
`invention
`
`exclude
`
`olopatadine,
`
`ketotifen,
`
`emedastine,
`
`pheniramine,
`
`pyrilamine,
`
`cromolyn, nedocromil and levocabastine.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 6
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`Formulations of the anti-allergy compounds for topical ophthalmic
`
`administration can be made using known techniques.
`
`Ophthalmically
`
`acceptable excipients, such as tonicity-adjusting agents, pH—adjusting agents,
`
`buffering
`
`agents, preservatives,
`
`comfort
`
`enhancing agents,
`
`viscosity-
`
`modifying agents, stabilizing agents, etc. may be included.
`
`For example,
`
`sodium chloride, glycerin, mannitol or the like may be used as the isotonic
`
`agent; p—hydroxybenzoic acid ester, benzalkonium chloride or the like as the
`
`preservative;
`
`sodium hydrogenphosphate,
`
`sodium dihydrogenphosphate,
`
`boric acid or the like as the buffering agent; sodium edetate or the like as the
`
`stabilizer; polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid or the like
`
`as the viscous vehicle; and sodium hydroxide, hydrochloric acid or the like as
`
`the pH controller.
`
`If desired, formulations containing the anti—a|lergy agents
`
`according to the present invention may also contain other active agents.
`
`15
`
`20
`
`Eye drop formulations produced according to the present invention will
`
`typically need only be applied to the eyes from once to a few times a day in
`
`an amount of one to several drops at a time, though in more severe cases the
`
`drops may be applied several times a day. A typical drop is about 30 pl.
`
`Certain embodiments of the invention are illustrated in the following
`
`examples.
`
`Page 7
`
`Page 7
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`Example 1: Topical Ophthalmic Solution Formulation
`
`Concentration
`
`Ingredient
`(WN%)
`
`Compound having a Surface Activity Rating S 11.2
`at the selected concentration
`
`0.01 — 0.5
`
`10
`
`15
`
`Dibasic Sodium Phosphate
`(Anhydrous), USP
`
`Sodium Chloride, USP
`
`Benzalkonium Chloride
`
`Sodium Hydroxide, NF
`7.0
`
`20
`
`Hydrochloric Acid, NF
`7.0
`
`Purified Water
`
`0.5
`
`0.65
`
`0.01
`
`q.s. pH =
`
`q.s. pH =
`
`g.s. 100
`
`Page 8
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`Example 2: Topical Ophthalmic Gel Formulation
`
`5
`
`Ingredient
`
`(WN%)
`
`Concentration
`
`Compound having a Surface Activity Rating S 11.2
`at the selected concentration
`
`0.01 — 0.5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Carbopol 974 P
`
`Edetate Disodium
`
`Polysorbate 80
`
`0.8
`
`0.01
`
`0.05
`
`Benzalkonium Chloride, Solution
`
`0.01+5 xs
`
`Sodium Hydroxide
`7.2
`
`Hydrochloric acid
`7.2
`
`Purified Water
`
`q.s. pH
`
`q.s. pH
`
`g.s. 100
`
`Example 3: Measurement of the Surface Activity Rating of Olopatadine and
`Ketotifen
`
`Water was purified by reverse osmosis and carbon filtration, passage through
`
`an Elix 3 deionization system (Millipore) and passage through a Milli Q UV
`
`Plus polishing system (Millipore).
`
`Buffer, comprised of 10mM HEPES
`
`containing 0.1M NaCl pH 7.5, was used to prepare solutions of olopatadine
`
`and ketotifen (and for control experiments). After mixing the drug with the
`
`buffer, it was necessary to readjust the pH to a value of 7.5 with 5 M NaOH.
`
`All chemicals were reagent grade.
`
`Page 9
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`Exchange of aqueous phase contents — The circular compartment of the
`
`automated interfacial monitor-controller described above was fitted with an
`
`inlet tube (1/32" ID Teflon) and an outlet tube (18 ga. Teflon) which entered
`
`through the outer wall of the sample compartment. These were connected to
`
`25—mL, gas-tight syringes (model 1025, Hamilton, Reno, NV) mounted in a
`
`microprocessor-controlled push-pull dual syringe pump (model sp260p, World
`
`Precision Instruments, Sarasota, FL)
`
`through three-way Teflon valves
`
`(Hamilton, Reno, NV) which were used for filling and flushing. About 42 cm of
`
`the inlet tube was coiled in the water—fi|led rectangular compartment of the
`
`trough in order to equilibrate the incoming solution to the temperature of the
`
`circular compartment. A custom Teflon—coated magnetic stirring bar (length =
`
`3.6 cm, diameter 2 mm) was used to mix the aqueous contents. The bar was
`
`at approximately 50 rpm by stepper motor-driven magnet mounted beneath
`
`the circular compartment and controlled by the microprocessor. The relatively
`
`slow stirring speed and small bar diameter were used to minimize disturbance
`
`of the lipid monolayer. To exchange the contents of the circular compartment
`
`with the solution in the inlet syringe while maintaining constant volume, the
`
`syringes were operated in unison, but in opposite directions, by the syringe
`
`pump.
`
`Control experiments showed that, during exchange of 25 ml of
`
`aqueous phase, the volume of liquid removed from a test container remained
`
`constant to within an average deviation of 0.023 ml (n = 2), or ~ 0.1%. This
`
`insured that the depth of immersion of the Wilhelmy probe was constant to
`
`within ~10 pm and, hence, the contact angle of the aqueous phase with the
`
`probe, remained essentially constant during exchange experiments.
`
`Measurement of oIoQatadine’s and ketot/'fen’s effect on surface QFGSSUI”
`
`-
`
`Saturated solutions of olopatadine and ketotifen, respectively, were prepared
`
`for each exchange experiment by gently warming an excess of drug in buffer,
`
`adjusting the pH to 7.5 and equilibrating the sample to 24° C.
`
`Following
`
`filtration to remove undissolved drug, drug concentration in the solution was
`
`determined spectrophotometrically.
`
`The concentration of drug in diluted
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 10
`
`Page 10
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`aliquots of the solution was determined by comparing their absorbance to a
`
`standard curve obtained with standard solutions of the drug. This solution or
`
`buffer (control) was loaded into the injection syringe of the apparatus and a
`
`monolayer of SOPC was spread onto the surface of the aqueous phase in the
`
`exchange compartment to slightly below the desired surface pressure of
`
`30 mN/m. The lipid film was equilibrated for 90 to 220 min.
`
`in order to
`
`achieve a surface pressure drift rate of <0.01 %/min, which was considered
`
`stable. Once the monolayer was stable, the exchange was carried out at a
`
`constant rate of 0.4 ml/min during which surface pressure was recorded as a
`
`10
`
`function of time.
`
`At
`
`least duplicate exchange and control
`
`(without drug) experiments were
`
`conducted. Each set of controls was normalized to the nominal pressure and
`
`the traces were averaged. The results are shown in Figure 1, where drug
`
`concentration vs. the surface pressure of the SOPC monolayer is plotted for
`
`each drug. Olopatadine caused a relatively small
`
`increase in surface
`
`pressure (7.1 mN/m) as its concentration in the aqueous sub-phase is
`
`increased from O to 5 mM. In contrast, ketotifen produced a two—fold greater
`
`increase in surface pressure (15 mN/m) than olopatadine when tested over a
`
`concentration range of O — 3.5 mM. Thus, the Surface Activity Rating of
`
`15
`
`20
`
`olopatadine is 7.1 and of ketotifen is 15.
`
`10
`
`Page 11
`
`Page 11
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`WHAT IS CLAIMED IS:
`
`1.
`
`A method for selecting an amphipathic drug suitable for topical
`
`ophthalmic anti-allergy use comprising the step of determining the drugs
`
`5
`
`Surface Activity Rating.
`
`2.
`
`A
`
`topically
`
`administrable
`
`ophthalmic
`
`pharmaceutical
`
`composition comprising an ophthalmic amphipathic anti-allergy drug at a
`
`concentration such that the drug has a Surface Activity Rating from about 2 —
`
`1o
`
`11, provided the drug is not selected from the group consisting of
`
`olopatadine;
`
`ketotifen;
`
`emedastine; pheniramine;
`
`pyrilamine;
`
`cromolyn;
`
`nedocromil; and levocabastine; and further provided that drug is present at a
`
`concentration of about 20 mM or less.
`
`15
`
`3.
`
`The composition of Claim 2 wherein the drug has a Surface
`
`Activity Rating from 4 — 11.
`
`4.
`
`The composition of Claim 2 wherein the anti-allergy drug is an
`
`antihistamine drug.
`
`11
`
`Page 12
`
`Page 12
`
`

`
`WO 00/78396
`
`PCT/US00/06890
`
`l/l
`
`m:_vEmao_OD
`
`cmEo..mv_O
`
`mVmN
`
`
`
`_>_Edozmbcmocoo9.5
`
`Page 13
`
`_...U_u_
`
`om
`
`[Lu/Nw]
`
`1£‘e.lnSSeJd eoeyng
`
`Page 13