as) United States
`a2) Patent Application Publication (10) Pub. No.: US 2011/0082145 Al
`
` Schneideretal. (43) Pub. Date: Apr. 7, 2011
`
`
`US 20110082145A1
`
`(54) OLOPATADINE COMPOSITIONS AND USES
`THEREOF
`
`(75)
`
`Inventors:
`
`.
`L. Wayne Schneider, Crowley, TX
`(US); Wesley Wehsin Han,
`Arlington, TX (US); Masood A.
`Chowhan,Arlington, TX (US)
`
`(73) Assignee:
`
`ALCON RESEARCH,LTD., Fort
`Worth, TX (US)
`
`(21) Appl. No.:
`(22)
`Filed:
`
`12/896,056
`Oct. 1, 2010
`
`Related U.S. Application Data
`(60) Provisional application No. 61/247,618, filed on Oct.
`1, 2009.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A6IK 31/5377
`AGOIK 31/496
`AGIP 37/08
`AG61P 29/00
`AG6IP 27/02
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(2006.01)
`A61P 27/00
`(2006.01)
`A61P 17/00
`(52) US. Ch oo eee 514/235.2; 514/253.07
`
`(57)
`
`ABSTRACT
`.
`.
`.
`.
`.
`.
`The invention provides solution compositions comprising
`olopatadine and a PDE4 inhibitor compound of Formula I:
`
`(Formula I)
`
`Ri0
`
`oO
`
`RS
`
`O
`
`Ryo.
`
`Ry
`k
`
`Z
`R5S
`|
`Re
`
`The invention also provides methods fortreating allergic and
`inflammatory diseases. Moreparticularly, the present inven-
`tion relates to formulations of olopatadine and their use for
`treating and/or preventing allergic or inflammatory disorders
`of the eye, nose, skin, and ear.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 1
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 1
`
`

`

`Patent Application Publication
`
`Apr. 7, 2011 Sheet 1 of 2
`
`US 2011/0082145 Al
`
`Plot of Olepatadine Free Base Solubility versus PDE4 inhibitor
`Concentration (% why}.
`
`(_@CompoundtatpH7.4aCompound1atpH64mCompound2atelO4
`y= O.2657x% 40.1829
`y= 0.9476x + 0.2008
`: 0.3282x + 0.2008
`RESOS8e
`Rr
`=
`0.988
`
`Read Olopatadine
`FreeBaseConc.(%wiy)
`
`Oo
`
`an
`
`a2
`
`o.3
`
` wfetn
`0.4
`0.8
`6.8
`OF
`0.8
`0.9
`41.0
`44
`42
`
`PDEInhibiter Concentration (% wiv}
`
`FIG. 4
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 2
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 2
`
`

`

`Patent Application Publication
`
`Apr. 7, 2011 Sheet 2 of 2
`
`US 2011/0082145 Al
`
`Pict of Olopatadine Free Base Solubility versus PDE4 Inhibitor Concentration
`GuilliMolar),
`
`y = 0 4626x + §.4208
`22
`ygds
`
`
`a
`
`{
`
`3,
`38%
`
`y = 0.8087x + 5.9414
`Pe 4
`
`
`
`
`
`OlopatadineFreeBaseConc.(mh)
`
`
`
`‘8
`48
`17
`18
`#19
`29
`GO
`4
`2
`3
`4
`6
`8
`F
`8
`8 1 4 42
`13
`44
`PDE4 inhibitor Concentration (mM)
`
`BEG. 2
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 3
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 3
`
`

`

`US 2011/0082145 Al
`
`Apr. 7, 2011
`
`OLOPATADINE COMPOSITIONS AND USES
`THEREOF
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application claims priority under 35 U.S.C.
`§119 to U.S. Provisional Patent Application No. 61/247,618
`filed Oct. 1, 2009, the entire contents of which are incorpo-
`rated herein by reference.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to olopatadine formu-
`lations used for treating allergic and inflammatory diseases.
`Moreparticularly, the present invention relates to formula-
`tions of olopatadine andtheir use for treating and/or prevent-
`ing allergic or inflammatory disorders of the eye, ear, skin,
`and nose.
`
`BACKGROUND OF THE INVENTION
`
`[0003] As taught in U.S. Pat. Nos. 4,871,865 and 4,923,
`892, both assigned to Burroughs Wellcome Co. (“the Bur-
`roughs Wellcome patents”), certain carboxylic acid deriva-
`tives of doxepin,
`including olopatadine (chemical name:
`Z-11-(3-dimethylaminopropylidene)-6, 1 1-dihydrodibenz[b,
`eloxepine-2-acetic acid), have antihistamine and antiasth-
`matic activity. These two patents classify the carboxylic acid
`derivatives of doxepin as mastcell stabilizers with antihista-
`minic action becausetheyare believed to inhibit the release of
`autacoids(i.e., histamine, serotonin, and the like) from mast
`cells and to inhibit directly histamine’s effects on target tis-
`sues, The Burroughs Wellcome patents teach various phar-
`maceutical
`formulations containing the carboxylic acid
`derivatives of doxepin, including nasal spray and ophthalmic
`formulations. See, for example, Col. 7,
`lines 7-26, and
`Examples 8 (H) and8 (1)of the ’865 patent.
`[0004] U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko
`Kogyo Co., Ltd., (“the Kyowa patent’), teaches that acetic
`acid derivatives of doxepin and, in particular, olopatadine,
`have anti-allergic and anti-inflammatory activity. Medica-
`ment forms taught by the Kyowapatent for the acetic acid
`derivatives of doxepin include a wide range of acceptable
`carriers; however, only oral and injection administration
`forms are mentioned.
`
`[0005] U.S. Pat. No. 5,641,805, assigned to Alcon Labora-
`tories, Inc. and Kyowa Hakko Kogyo Co., Ltd., teaches topi-
`cal ophthalmic formulations containing olopatadinefortreat-
`ing allergic eye diseases. According to the *805 patent, the
`topical formulations may be solutions, suspensionsorgels.
`The formulations contain olopatadine, an isotonic agent, and
`“af required, a preservative, a buffering agent, a stabilizer, a
`viscous vehicle and the like.” See Col. 6, lines 30-43. “[P]
`olyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid or
`the like” are mentioned as the viscous vehicle. See Col. 6,
`lines 55-57.
`
`Phosphodiesterase type-IV (PDE4 or PDE-IV)is
`[0006]
`the predominantcyclic nucleotide hydrolyzing enzyme found
`in inflammatory leukocytes, such as mastcells, neutrophils,
`monocytes and T-lymphocytes. PDE4 inhibitor compounds
`are knownto be usefulas anti-inflammatory andanti-allergy
`agents.
`In general, it is more desirable for active ingredients
`[0007]
`to be in solution rather than suspension in a pharmaceutical
`composition. For instance, solutions are easier to manufac-
`
`ture, easier to handle, provide better penetration to a target
`site of action, and provide better dosage consistency.
`[0008] A formulation comprising both olopatadine and
`PDE4 inhibitor compoundsis desirable because the combi-
`nation addresses both the early andlate phasesofthe allergic
`response. In addition, a formulation comprising compounds
`that enhance the solubility of olopatadine is desirable,
`because it assures that the olopatadine will not precipitate
`during a desired shelf life, and allows for an increased con-
`centration of solubilized olopatadine.
`
`SUMMARY OF THE INVENTION
`
`[0009] The invention provides pharmaceutical aqueous
`solution compositions comprising olopatadine and a PDE4
`inhibitor compound of Formula I, as provided herein. The
`invention also provides methods for treating allergic and
`inflammatory conditionsofthe eye, ear, skin, and nose. In one
`aspect, the concentration of olopatadineis at least 0.17% w/v,
`and the concentration of the PDE4 inhibitor compound of
`Formula I is at least 0.05% w/v in a solution composition.
`[0010]
`Specific preferred embodiments of the invention
`will become evident from the following more detailed
`description of certain preferred embodiments andthe claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph showing Olopatadine Free Base
`[0011]
`Solubility versus PDE4 Inhibitor Concentration (% w/v).
`[0012]
`FIG. 2 is a graph showing Olopatadine Free Base
`Solubility versus PDE4 Inhibitor Concentration (milliMo-
`lar).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0013] The particulars shownherein are by way of example
`and for purposes ofillustrative discussion of the preferred
`embodiments of the present invention only and are presented
`in the cause of providing what is believed to be the most
`useful and readily understood description of the principles
`and conceptual aspects of various embodimentsof the inven-
`tion. In this regard, no attempt is made to show structural
`details ofthe invention in more detail than is necessary for the
`fundamental understanding of the invention, the description
`taken with the drawings and/or examples making apparent to
`those skilled in the art how the several forms of the invention
`
`may be embodiedin practice.
`[0014] As used herein and unless otherwise indicated, the
`terms“a” and “an”are taken to mean “one”, “at least One” or
`“one or more”. Unless otherwise required by context, singu-
`lar terms used herein shall include pluralities and plural terms
`shall include the singular.
`[0015] Unless indicated otherwise, all component amounts
`provided herein are presented on a % (w/v) basis andall
`references to olopatadine are to olopatadine free base.
`[0016]
`In certain embodiments,
`the invention provides
`solution compositions comprising a therapeutically effective
`amount of olopatadine and a PDE4inhibitor compound of
`Formula I that enhances the aqueous solubility of approxi-
`mately 0.2-0.6% olopatadine.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 4
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 4
`
`

`

`US 2011/0082145 Al
`
`Apr. 7, 2011
`
`[0017] The term “therapeutically effective amount”refers
`to the amount of a solution composition of the invention,
`olopatadine, or a PDE4 inhibitor compound of Formula I
`determined to produce a therapeutic response in a mammal.
`Such therapeutically effective amounts are readily ascer-
`tained by one of ordinary skill in the art and using methods as
`described herein.
`
`[0018] The terms “pharmaceutical aqueous solution com-
`position”and “solution composition”as used herein refer to a
`composition comprising olopatadine or a pharmaceutically
`acceptable salt thereof, a PDE4 inhibitor compoundof For-
`mula I or a pharmaceutically acceptable salt thereof, and a
`pharmaceutically acceptable carrier (such as an ophthalmo-
`logic or nasal or otic carrier, or carrier suitable for delivery to
`the skin), excipient, or diluent as described herein that is
`capable of inducing a desired therapeutic effect (e.g. reduc-
`ing, preventing, and/or eliminating allergies or allergy symp-
`toms or inflammation) when properly administered to a
`patient. As used herein, the terms “pharmaceutical aqueous
`solution composition” and “solution composition” include
`compositions in which olopatadine (or a pharmaceutically
`acceptable salt thereof) and a PDE4inhibitor compound of
`Formula I (or a pharmaceutically acceptable salt) are in solu-
`tion, and wherein the overall composition is a solution, sus-
`pension, or semi-solid (for example cream, gel, or emulsion),
`depending on the presenceor absence of any excipientsin the
`composition.
`[0019] As used herein, the term “pharmaceutically accept-
`able ophthalmologic or nasal or otic carrier” refers to those
`carriers that cause at most, little to no ocular, otic, or nasal
`irritation, provide suitable preservation if needed, and deliver
`olopatadine and a compoundof Formula I in a homogenous
`dosage.
`[0020] As used herein, the term “patient” includes human
`and animal subjects.
`[0021]
`In one embodiment, a solution composition of the
`invention comprises a PDE4 inhibitor compound having
`structural Formula I:
`
`heteroaryl, heteroaralkyl, and hydroxyalkyl, any of
`which maybeoptionally substituted;
`[0024]
`sis 1-8;
`[0025] G" is selected from the group consisting of
`alkoxy, amino, amido, carbonyl, hydroxy, ether, an
`amino acid, and null;
`[0026]
`G7?is selected from the group consisting ofalkyl,
`alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl,
`heteroaryl, carboxylalkylamino, guanidine, an amino
`acid, and null, any of which may be optionally substi-
`tuted;
`[0027] Gis selected from the group consisting ofalkyl,
`alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic
`acid, an amino acid, phosphonate, phosphoamide, and
`null, any of which may be optionally substituted;
`[0028] R° is selected from the group consisting of
`—(CR®R”),,W(CR'°R"*),— and —(CR’”’R"*),—;
`[0029] W is selected from the group consisting of O,
`N(R’), C(OYN(R’), and SO,;
`[0030] m,n, and q are independently 0, 1 or 2;
`[0031] pis 1 or 2;
`[0032] R° is selected from the group consisting of car-
`boxyl, alkylcarboxy, amido,aryl, heteroaryl, cycloalkyl,
`heterocycloalkyl, alkyl, heteroalkyl, acyl, and hydrox-
`amic acid, any of which may beoptionally substituted;
`[0033] R’ and R'are independently selected from the
`group consisting of hydrogen, halogen, hydroxyl, lower
`alkyl, hydroxyalkyl, haloalkyl, and aminoalkyl;
`[0034]
`R®*, R°, R'°, R', R’ and R’* are independently
`selected from the group consisting of hydrogen and
`optionally substituted lower alkyl;
`[0035]
`and R’is selected from the group consisting of
`hydrogen, halogen, loweralkyl and haloalkyl; and
`[0036]
`a pharmaceutically acceptable carrier or
`excipient.
`In one embodiment, the PDE4 inhibitor compound
`[0037]
`of Formula I is (4-(3,5-Dichloropyridin-4-ylamino)-7-meth-
`oxy-8-(6-(4-methylpiperazin-1-yl)hexyloxy)quinolin-2
`(1H)-one):
`
`Ri
`
`o Rug
`|
`N
`
`oO
`
`O
`
`Re
`
`(Formula I)
`
`oy
`
`O
`
`ZA
`
`Ryo.
`
`Rs
`
`|R
`
`e
`
`In certain embodiments:
`[0022]
`[0023] R’ and R?are independently selected from the
`group consisting of —(CH,),G'G?G®,acyl, acylalkyl,
`carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, ami-
`doalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl,
`alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl,
`haloalkyl,
`cycloalkyl,
`cycloalkylalkyl,
`heterocy-
`cloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine,
`
`HN aO
`
`x ~H
`Cl
`
`O
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 5
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 5
`
`

`

`US 2011/0082145 Al
`
`Apr. 7, 2011
`
`In another embodiment, the compound of Formula I
`[0038]
`(4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-
`is
`morpholinohexyloxy)quinolin-2(1H)-one):
`
`C)N
`
`0
`
`HN
`
`0
`
`Cl A ;
`
`N we
`H
`Cl
`
`[0039] These compounds, and other PDE4 inhibitor com-
`poundsof Formula I, are PDEIV inhibitors, and are described
`in detail in co-pending U.S. application Ser. No. 11/774,053
`filed Jul. 6, 2007, and U.S. application Ser. No. 12/544,185
`filed Aug. 19, 2009, the disclosures ofwhich are incorporated
`by reference in their entirety.
`[0040] Olopatadine is a known compound that can be
`obtained by the methods disclosed in U.S. Pat. No. 5,116,863,
`the entire contents of which are hereby incorporated byref-
`erence in the present specification.
`[0041] Generally, olopatadine will be added in the form of
`a pharmaceutically acceptable salt. Examples of the pharma-
`ceutically acceptable salts of olopatadine include inorganic
`acid salts such as hydrochloride, hydrobromide, sulfate and
`phosphate; organic acid salts such as acetate, maleate, fuma-
`rate, tartrate andcitrate; alkali metal salts such as sodiumsalt
`and potassium salt; alkaline earth metal salts such as magne-
`sium salt and calcium salt; metal salts such as aluminum salt
`and zinc salt; and organic amine addition salts suchastriethy-
`lamine addition salt (also knownas tromethamine), morpho-
`line addition salt and piperidine addition salt. The most pre-
`ferred form of olopatadine for use in the
`solution
`compositions of the present invention is the hydrochloride
`salt of
`(Z)-11-(3-dimethylaminopropylidene)-6,11-dihy-
`drodibenz-[b,e]oxepin-2-acetic acid. When olopatadine is
`added to the compositions of the present invention in this salt
`form, 0.222% olopatadine hydrochloride is equivalent to
`0.2% olopatadine free base, 0.443% olopatadine hydrochlo-
`ride is equivalent to 0.4% olopatadine free base, and 0.665%
`olopatadine hydrochloride is equivalent to 0.6% olopatadine
`free base. As used herein, reference to a concentration of
`olopatadine refers to olopatadine free base concentration,
`unless otherwise specified.
`[0042] The PDE4 inhibitor compounds of Formula I have
`been unexpectedly found to increasethe solubility of olopata-
`dine. Thus, an aqueous solution composition of the present
`invention can be prepared without the need for any other
`solubility enhancing components.
`[0043] The compositions administered according to the
`present invention mayalso include various other ingredients,
`
`including but not limited to surfactants, tonicity agents, buff-
`ers, preservatives, and viscosity building agents.
`[0044] An appropriate buffer system (e.g., sodium phos-
`phate, sodium acetate, sodium citrate, sodium borate or boric
`acid) may be added to the compositions to prevent pH drift
`under storage conditions. The particular concentration will
`vary, depending on the agent employed. Preferably, however,
`the buffer will be chosen to maintain a target pH within the
`range of pH 6.0-7.5.
`[0045]
`In certain embodiments, the concentration of olo-
`patadine in a solution composition of the inventionis at least
`0.05% w/v. For example, the concentration of olopatadine
`can be about 0.05%, 0.075%, 0.10%, 0.15%, 0.20%, 0.25%,
`0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, or 0.60% w/v,
`or higher. In certain embodiments, a solution composition of
`the invention is a solution formulation that contains at least
`0.05% w/v olopatadine. In certain embodiments, solution
`formulationsofthe present invention contain 0.17-0.62% w/v
`olopatadine. In certain embodiments, solution formulations
`intended for use in the eye contain 0.17-0.25% olopatadine,
`and preferably 0.18-0.22% w/v olopatadine.
`In certain
`embodiments, solution formulations intended for use in the
`nose contain 0.38-0.62% w/v olopatadine.
`[0046]
`In certain embodiments,
`the concentration of a
`PDE4 inhibitor compound of FormulaI in a solution compo-
`sition ofthe invention is at least 0.05% w/v. For example, the
`concentration of a PDE4 inhibitor compound of Formula I
`can be about 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%,
`0.35%, 0.40%, 0.45%, 0.50%, 0.55%, or 0.60% w/v, or
`higher.
`In certain embodiments, solution compositions of
`[0047]
`the invention are useful fortreating allergic or inflammatory
`disorders, including allergic or inflammatory disorders ofthe
`eye, nose, skin, andear.
`[0048]
`Incertain embodiments, an ophthalmic formulation
`is administeredto the cyc of a patient in need thereofto treat
`an ocular disorder. The term “ocular disorder”as used herein
`
`includesallergic and/or inflammatory conditions of the eye,
`such as ophthalmicallergic disorders, including allergic con-
`junctivitis, vernal conjunctivitis, vernal keratoconjunctivitis,
`and giant papillary conjunctivitis, dry eye, glaucoma, corneal
`neovascularization, optic neuritis, Sjogren’s syndrome,reti-
`nal ganglion degeneration, ocular ischemia, retinitis, retino-
`pathies, uveitis, ocular photophobia, and of inflammation and
`pain associated with acute injury to the eye tissue. Specifi-
`cally, the compounds may be used to treat glaucomatous
`retinopathy and/or diabetic retinopathy. The compounds may
`also be used to treat post-operative inflammation or pain as
`from ophthalmic surgery such as cataract surgery andrefrac-
`tive surgery. In certain embodiments, the compoundsof the
`present invention are used to treat an allergic eye disease
`selected from the group consisting of allergic conjunctivitis;
`vernal conjunctivitis; vernal keratoconjunctivitis; and giant
`papillary conjunctivitis. allergic conjunctivitis.
`[0049]
`In one embodiment, a solution composition of the
`invention is an ophthalmic formulation for delivery to the eye,
`such as a topical ophthalmic formulation. The solution com-
`position may comprise ophthalmologically acceptable pre-
`servatives,
`surfactants, viscosity enhancers, penetration
`enhancers, buffers, tonicity agents, and water to form an
`aqueous, sterile ophthalmic solution, suspension, or emul-
`sion. Gelling agents can also be used, including, but not
`limited to, gellan and xanthan gum.In orderto preparesterile
`ophthalmic ointment formulations, olopatadine and a PDE4
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 6
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 6
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`

`US 2011/0082145 Al
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`Apr. 7, 2011
`
`inhibitor compound of Formula I are combined with a pre-
`servative in an appropriate vehicle. Sterile ophthalmic gel
`formulations maybe prepared by suspending olopatadine and
`a PDF4inhibitor compound of Formula I in a hydrophilic
`base prepared from the combination of, for example, CAR-
`BOPOL®-974, CARBOPOL®-940 (BF Goodrich, Char-
`lotte, N.C.), or the like, according to the published formula-
`tions for analogous ophthalmic preparations; preservatives
`and tonicity agents can be incorporated.
`[0050]
`Solution compositions of the invention can be
`administered topicallyto the eye, for example,to treat allergic
`conjunctivitis and/or ocular inflammation. In general, the
`doses used for the above described purposeswill vary, but will
`be in an effective amount to reduce or eliminate allergic
`conjunctivitis and/or ocular inflammation. Generally, 1-2
`drops of such compositions will be administered one or more
`timesper day. For example, the composition can be adminis-
`tered 2 to 3 timesa day or as directed by an eye care provider.
`[0051] Topical ophthalmic products may also be packaged
`in multidose form. Preservatives may thus be required to
`prevent microbial contamination during use. Suitable preser-
`vatives include: benzalkonium chloride, benzododecinium
`bromide, chlorobutanol, methyl paraben, propyl paraben,
`phenylethyl
`alcohol,
`edetate
`disodium,
`sorbic
`acid,
`polyquaternium-1, or other agents knownto those skilled in
`the art. Such preservatives are typically employedata level of
`from 0.001 to 5.0% w/v. Unit dose compositions of the
`present invention will be sterile, but typically unpreserved.
`Such compositions, therefore, generally will not contain pre-
`servatives. The ophthalmic compositions of the present
`invention may also be provided preservative free and pack-
`aged in unit dose form.
`[0052] The compositions of the present invention option-
`ally comprise one or more excipients. Excipients commonly
`used in solution compositions intendedfor topical application
`to the eyes or nose, such as solutions or sprays, include, but
`are not limited to, tonicity agents, preservatives, chelating
`agents, buffering agents, surfactants and antioxidants. Suit-
`able tonicity-adjusting agents include mannitol, sodium chlo-
`ride, glycerin, sorbitol and the like. Suitable preservatives
`include p-hydroxybenzoic acid ester, benzalkonium chloride,
`benzododecinium bromide, polyquaternium-1 and the like.
`Suitable chelating agents include sodium edetate andthelike.
`Suitable buffering agents include phosphates, borates, cit-
`rates, acetates, tromethamine, and the like. Suitable surfac-
`tants include ionic and nonionic surfactants, though nonionic
`surfactants are preferred, such as polysorbates, polyethoxy-
`lated castor oil derivatives, polyethoxylatedfatty acids, poly-
`ethoxylated alcohols, polyoxyethylene-polyoxypropylene
`block copolymers, and oxyethylated tertiary octylphenol
`formaldehyde polymer (tyloxapol). Suitable antioxidants
`includesulfites, thiosulfate, ascorbates, BHA, BHT, toco-
`pherols, and the like. The compositions of the present inven-
`tion optionally comprise an additional active agent. The com-
`positions of the present invention may contain one or more
`nonionic, anionic, or cationic polymers as lubricants or as
`viscosity agents, including but not limited to hydroxypropyl
`methylcelluloses (HPMCs), methylcelluloses, carboxymeth-
`ylcelluloses (CMCs), polyethylene glycols (PEGs), polox-
`amers, polypropylene glycols, xanthan gums, guar gums,
`carbomers, polyvinyl alcohols (PVAs), polyvinylpyrroli-
`dones (PVPs), alginic acids and salts, gellan gums, carrag-
`eenans, and chitosans.
`
`[0053] Various tonicity agents may be employedto adjust
`the tonicity of the composition, preferably to that of natural
`tears for ophthalmic compositions. For example, sodium
`chloride, potassium chloride, magnesium chloride, calcium
`chloride, dextrose, mannitol, sorbitol, propylene glycol, or
`glycerol may be added to the composition to approximate
`physiological tonicity. Such an amountoftonicity agent will
`vary, depending on the particular agent to be added. In gen-
`eral, however, the compositions will have a tonicity agent in
`an amountsufficient to cause the final composition to have an
`ophthalmically acceptable osmolality (generally about 150-
`450 mOsm,preferably 250-350 mOsm).
`[0054]
`Incertain embodiments, a composition ofthe inven-
`tion has a pH of about 3.0 to about 8.5. In one embodiment, an
`ophthalmic composition of the present invention has a pH of
`4.0-8.0, preferably a pH of 5.0-7.5, and most preferably a pH
`of 6.0-7.4. Compositionsofthe present invention intended for
`use in the nose preferably have a pH of 3.0-8.0 and most
`preferably a pH of 5.0-7.5.
`[0055]
`In certain embodiments, a solution composition of
`the invention can be formulated for nasal applications, and
`can be usedto treat nasal disorders. Thus, in certain embodi-
`ments, the invention provides methods for treating a nasal
`disorder, comprising administering a solution composition of
`the inventionto the nose ofa patient in need thereof. The term
`“nasal disorder” as used herein includes allergic and/or
`inflammatory conditions of the nose.
`[0056]
`Ina further embodiment, nasal solution composi-
`tions of the invention are formulated to provide for a thera-
`peutically effective intranasal concentration. For example, a
`nasal solution composition of the invention may have an
`intranasal concentration of about 0.1-1000 nM or 1-100 nM.
`
`Intranasal compositions are delivered to the nasal mucosa one
`to four times per day accordingto the routine discretion of a
`skilled clinician. The pH of the formulation should range
`from 3 to 8 or preferably from 5 to 7.5. Topical administration
`directly onto the nasal mucosa via an intranasal insert or
`implant device or a solution drug-delivery-sponge (GEL-
`FOAM®, Pharmacia & Upjohn, Kalamazoo, Mich.) may
`deliver olopatadine and a PDE4inhibitor compoundofFor-
`mula J at the rate of 1-2 wl/hour(e.g. 0.0001-10 mg/day) for
`several weeks according to the device design, its drug release
`characteristics, and according to the discretion of a skilled
`clinician.
`
`[0057] While the precise regimen1s left to the discretion of
`the clinician, the resulting solution or solutionsare preferably
`administered intranasally as described herein one to four
`timesa day, or as directed by the clinician.
`[0058] A nasally acceptable carrier refers to those carriers
`that cause at most,little to no nasalirritation, provide suitable
`preservation if needed, and deliver a solution composition of
`the present invention in a homogenous dosage. For nasal
`delivery; a solution composition of the invention may be
`combined with nasally acceptable preservatives, co-solvents,
`surfactants, viscosity enhancers, penetration enhancers, buff-
`ers, tonicity agents, and water to form an aqueous, sterile
`suspension, solution, emulsion, or viscous, semi-viscous, or
`semi-solid gels. Nasal solution formulations may be prepared
`by dissolving the agent in a physiologically acceptable iso-
`tonic aqueous buffer. Further, the nasal solution may include
`a nasally acceptable surfactant. Viscosity building com-
`pounds, such as hydroxymethylcellulose, hydroxyethyl cel-
`lulose, methylcellulose, or carbomers, for example, may be
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 7
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1006, Page 7
`
`

`

`US 2011/0082145 Al
`
`Apr. 7, 2011
`
`addedto the compositionsofthe present invention to improve
`the retention of the compounds.
`[0059]
`In order to prepare a sterile nasal ointment formu-
`lation, a solution composition of the invention may comprise
`a preservative in an appropriate vehicle. Sterile nasal gel
`formulations may be prepared by suspending olopatadine
`and/or the PDE4 inhibitor compoundof Formula I in a hydro-
`philic base prepared from, for example, CARBOPOL®-974,
`CARBOPOL®-940 (BF Goodrich, Charlotte, N.C.), or the
`like, according to methods knownin theart for other suitable
`nasal formulations. VISCOAT® (Alcon Laboratories, Inc.,
`Fort Worth, Tex.) may be used for intranasal injection, for
`example. Other compositions of the present invention may
`contain penetration enhancing materials such as CREMO-
`PHOR® (Polyoxyethylene castor oil) and TWEEN® 80
`(polyoxyethylene sorbitan monolaureate).
`[0060] The compositions of the invention can be adminis-
`tered intranasally in the form of a nasal spray, as is known to
`those skilled in the art.
`
`[0061] Nasal delivery may be achieved by incorporation of
`olopatadine and the PDE4 inhibitor compound of Formula I
`into bioadhesive particulate carriers (<200 um) such as those
`comprising cellulose, polyacrylate or polycarbophil, in con-
`junction with suitable absorption enhancers such as phospho-
`lipids or acylcarnitines. Available systems include those
`developed by DanBiosyst and Scios. The formulation can be
`administered using a simple nasal spray device available from
`companies such as Valois or Pfeiffer.
`[0062]
`In certain embodiments, a solution composition
`comprising olopatadine and a PDE4 inhibitor compound of
`Formula I is formulated for delivery to the skin. Particularly
`compositions intendedfor application to the skin can be solu-
`tion, suspension or semisolid. However, the olopatadine (or
`pharmaceutically acceptable salt thereof) and PDE4inhibitor
`compound (or pharmaceutically acceptable salt thereof) pre-
`sented in the said dosage forms should be all molecularly
`dissolved as a solution. The excipients presented in the dos-
`age forms can be solid as a suspension or semisolid as a
`cream, for example. The viscosity of the said compositions
`can be variant from 1 to 100,000 cps or higher depending on
`the needs of the dermatological product.
`[0063]
`In a further embodiment, otic compositions com-
`prising olopatadine and a PDE4 inhibitor compoundof For-
`mula I are formulated to provide for a pharmacologically
`effective intraotic concentration. Topical otic compositions
`maybe delivered to the ear one to four or more times, per day
`accordingto the routine discretion of a skilled clinician. The
`pH ofthe formulation should range from 4.0 to 9.0, or from
`4.5 to 7.4. Topical administration directly onto the otic nerves
`(auditory and vestibular) and/or otic nerve-heads via an
`intraotic insert or implant device or a solution drug-delivery-
`sponge (GELFOAM®, Pharmacia & Upjohn, Kalamazoo,
`Mich.) maydeliver a solution composition of the inventionat
`the rate of 1-2 ul/hour (e.g. 0.0001-10 mg/day) for several
`weeks according to the device design, its drug release char-
`acteristics, and accordingto the discretion of a skilled clini-
`cian.
`
`For otic delivery, a solution composition of the
`[0064]
`invention may be combined with otically acceptable preser-
`vatives, co-solvents, surfactants, viscosity enhancers, pen-
`etration enhancers, buffers, tonicity agents, or water to form
`an aqueous, sterile suspension, solution, or viscous, semi-
`viscous, or semi-solid gels.
`
`Solution compositions of the present invention may
`[0065]
`be delivered directly to the ear (for example: topical otic drops
`or ointments; slow release devices in the ear or implanted
`adjacentto the ear). Local administration includesotic intra-
`muscular, intratympanic cavity and intracochlear injection
`routes of administration. Furthermore, a solution composi-
`tion of the invention can be administered to the inner ear by
`placement of a gelfoam, or similar absorbent and adherent
`product, soaked with a solution composition of the invention
`against the window membrane of the middle/inner ear or
`adjacentstructure with due discretion and caution by a skilled
`clinician.
`[0066] The compositions of the present invention are pref-
`erably packaged in opaque plastic containers. A preferred
`containerfor an ophthalmic product is a low-density polyeth-
`ylene containerthat has been sterilized using ethylene oxide
`instead of gamma-irradiation. A preferred container for a
`nasal product
`is a high-density polyethylene container
`equipped with a nasal spray pump.
`[0067] The references cited herein, to the extent that they
`provide exemplary procedural or other details supplementary
`to those set forth herein, are specifically incorporated by
`reference.
`
`[0068] Unless otherwise required by context, singular
`terms used herein shall include pluralities and plural terms
`shall include the singular.
`
`EXAMPLES
`
`[0069] The following examples, including the experiments
`conducted and results achieved are provided for illustrative
`purposes only and are not to be construed as limiting the
`invention.
`
`Example 1
`
`Olopatadine-PDE4 Inhibitor Solubility Study
`
`[0070] The following experiments were conductedto deter-
`mine the effect of compounds of Formula I on the aqueous
`solubility of olopatadine.
`[0071]
`Formulations with the compositions shownin Table
`1 were prepared for olopatadine solubility testing as follows:
`ten milliliter samples of the formulations containing either
`0%, 0.1%, 0.3%, or 1% ofeither Compound 1 (4-(,5-Dichlo-
`ropyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin-
`1-yl)hexyloxy)quinolin-2(1H)-one) or Compound 2 (4-(3,5-
`Dichloropyridin-4-ylamino)-7-methoxy-8-(6-
`morpholinohexyloxy)quinolin-2(1H)-one) with at least 1%
`Olopatadine Hydrochloride as shown in Table 2 were pre-
`pared and adjusted to the target pH. Compound 2 was not
`tested at pH 7.4 as it was not sufficiently soluble at that pH.
`The samples were mixed on a rocker and the pH was read-
`justed to the target pH after one and six days of