`(12) Patent Application Publication (10) Pub. No.: US 2004/0198828 A1
`Abelson et al.
`(43) Pub. Date:
`Oct. 7, 2004
`
`US 20040198828A1
`
`(54) COMBINATIONAL USE OF LONG-ACTING
`AND SHORT-ACTING ANTI-HISTAMINES
`
`Related U.S. Application Data
`
`FOR OCULAR ALLERGIES
`
`(60) Provisional application No. 60/440,730, filed on Jan.
`17, 2003.
`
`(76)
`
`Inventors: Mark B. Abelson, Andover, MA (US);
`Matthew J, Chapin, Haverhfll, MA
`(US); Paulo J. Gomes, Haverhill, MA
`(US)
`
`Correspondence Address:
`Foley Hoag LLP
`155 Seaport Blvd.
`Boston, MA 022104600 (Us)
`
`(21) Appl, No;
`
`10/762,201
`
`(22)
`
`Ffled:
`
`Jan.20,2004
`
`Publication Classification
`
`Int. Cl.7 ................................................ .. A61K 31/192
`(51)
`(52) U.S. Cl.
`............................................................ .. 514/571
`
`(57)
`
`ABSTRACT
`
`The present invention features the combinational use of
`short-acting anti-histamine agents in combination with long-
`acting anti-histamine agents to provide rapid, synergistic
`and long lasfing rehef tovvards ocular aflergy signs and
`synunonm.
`
`000001
`
`ARGENTUM PHARM. 1052
`
`ARGENTUM PHARM. 1052
`
`000001
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 1 of 23
`
`US 2004/0198828 A1
`
`o$o.o93.IonmomiE
`
`
`
`
`
`Amuz.EoE=3._._.>mmm._oommwwcuwm_mno_0._a_:oO:aos_<p2:2".
`
`
`
`
`
`
`
`
`
`
`
`wmco__m:u592_<«non.¢.__EVwE_._.
`
`
`
`
`
`Emao52,8.
`
`..o2noIF
`,5
`
`..$o.o23.I
`
`(mass 7 ; o) ssaupaa geq 19 Jemoo ueaw
`
`000002
`
`000002
`
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 2 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`Amuzv.:oEuaw._._.>mmfloom95.3.3:50:35.9.2:9”.
`
`..\..mo.o23.Ionmom_n_E
`
`_»zoi_»<m:
`Lose:8
`
`(a|eos 1; 010) 6ugq:n| .|e|noo ueaw
`
`000003
`
`2
`
`mum.
`
`EEm
`
`2;
`
`mam
`
`row
`
`..\..mo.o93.I
`
`OQ®0®_n_E
`
`
`
`
`
`om:o__s;o:om._u=<«won.E2595...
`
`000003
`
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 3 of 23
`
`US 2004/0198828 A1
`
`
`
`..\..m.oo:_E9_:mcn_I
`
`oooum_n_H
`
`
`
`
`
`AnuzvEwEuao.F>mw2ouwmmocuam_mno_o._a_:oo:mo_>_<~23?.
`
`
`
`
`
`
`
`
`
`um:o__mcocwm._o__<“momE_EvmE_.r
`
`
`
`
`
`zo_»<m:oi5o:.,9
`
`EmzoEEmi.
`
`
`
`5MMVgr.:Ma
`
`(a|e:>s 7 1 o) ssaupau |eqo|9 JEHIOO ueaw
`
`onmom_n:u
`
`000004
`
`000004
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 4 of 23
`
`US 2004/0198828 A1
`
`
`
`..$.o2_ee_:9_n_I
`
`OD@ON_QE
`
`
`
`
`
`finzE2._mnz.:_Em:Eozzaflh>mmfloomm:Eo._._a_:oo:35.mm2:9".
`
`
`
`
`
`
`
`um:o__m_..o:um._o__<«momA_..___..5oE_._.
`
`
`
`
`
`
`
`zo:<%9_sI3.4.ii.,M,_Ew,zo,,{__:_,,M.:
`
`.m
`
`ma
`
`N
`
`_
`
`o
`
`3
`
`no
`
`
`
`..$.om_.__Ew.__cm.._n_I
`
`38m_n_n_
`
`(auaos 7 010) fiugqau .I2|nao ueaw
`
`000005
`
`000005
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 5 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`Anuzv:o=E:n_.52..weEoEum9._.>mmmzoommwocuom_mn_o_0$.30:35.<n2:9”.
`
`
`
`
`
`
`
`885E
`
`
`
`«cooc2n_+§.o.o23..I.
`
`oo.N_,taE;
`
`
`
`
`
`am:a__mco:om._o=<“mom.c_EVoE_._.
`
`
`
`
`
`..$.oc9_n_+o\..vo.o23.!
`
`8.».
`
`oma
`
`8.~
`
`8_.
`
`8.V
`
`.one
`
`23
`
`(mass 1: 0; o) ssaupaa |eqo|9 Jemao ueaw
`
`88m_n__u
`
`000006
`
`000006
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 6 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`..\..m.oc9E+..\%o.osaxI
`
`an
`
`B8m_n_E
`
`
`
`
`
`om:w__m:o:mm.m=<“momAEEVmE_.r
`
`
`
`33§_%..§.o29=._H
`
`H H O
`
`QO0N_n_U
`
`8..
`
`8..
`
`1.91
`
`om.F
`
`8..
`
`8.0
`
`8.o
`
`(a|e:>s 1; 10) Buguau Jemoo ueaw
`
`000007
`
`
`
`
`
`
`
`2V:o_um._:o.=..OIor.:¢:=mw.._.>mmmzoow9.20:._w_:oOcams.mm2:9”.
`
`000007
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 7 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`:u..=Bmv_Annzv:o=m._:o..:o_._S..:oE«mm._._.>mmo._ouwm:_.§_._m_:oO:m_uo_>_on2.5:.
`
`
`
`
`
`
`
`
`
`macm__m:o:mm._m__<anon.E_E.0:.__._.
`
`
`
`
`
`
`
`w:_Em.__:o:n_.\.....o+.\.8.o
`
`(aleos v 01 0) 5u!u=uI Jelnoo uemew
`
`onmomiD
`
`000008
`
`
`
`
`
`o\om.oc2n_§_3.osoxu
`
`000008
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 8 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`Anuz.E3552...>mmfloommmacuwm_mao_0.5300:32<v2:9”.
`
`
`
`
`
`
`
`
`
`..$.o_§_n_+.x_mo.o93.I
`
`onwom_n_E
`
`
`
`5025:.o_.+3
`
`K:3
`
`3
`
`on
`
`3
`
`no
`
`(owns 7 01 o) ssaupau |eqo|9 Jelnoo ueaw
`
`000009
`
`«S
`
`fig
`
`_,.
`
`NNN8.~5m5m
`
`Cd
`
`m
`
`Ea
`
`On00N_n_U
`
`moo8.9
`
`,..\..m.o$_i.s$o.o933
`
`
`
`om:w__mz0:cm._w__<“won.A:_EvwE_._.
`
`
`
`
`
`000009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Anuzvu:mF_uN¢._.Fammfioumm:E8_._m_:oo:uos_mve=m_n_
`
`Patent Application Publication
`
`7:LC
`
`ehS
`
`20.109
`
`US 2004/0198828 A1
`
`
`
`
`
`
`
`zo:<m:oso:.94,.Emzo552«pf,:.~§P.wm.;.rw,.pc..I,»m
`
`4..W0%o8&+§oo28.:
`
`.2onmom_n:m_.m_.
`
`ON
`
`a,.
`
`344no
`
`
`
`om:o__m:o:mm._u__<Won.E__595»
`
`o
`
`goo$.E+..\..8_o23_
`
`onmom_n_D
`
`3
`
`(aueas 7 01 o) fiugqou JE|l100 ueaw
`
`000010
`
`000010
`
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 10 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`.\.m.o:2...+.x.mc.oofivimuzvcozeau52.2Eosfizp>mmeoow9.22.3.305:35.9.Saar.
`
`
`
`
`
`
`
`..\..m.o5__n=..\..mo.o83.IonmomiE
`
`on
`
`on
`
`me
`
`no
`
`
`
`..$.ocm.._n:..\..mo.o93.E
`
`onmom_n__U
`
`(sum 1»
`
`1 0) Buauou J9l"9O uewaw
`
`000011
`
`
`
`
`
`wm:o__u:o:o9w__<«momAEEV¢EF
`
`000011
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 11 of 23
`
`US 2004/0198828 A1
`
`
`
`..$.o.§E+o$o.o28.:
`
`onwum_n_E
`
`
`
`
`
`Anuz.:o_.E:n_.50:2.EcE.mm.F>mmfloowm.mw:_uom__ano_08:80cams.<m2:9”.
`
`
`
`
`
`
`
`
`
`22.2.9.0:wm.m__<umom3:595...
`
`8.»
`
`
`
`..\..m.o:9_n_+$8.o285
`
`88m_n_D
`
`(a|e:>s p 1 o) ssaupag |eqo|9 :e|n:>o ueaw
`
`000012
`
`000012
`
`
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 12 of 23
`
`US 2004/0198828 A1
`
`
`
`..\..m.oS;n_+.x.mo.o28.I
`
`onmom_n_E
`
`
`
`
`
`Annzv:o=E:o._:O_._orEoE.aw._._.>mmfloom9.22.._m_:oocams..
`
`
`
`
`
`
`
`
`
`om:m__m;o:um.5__<«won:55BE...
`
`mm2:9".
`
`8.»,
`
`(auaos 7 0; o) Sugqau .lB|l‘I30 ueaw
`
`onmom_n_n_
`
`000013
`
`
`
`
`
`o\om.o:9E+..$o.oemxE
`
`000013
`
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 13 of 23
`
`US 2004/0198828 A1
`
`
`
`..$.o_§_n_+..\o8.o23.I88?.E
`
`my6«x
`
`
`
`mm:o__m:U:wm._u=<“momT.__:.©OE_.—.
`
`
`
`
`
`
`
`
`
`
`
`—._O_uN._3fi_._=OT___.:0—._._uN0._.—.mmzoumDr___._U__._._N_:Uo:a=uw_2
`
`
`
`
`
`
`
`on2:9".
`
`ma
`
`me
`
`
`
`.\..m.ocm§_+$oo.o20!I
`
`onoomiH
`
`(‘N993 V 10) 5U!|I°1| -“W190 “9!P3W
`
`000014
`
`000014
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 14 of 23
`
`02
`
`91
`
`1AR
`
`
`
`
`
`Annzv..\..m.oo:_Em.__:m:n=o\..x23.mou:oE.aa._._.>n>omu_tmmmwzuamcams.<o2:9".
`
`
`
`
`
`S.UTNo
`
`
`8om2E8_IllI'|‘|I|_O
`
`mMM266oEm_3a..
`
`wm.._w__m_._o32.A275wEF
`
`2W_.U3..m...
`
`P.
`
`
`
`$8.osoxlql.m..\..mo.o23.11:+woM$3.028.19.m
`
`
`
`.IuIuI:InI..IuInInInI|I:III..I:InI:I:IIluI:IoI|InInIululnIIIululolslnInI:I:IuI..IIIiIsInInIuIulII:IIInIIInIuIuInInl—
`
`1com
`
`....
`
`U-m.
`
`000015
`
`
`
`»z<o_“__zw_w>j<o_z:om:o_ooEm922
`
`
`
`
`
`we
`
`000015
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 15 of 23
`
`US 2004/0198828 A1
`
`
`
`suz..x.....o9__se_:2_.=..\..x23.3235.3:3385m9__._2_535.mo2:9".
`
`
`
`
`
`
`
`.x.8.o28.14!m§.o.o23.LT»z<om_zo_m>j<o_z:om..\%o.o28.ITm
`
`
`
`
`
`
`
`.I:IIIIIII:I:I|IIIIIII:InI»IxIxI:IxI:IuI:I:I:I:IuI:«iolvI:l»IxI..Iu=uIvlnIIIIIuIIIuIIInIulululnlninlllulxF%
`
`3
`
`mu9BU
`
`000016
`
`om:m__m:u32.E25wE_._.
`
`Nmm
`
`,no
`
`
`
`m:o_omo_tm_mwmfi
`
`re
`
`-3
`
`
`
`w:o_omuEmw.o_>_
`
`-N
`
`-3MV.wM.
`
`000016
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 16 of 23
`
`US 2004/0198828 A1
`
`$86wc=mm_mN<Ionmom_n__m.._
`
`
`
`
`
`
`
`EoE=wo._._.>mmo._oowwmmcumm_mno_0._m_:oOcams.<n2:9".
`
`
`
`
`
`
`
`
`
`umcuzmco:um.w__<«man.3:5uEF
`
`cuz.._._eauz..__s_m:
`
`
`
`
`
`zo_»<m:o.501v.._.mmzOEEwe
`
`HHE
`
`ma
`
`3
`
`no
`
`(3|E3S V 1 0) ssaupaa |eqo|9 JE|nOO UBQW
`
`000017
`
`000017
`
`
`
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 17 of 23
`
`US 2004/0198828 A1
`
`
`
`§o.o2_um_o~<I
`
`883E
`
`
`
`om:m__m:o:mm._u__<«mom?_EvoE_.r
`
`
`
`
`
`
`
`
`
`Euz.._._.1nuz.=_s_2.
`
`
`
`
`
`EoEuaw._._.amm2oowm.__._2_._m_:oocams.mu2:9".
`
`zo:<m_.552..v
`
`1%
`
`EwzoasE..V
`
`(a|e:>s p 30) Buguou JB|l‘I30 ueauu
`
`onoom_n_D
`
`c=mm_mN<fl
`
`000018
`
`000018
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 18 of 23
`
`US 2004/0198828 A1
`
`
`
`
`
`AmnzvEwE.m....:._.>mmmzoommmocuwm_mno_O._m_:uocams.<w2:9".
`
`
`
`
`
`
`
`onoumiE
`
`X“,
`
`
`
`zoEE:oso:<..Emzo25.3.
`
`mm
`
`
`
`wmod9_=$_o~<I,00H._.0..,3
`
`
`
`
`
`
`
`Ddo:_Em.__:mcn__,._,
`
`o
`
`.no
`
`
`
`3mm;882m.B
`
`
`
`mmdmzo7nom_.__Em.__:mr_n_amodmc_um_a~<:
`
`
`
`
`
`omcozmco:m.m._o__<amen.E250E_.F
`
`(auaos 1; 0; o) ssaupau |eq l9 Jemao uaaw
`
`000019
`
`000019
`
`
`
`
`
`
`
`Patent Application Publication
`
`7LC0
`
`AH
`
`hQu
`
`0.1091
`
`US 2004/0198828 A1
`
`
`
`
`
`Annz.EmE.ao.._.>mwmzouw9.__§_._a_:oOcmw_>_mm2:9“.
`
`
`
`
`
`
`
`
`
`Wm.o2_E9__§_n_amod8_.$_o~<lme2!OQ00®_n_E
`
`a.
`6_.
`
`.6.no
`
`ma,
`
`,on
`
`.N
`
`(a|eas y 0; 0) 6ugq:>;| Jelnoo ueaw
`
`no
`
`000020
`
`
`
`zoEE:osex...»Emzo___im_,8m
`
`
`
`
`
`
`
`om:a__w:o:am.o__<«momAEE.oE_._.
`
`
`
`
`
`000020
`
`
`
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 20 of 23
`
`US 2004/0198828 A1
`
`
`
`..\om.om:__o~mE<I
`
`onmom_n_E
`
`
`
`
`
`om:o=m_._o§..:2_<.mo..._?__EvoE_._.
`
`
`
`
`
`
`
`
`
`..:mE_mw._.p>mmfioummmocuom_mno_0._m_=oOcams.<m0._:m_u_
`
`
`
`
`
`
`
`
`
`SuzyEwzosass.2.
`
`mm
`
`(a|eas 7 o1o)ssaupau yeq 19 .ae|noo ue w
`
`
`
`o\..m.omc_o~mE<fl
`
`8830
`
`000021
`
`000021
`
`
`
`
`Patent Application Publication
`
`Oct. 7, 2004 Sheet 21 of 23
`
`US 2004/0198828 A1
`
`
`
` oxemdoc__o~mE<Ionmom_n_E
`
`
`
`
`
`SuzyEmzo2:55.mp
`
`
`
`
`
`..:o:=mo._._.>mmmzoomm=_._2_.m_:oOcums.mm9.39".
`
`
`
`
`
`wn:o__m:o:mm.o__<«won.E25oE_._.
`
`
`
`o\..m.omc__oNm.E<E
`
`onmomiD
`
`(aueos 7 0; o) Bugqau .lB|l'I30 ueaw
`
`000022
`
`000022
`
`
`
`Patent Application Publication Oct. 7, 2004 Sheet 22 of 23
`
`US 2004/0198828 A1
`
`
`
`$8.0m::mm_0N<wo\..m_ooc__oNmE<I
`
`oaoom_n_E
`
`
`
`
`
`AmuzvEwE.mm._._.>mmw._oummmwcuwm.320._m_:uOE35.<3._..::m_u
`
`
`
`
`
`
`
`
`
`mm:m__m:U:mm._w__<«mom?.__:._v95...
`
`
`
`
`
`
`
`zo:<,.mao,soaeiM
`
`.4s..>u
`
`mm
`
`(a|e::s 1; oz 0) ssaupaa |eqo|9 Jemoo ueaw
`
`88m_n_D
`
`000023
`
`
`
`
`
`§,o.om.:_.mm_mN<wo\..m.om:__oNmE<fi
`
`000023
`
`
`
`
`
`Patent Application Publication
`
`O
`
`ehCu
`
`pl01.2
`
`US 2004/0198828 A1
`
`
`
`AmnzEwe_nnz.:_Em5EwE_mu._._.>mmwhoowm:Eo=._a_:uO:mos_mowo._:m_n.
`
`
`
`
`
`7:oamom_n:mm.N
`
`Wo
`
`W
`
`Hmm
`
`
`
`
`
`..:/,_izuyr»,_,i.0¢,,..«A.2r»%L.$4.uu,
`
`..Hzo_EmB_§_mmMMWHmm,_,%_e3,X93.
`,...;.,,4.v.,s.»_..},,é,..a,5..NW
`
`8_am_m~<w.x.m.o8__o~2:<I
`
`
`
`M3M...$o.o
`
`mu...w
`
`Bno
`
`
`
`mc_~mm_wN<w.x.m.owc__oNmE<fl
`
`oxomod
`
`onwum_n_D
`
`(a|eos 9 1 o) Buguau .Ie|nao uaaw
`
`000024
`
`
`
`mm:u__m.._o:om._u__<«non.€_E.mE_._.
`
`
`
`
`
`000024
`
`
`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`COMBINATIONAL USE OF LONG-ACTING AND
`SHORT-ACTING ANTI-HISTAMINES FOR
`OCULAR ALLERGIES
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims priority to U.S. Provisional
`Application Serial No. 60/440,730 filed Jan. 17, 2003.
`BACKGROUND
`
`[0002] The eye, particularly the conjunctiva, has a rela-
`tively large number of mast cells. When allergens are
`present, they can bind to immunoglobulins on the surface of
`these mast cells and trigger the release of cellular contents,
`known as degranulation. Upon degranulation, mast cell
`components, including histamine, are released into the envi-
`ronment outside the mast cell. In seasonal or perennial
`allergic conjunctivitis, these components, particularly hista-
`mine are responsible for signs and symptoms associated
`with allergic responses such as itching, redness, lid swelling,
`chemosis, tearing, and mucus discharge. In extreme severe
`chronic cases of ocular allergy (atopic keratoconjunctivitis
`(AKC) or vernal keratoconjunctivitis (VKC), the sustained
`reaction produces an inflammatory condition that leads to
`tissue damage which may result in corneal ulcers.
`
`In the US, an estimated 80 million people experi-
`[0003]
`ence ocular allergies, according to the American Academy of
`Allergy, Asthma, and Immunology, and the incidence
`appears to be on the rise. 90-95% of cases of ocular allergy
`are either seasonal or perennial allergic conjunctivitis. Aller-
`gic symptoms often interfere with everyday activities, such
`as reading, working on a computer, driving and playing
`sports. As such, there is a need for pharmaceutical formu-
`lations that provide rapid relief from ocular allergic symp-
`toms. Such formulations should also have a long duration of
`action to eliminate the need for frequent dosing.
`SUMMARY
`
`[0004] The invention features novel pharmaceutical com-
`positions of long acting anti-histamine agents and short
`acting anti-histamine agents that provide synergistic effects
`towards alleviating the signs and symptoms of ocular aller-
`gies. A preferred combination includes an effective concen-
`tration of ketotifen and an effective concentration of phe-
`niramine. Another preferred combination includes
`an
`effective concentration of azelastine and an effective con-
`centration of antazoline.
`
`[0005] A preferred concentration of ketotifen is in the
`range of about 0.04% to 0.06%. Apreferred concentration of
`pheniramine is in the range of about 0.4% to 0.6%. A
`preferred concentration of antazoline is in the range of about
`0.4% to 0.6% and a preferred concentration of azelastine is
`in the range of about 0.04% to 0.06%.
`
`[0006] The invention also provides for methods of using
`combinations of long acting anti-histamine agents and short
`acting anti-histamine agents to treat ocular allergies.
`
`[0007] Other features and advantages of the invention will
`become apparent from the following detailed description
`and claims.
`
`of subjects treated with placebo or with 0.05% ketotifen
`(keto) for 15 minutes or 16 hours.
`
`[0009] FIGS. 2A and 2B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% pheniramine
`(phen) for 15 minutes or 16 hours.
`
`[0010] FIGS. 3A and 3B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.04% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 16
`hours. FIG. 3C is a bar graph comparing median ocular
`itching scores of subjects treated with placebo or with 0.04%
`ketotifen (keto) in combination with 0.5% pheniramine
`(phen) for 16 hours.
`
`[0011] FIGS. 4A and 4B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 15
`minutes or 16 hours. FIG. 4C is a bar graph comparing
`median ocular itching scores of subjects treated with placebo
`or with 0.05% ketotifen (keto) in combination with 0.5%
`pheniramine (phen) for 16 hours.
`
`[0012] FIGS. 5A and 5B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.06% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 16
`hours. FIG. 5C is a bar graph comparing median ocular
`itching scores of subjects treated with placebo or with 0.06%
`ketotifen (keto) in combination with 0.5% pheniramine
`(phen) for 16 hours.
`
`[0013] FIG. 6A is a graph showing mean redness efficacy
`by treatment with 0.04%, 0.05% or 0.06% ketotifen (keto) in
`combination with 0.5% pheniramine (phen). FIG. 6B is a
`graph showing mean itching efficacy by treatment with
`0.04%, 0.05% or 0.06% ketotifen (keto)in combination with
`0.5% pheniramine (phen).
`
`[0014] FIGS. 7A and 7B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05 % azelastine for
`15 minutes or 4 hours.
`
`[0015] FIGS. 8A and 8B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05% azelastine in
`combination with 0.5% pheniramine for 15 minutes or 4
`hours.
`
`[0016] FIGS. 9A and 9B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% antazoline for
`15 minutes.
`
`[0017] FIGS. 10A and 10B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% antazoline in
`combination with 0.05% azelastine for 15 minutes or 16
`hours.
`
`DETAILED DESCRIPTION
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`1. General
`
`[0008] FIGS. 1A and 1B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`
`[0018] The invention is based in part on the surprising
`discovery that combinational use of short-acting anti-hista-
`
`000025
`
`000025
`
`
`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`mine agents such as pheniramine or antazoline, in combi-
`nation with long-acting anti-histamine agents such as keto-
`tifen or azelastine provide rapid, synergistic and long lasting
`relief towards ocular allergy signs and symptoms.
`
`2. Combinational Use of Long-Acting and
`Short-Acting Anti-Histamines
`
`[0019] The present invention features the combinational
`use of a long-acting anti-histamine agent and a short-acting
`anti-histamine agent in the treatment of ocular allergy signs
`and symptoms such as eye itching, redness, chemosis, lid
`swelling, tearing and mucus discharge. The term “ocular
`allergy” refers to any allergic disease of the eye. Examples
`of such ocular allergies include but are not
`limited to
`seasonal/perennial allergic conjunctivitis, vernal keratocon-
`junctivitis, giant papillary conjunctivitis, perennial allergic
`conjunctivitis and atopic keratoconjunctivitis. “Seasonal and
`perennial allergic conjunctivitis” typically occurs in the
`individual with sensitivities to air borne allergens such as
`pollens, dust, and animal danders. It is typically seasonal,
`unlike its year-long cousin, “perennial allergic conjunctivi-
`tis”. Both seasonal allergic or perennial allergic conjunctivi-
`tis are allergic reactions to materials that do not usually
`produce such reactions in the normal population. The symp-
`toms of exposure to the material
`to which the allergic
`individual is sensitive can include: itchy, running nose with
`sneezing, and itchy, watery, red, swollen eyes. “Giant pap-
`illary conjunctivitis” typically occurs in allergy-prone indi-
`viduals who wear soft contact
`lenses.
`It can occur in
`
`individuals who wear other types of contact lenses, but it is
`more common in soft lens wearers. It occurs as a result of
`
`adherence of airborne allergens onto the surface of the
`contact lens, with eventual development of bumps in the
`conjunctiva lining the upper eyelid as the allergic/inflam-
`matory response develops over a period of months. The
`symptoms of this disorder include decreased comfort with
`contact
`lens wear, mild itching, excessive contact
`lens
`movement, and excessive mucus production. “Vernal kera-
`toconjunctivitis” involves a more complex immunologic/
`inflammatory process. This disease has major potential for
`damage to the cornea and loss of vision. The disease affects
`young people, much more often than older people, is con-
`siderably more common in males than in females, and
`generally occurs in the spring, in temperate climates and is
`much more common in warmer climates than in temperate
`or cold climates. It is particularly prevalent in the Middle
`East and is characterized by the development of very large
`bumps on the lining of the upper eyelid.
`Itching is a
`prominent symptom. Other symptoms and signs include
`ocular burning, foreign body sensation, excessive tearing,
`excess mucus production, and blurred vision. “Atopic kera-
`toconjunctivitis” is also a serious allergic eye disease with
`major blinding potential. It typically occurs in young adults
`and adults with atopic dermatitis (eczema). Ocular itch is the
`primary beginning symptom but foreign body sensation,
`ocular burning, excessive tearing, mucus production, and
`blurred vision generally eventually occur (http://www.u-
`veitis.org/).
`
`the term “anti-histamine agent”
`[0020] As used herein,
`may include drugs that counteract the action of histamine.
`Generally, allergy drugs may include drugs that are more
`selective for certain sub-types of histamine receptors such as
`H1 histamine receptor, H2, H3 or H4 receptors. Some
`anti-histamine agents have less selectivity, and thus more
`
`activity across the different histamine receptors, and may
`even possess activity against other receptors (e.g. cholin-
`ergic or adrenergic) which may be involved in regulation of
`the vasculature. Other anti-histamine agents may addition-
`ally act on certain cells, called mast cells, to prevent them
`from releasing substances that cause the allergic reaction
`and may also have anti-inflammatory properties.
`
`[0021] The term “short-acting anti-histamine agent” may
`apply to an anti-histamine agent that is typically applied or
`taken more than once per day or an anti-histamine agent that
`has varying specificity for histamine receptors and acts to
`block not just H1 but also to some degree H2, H3, H4
`histamine receptors, or other receptors. Such anti-histamine
`agents may also possess other desirable anti-allergy activi-
`ties and still have a short duration of action. As used herein
`
`“short-acting anti-histamine agent” may include but is not
`limited to pheniramine (Naphcon-A), chlorpheniramine,
`dexbrompherniramine,
`pyrilamine,
`diphenhydramine
`(Benadryl), promethazine, hydroxyzine, antazoline, emdas-
`tine
`(Emadine)
`and pharmaceutically acceptable
`salts
`thereof.
`
`[0022] The term “long-acting anti-histamine agent” may
`apply to an anti-histamine agent that is typically applied or
`taken once or twice per day or an anti-histamine agent that
`is generally more selective for a particular receptor such as
`the H1 histamine receptor. Such agents may additionally act
`on certain cells, called mast cells,
`to prevent them from
`releasing substances that cause the allergic reaction and may
`also have anti-inflammatory properties. As used herein
`“long-acting anti-histamine agent” refers to but is not lim-
`ited to ketotifen (Zaditor), loratadine (Claritin), mizolastine,
`ebastine, fexofenadine (Allegra), Cetrizine (Zyrtec), azelas-
`tine, olopatadine (Patanol), desloratadine, carebastine, levo-
`ceterizine, astemizole,
`tecastemizole, epinastine (Elestat),
`levocabastine (Livostin) and pharmaceutically acceptable
`salts thereof.
`
`[0023] Particular preferred combinations of long-acting
`anti-histamine agents and short-acting anti-histamine agents
`reduce ocular redness in about 1 minute, 3 minutes, 5
`minutes, 7 minutes, 10 minutes, 15 minutes or 20 minutes.
`Such combinations may also reduce ocular redness for a
`duration of 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22,
`or 22-24 hours. Particular preferred combinations of long-
`acting anti-histamine agents and short-acting anti-histamine
`agents reduce ocular itching in about 1 minute, 3 minutes, 5
`minutes, 7 minutes, 10 minutes, 15 minutes or 20 minutes.
`Such combinations may also reduce ocular itching for a
`duration of 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22,
`or 22-24 hours.
`
`[0024] A preferred combination of long-acting anti-hista-
`mine agent and short-acting anti-histamine agent is ketotifen
`or pharmaceutically acceptable salt thereof and pheniramine
`or pharmaceutically acceptable salt
`thereof. Yet another
`preferred combination of long-acting anti-histamine agent
`and short-acting anti-histamine agent is azelastine or phar-
`maceutically acceptable salt thereof and antazoline or phar-
`maceutically acceptable salt thereof.
`
`[0025] As used herein, the term “ketotifen” may include a
`pharmaceutically acceptable salt of ketotifen such as keto-
`tifen fumarate. Particularly preferred concentrations of keto-
`tifen or a pharmaceutically acceptable salt thereof, are in the
`
`000026
`
`000026
`
`
`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`range of about 0.01 to 0.10%, more preferably in the range
`of about 0.040 to 0.045%, 0.046 to 0.050%, 0.051 to 0.055%
`or 0.056 to 0.060%.
`
`[0026] As used herein, the term “azelastine” may include
`a pharmaceutically acceptable salt of azelastine such as
`azelastine acetate, azelastine guconate, azelastine lactate or
`azelastine maleate. Particularly preferred concentrations of
`azelastine or a pharmaceutically acceptable salt thereof, are
`in the range of about 0.01 to 0.10%, more preferably in the
`range of about 0.040 to 0.045%, 0.046 to 0.050%, 0.051 to
`0.055% or 0.056 to 0.060%, more preferably about 0.05%.
`
`the term “pheniramine” may
`[0027] As used herein,
`include a pharmaceutically acceptable salt of pheniramine or
`derivatives of pheniramine such as brompheniramine male-
`ate (Demitane), chlorpheniramine maleate (Chlor-Trime-
`ton), dexbrompheniramine maleate, dexchlorpheniramine
`maleate (Polaramine), and pheniramine maleate (Naphcon-
`A). Particularly preferred concentrations of pheniramine or
`a pharmaceutically acceptable salt thereof, are in the range
`of about from 0.1 to 1%, more preferably in the range of
`about 0.40 to 0.45%, 0.46 to 0.50%, 0.51 to 0.55%, or 0.56
`to 0.60%, more preferably about 0.5%.
`
`[0028] As used herein, the term “antazoline” may include
`a pharmaceutically acceptable salt of antazoline. Particularly
`preferred concentrations of antazoline or a pharmaceutically
`acceptable salt thereof, are in the range of about 0.1 to 1%,
`more preferably in the range of about 0.40 to 0.45%, 0.46 to
`0.50%, 0.51 to 0.55%, or 0.56 to 0.60%, more preferably
`about 0.5%.
`
`[0029] Alternatively, pheniramine or pharmaceutically
`acceptable salt of pheniramine may be used in combination
`with another long-acting anti-histamine agent
`that may
`include but is not limited to loratadine (Claritin), mizolas-
`tine, ebastine, fexofenadine (Allegra), Cetrizine (Zyrtec),
`olopatadine (Patanol), desloratadine, carebastine, levoceter-
`izine, astemizole, tecastemizole, epinastine (Elestat), eme-
`dastine (Emadine) or pharmaceutically acceptable salts
`thereof.
`
`pharmaceutically
`or
`antazoline
`[0030] Alternatively,
`acceptable salt of antazoline may be used in combination
`with another long-acting anti-histamine agent
`that may
`include but is not limited to ketotifen (Zaditor), loratadine
`(Claritin), mizolastine, ebastine,
`fexofenadine (Allegra),
`Cetrizine (Zyrtec), olopatadine (Patanol), desloratadine,
`carebastine, levoceterizine, astemizole, tecastemizole, epi-
`nastine (Elestat), emedastine (Emadine) and pharmaceuti-
`cally acceptable salts thereof.
`
`pharmaceutically
`or
`ketotifen
`[0031] Alternatively,
`acceptable salt of ketotifen may be used in combination with
`another short-acting anti-histamine agent that may include
`but
`is not
`limited to chlorpheniramine, dexbromphe-
`niramine, pyrilamine, diphenhydramine (Benadryl), promet-
`hazine, hydroxyzine, antazoline, levocabastine (Livostin) or
`pharmaceutically acceptable salts thereof.
`
`pharmaceutically
`or
`azelastine
`[0032] Alternatively,
`acceptable salt of azelastine may be used in combination
`with another short-acting anti-histamine agent
`that may
`include but is not limited to chlorpheniramine, dexbromphe-
`niramine, pyrilamine, diphenhydramine (Benadryl), promet-
`hazine, hydroxyzine, levocabastine (Livostin) or pharma-
`ceutically acceptable salts thereof.
`
`In one embodiment, an effective concentration of
`[0033]
`ketotifen or a pharmaceutically acceptable salt thereof may
`be administered separately from an effective concentration
`of pheniramine or
`a pharmaceutically acceptable salt
`thereof. As used herein, the term “effective concentration”
`refers to the concentration sufficient to effect a beneficial or
`
`desired clinical effect on signs and/or symptoms of ocular
`allergy upon treatment. An effective concentration of keto-
`tifen may be administered first to the eye surface followed
`by the administration of an effective concentration of phe-
`niramine. Alternatively, an effective concentration of phe-
`niramine may be administered first
`to the eye surface
`followed by the administration of an effective concentration
`of ketotifen. In another embodiment of the invention, an
`effective concentration of ketotifen may be administered in
`combination with an effective concentration of pheniramine
`at the same time.
`
`In another embodiment, an effective concentration
`[0034]
`of azelastine or a pharmaceutically acceptable salt thereof
`may be administered separately from an effective concen-
`tration of antazoline or a pharmaceutically acceptable salt
`thereof. An effective concentration of azelastine may be
`administered first to the eye surface followed by the admin-
`istration of an effective concentration of antazoline. Alter-
`
`natively, an effective concentration of antazoline may be
`administered first to the eye surface followed by the admin-
`istration of an effective concentration of azelastine.
`In
`another embodiment of the invention, an effective concen-
`tration of azelastine may be administered in combination
`with an effective concentration of antazoline at the same
`time.
`
`[0035] A pharmaceutical composition of the invention
`may be formulated with any of a variety of carriers including
`water, mixtures of water and water-miscible solvents, such
`as C1- to C7-alkanols, vegetable oils or mineral oils com-
`prising from 0.5 to 5% by weight hydroxyethyicellulose,
`ethyl oleate, carboxymethyl-cellulose, polyvinyl-pyrroli-
`done and other non-toxic water-soluble polymers, in par-
`ticular for ophthalmic uses, such as, for example, cellulose
`derivatives, such as methylcellulose, alkali metal salts of
`carboxymethylcellulose, hydroxymethylcellulose, hydroxy-
`ethylcellulose, methylhydroxypropylcellulose and hydrox-
`ypropylcellulose, acrylates or methacrylates, such as salts of
`polyacrylic acid or ethyl acrylate, polyacrylamides, natural
`products, such as gelatin, alginates, pectins,
`tragacanth,
`karaya gum, xanthan gum, carrageenin, agar and acacia,
`starch derivatives, such as starch acetate and hydroxypropyl
`starch, and also other synthetic products, such as polyvinyl
`alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, poly-
`ethylene oxide, preferably cross-linked polyacrylic acid,
`such as neutral Carbopol, or mixtures of those polymers.
`Preferred carriers are water, cellulose derivatives, such as
`methylcellulose, alkali metal salts of carboxymethylcellu-
`lose, hydroxymethylcellulose, hydroxyethylcellulose, meth-
`ylhydroxy-propylcellulose
`and
`hydroxypropylcellulose,
`neutral Carbopol, or mixtures thereof. A highly preferred
`carrier is water or saline solution. The concentration of the
`
`carrier is, typically, from 1 to 100000 times the concentra-
`tion of the active ingredient. The term “aqueous” typically
`denotes an aqueous composition wherein the carrier is to an
`extent of >50%, more preferably >75% and in particular
`>90% by weight water.
`
`000027
`
`000027
`
`
`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`[0036] A composition of the invention may include but is
`not limited to a solution, a suspension, a gel, an ointment, an
`emulsion and/or a mixture thereof.
`
`drops and/or those with an already compromised ocular
`surface (e.g. dry eye) wherein limiting exposure to a pre-
`servative may be more desirable.
`
`[0037] Further preference is given to pharmaceutical com-
`positions which are suitable for ocular administration.
`Therefore such a pharmaceutical composition preferably
`comprises a pharmaceutically acceptable carrier that include
`ingredients that meet the prerequisites for ocular tolerability.
`These further ingredients may include but is not limited to
`tonicity enhancers, preservatives, solubilizers, non-toxic
`excipients, demulcents, sequestering agents and pH adjust-
`ing agents.
`
`[0038] For the adjustment of the pH, preferably to a
`physiological pH, buffers may especially be useful. The pH
`of the present solutions should be maintained within the
`range of 4.0 to 8.0, more preferably about 4.0 to 6.0, more
`preferably about 6.5 to 7.8. Suitable buffers may be added,
`such as boric acid, sodium borate, potassium citrate, citric
`acid, sodium bicarbonate, TRIS, and various mixed phos-
`phate buffers
`(including combinations of Na2HPO4,
`NaH2PO4 and KHZPO4) and mixtures thereof. Borate buffers
`are preferred. Generally, buffers will be used in amounts
`ranging from about 0.05 to 2.5 percent by weight, and
`preferably, from 0.1 to 1.5 percent.
`
`[0039] Tonicity is adjusted if needed typically by tonicity
`enhancing agents. Such agents may, for example be of ionic
`and/or non-ionic type. Examples of ionic tonicity enhancers
`are alkali metal or earth metal halides, such as, for example,
`CaCl2, KBr, KCl, LiCl, Nal, NaBr or NaCl, Na2SO4 or boric
`acid. Non-ionic tonicity enhancing agents are, for example,
`urea, glycerol, sorbitol, mannitol, propylene glycol, or dex-
`trose. The aqueous solutions of the present invention are
`typically adjusted with tonicity agents to approximate the
`osmotic pressure of normal
`lachrymal
`fluids which is
`equivalent to a 0.9% solution of sodium chloride or a 2.5%
`solution of glycerol. An osmolality of about 225 to 400
`mOsm/kg is preferred, more preferably 280 to 320 mOsm.
`
`[0040] A preservative may typically be selected from a
`quaternary ammonium compound such as benzalkonium
`chloride, benzoxonium chloride or the like. Benzalkonium
`chloride is better described as: N-benzyl-N-(C8-C18 alkyl)-
`N,N-dimethylammonium chloride. Examples of preserva-
`tives different from quaternary ammonium salts are alkyl-
`mercury salts of thiosalicylic acid, such as, for example,
`thiomersal, phenylmercuric nitrate, phenylmercuric acetate
`or phenylmercuric borate, sodium perborate, sodium chlo-
`rite, parabens, such as,
`for example, methylparaben or
`propylparaben, alcohols, such as, for example, chlorobu-
`tanol, benzyl alcohol or phenyl ethanol, guanidine deriva-
`tives, such as, for example, chlorohexidine or polyhexam-
`ethylene biguanide, sodium perborate, Germal®II or sorbic
`acid. Preferred preservatives are quaternary ammonium
`compounds,
`in particular benzalkonium chloride or
`its
`derivative such as Polyquad (see U.S. Pa