Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMBI~I~TION T~RAPY FOR Tl~E TREATNENT O~ GLAUCOMA
BackRround of the Invention
The present invention relates generally to the
field of ophthalmology. In particular~ the invention
relates to the treatment of glaucoma using a combination of
a compound which lcwers intraocular pressure (IOP) and a
calcium channel antagonist to prevent or reduce the loss of
visual field.
Although the underlying causes of glaucoma are not
understood at this time, glaucoma is characterised by damage
to the optic nerve, accompanied by a ~ecrease in the normal
visual field. One early warning s-ign of possible
glaucomatous visual .field loss is elevated IOP. In fact,
glaucoma has historlcally been treated by medically and/or
surgically lowering elevated IOP. US-A-4981871 describes
the use of Class I caIcium anta~gonists, preferably
verapamil, to treat glaucoma by lowering~IOP. FR-A~-2585~574
discloses pharmaceutical compositions compri~sing l,
4-~i:hydropyridines or 3-aceto~y-5-(2-dimethylaminoethyl)-
2~3 dihydro-2-(4-metho~ypheryl)-1.5- be~othiazepin-4-one to
treat glaucoma for lowering IOP. However, ele~ated~lOP does
no~ always result in the occurrence of visual ~ield lo~ss::
moreover,~ visu~al field loss may occur at~levels ~of IOP which
are considered within the normal range. Thus, factor~ other
than IOP play ~a lole in determining the occurrence of visual :~
field loss. Microcirculatory disturbances which restrict
nutritive blood flow to the choroid, retina and opti~c nerve
fibres are undoubtedly also involved.
:
o ~ o ~o o ~ o :o~ o : ~
2131101 ~; :
::: : The present invention provides compositi~ns useful : ~ :
in the treatment~ of gla~coma and ocular~hypert~ension;.~;~The~
compositions contain a~ combination of at~least one~calci~um
channel ant~gonist ~and: a;t least one compouxld ~which l~owers~
IOP. The combination is effective in reducing or preventing
visual field loss,~as~well as reducing ~IOP to normal lev~ls.
: Further, the reduetion~of IOP provides both the~pati: nt and
the physician with an easy means Q~ tracki~ng~a:~patient's
progregs.
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Wo 93/:~308~ 2 13 1 1~ 1 PCI`/US"3/04505
In an alternate embodimeng ~f the compositions of the present invention, the
above eombination may further inelude ~n anionic mucomimetiG polymer, a gelling
polysaccharide, a fin~ly divid~d drug carrier substrate ~defined below), or a
combination of these components. These adc~i~ional components proviele
compositions which are comfor~able and havè sus~a~ned r~lease.
etail~ rip~ionQ~ th~ entiQn
To remain heaHhy and function normally, th~ rebna and the optic nerve
fibers (neurons) must receive a proper supply of nu~rients and oxygen and must
have th~ir metabolic waste products and carbon dioxide removed. This is
o accompiished by the microcirculation of thes~3 tissues. As us0d herein, the term
"microcirculation" refsrs to th~ blood fiow through the nutritive blood vessels, across
whose walis nutrients, gas~s and waste products move. Blood flow to the eye
depends upon th~ perfusion pressure (th~ systemic blood pressur~ minus the IC)P).
Blood pressure is partially de~rmined by th~ caliber o~ the blood vess~l lum~n,
t~ which is due ~o the degree of contraction of the vascular smooth muscle ~the
vascular tone). A recluction of the caliber of the vess21 lumen causes a decrease
in the blood flow, r~lated to the vessel's eross-sectional diameter. Ischemic
vasoconstriction (ischemia) is a condition wherein the oxy~en supply to a tissue is
severely ~ee~eas~d as a result of marked decrease in blood flow. Prolong~d
ischemia can result in the n~crosis, or death, of tissue. In the ~se of neuronaltissu~ such as th~ DptiC nerv~, a state ~f dysfunction may precede the death of the
neurons. If ischemia is involved in the death of optic nerve ~ibers whioh occurswith glaucoma, then its prevention could pro~e~t the neurons frorn death and loss
function.
Vasoconstri~ive substances cause a decr~ase in vessel diameter, while
vasodilative subst~nGes causR the opposl~e eff~ct. Among th~ known
vasoconstriotors in the body are the following: angiotensin 11, nor~pinephrine,
serotonin, vasopressin and ~ndothelin. The local constriction of blood vessels
2 ~ 3 ~
WO 93/230~ PCI /l IS93/84505
-3 -
supplying the r~tina and optic nerv~ can result in decreased blood fiow to the
tissues and markd vasoconstriction induced by vasocons~rictive substances can
rssult in ischemia.
Calcium plays a key rol~ in the regulation ~ intracellular processes.
Calcium ion exists in ~xtracellular and intracellular fluids and is found in bound ~nd
fr~ forms. Calcium reglJlates the actin myosin-~TP in~eraction which is involv~d in
vascular smooth muscle contraction. Calcium antagonists are known to inhibit
potential-operat~d and rec~ptor channels, thereby prcv~nting the moYement of
~xtracallular calciurn into the c~ll and va~cuiar smoo~h muscle c:ontraction. Some
calcium antagonists have been shown to inhibit myogenic a~ivity in vascul~r
smooth muscle. Calcium antagonists ean prevent ischemic vasoconstriction by
decreasing caloium f!ux into the sarcoplasmic r~ticulum of vascular smooth muscle
cells. Th~refore, calciurn antagonists ean be beneficial to tr~at ischemia of th~
retina and optir~ nerve tissues that may be present in ~laucoma patients.
Furthermore, aside from its involvement in isch~mic vasoconstriGtion,
calcium plays a more direct role in the dea~h of cells and tissues. During ischemia,
calcium is translocat~d from the extra- to the intra-cellular fluid which rnay result in
th~ sequestration of calcium by mitochvndria. Furthermore, glutamate-gated
calcium channeis and voltage-regulated calcium channels can op~n during
activation by ~lutamate or depolariza~ion of re~inal ~anglion c~lls, respe~tively,
which can result in a dramatic rise of calciurn in the cell ~ytosol. Calcium overload ~:
of retinal gan~lion cells can result in cell death and neuronal d~generation. Inischemia, calcium an~agonis~s can protect mitochondria against calcium overload
and pre~erve mitochondrial ultrastructur0 and functi~n. The excitatory amino acid,
~lutamate, has been implicated in neurotoxiGity, and causes depolarization of retinal
ganglton c lls; h~wever, this is not sufficient to cause neurotoxicity. Neuronal ceil
death ~ollowing glutamate-induced injury has been observed in the presenc~ of
calcium ion in the bathing medium. Thus, the prevention of calcium flux into
neuronal and r~tinal cells may directly offer protection agains~ damaging result of
ischemia.
2 ~ 3 '~
WC~ 93/23082 PCT/US93/04~0
Calcium antagonists are compounds which modulate th0 channels that
condu~t ~tcium b~ een th~ outsid~ ancl the inside of cells. Th~ir major action is
to mo~ulate the entry of calcium into the cell. As calcium is involv0d in the process
of vascular contraction, c~lcium antagonis~s can inteffere with this process ~ndmodula~e con~raction. B3f d~creasing the degree o~ vascular contraction, calciumantagonis~s bring about vasodila~ion, i.e., an incr~ase in th~ calib~r o~ the blood
vesssel lumen. Alsol to the extent that calcium influx is delet~rious to the cell1
~lcium antagonists can ameliorat~ this sitlJation and preser~e the cell against
d ath. In ischemia, caicium antagonists can protect mitochondria a~ains~ calciLlm
~o overload and pr~,erve mitochondrial uttrastructur@ and function. Therefore,
calcium antagonists can have a double benefit to tiSSUB~; exp~riencin~
vassconstrictive ischemia. First, they can caus~ vasodilation to increase blood flow
alld counter ~h~ ischemic condi~ions; sQconld, th~y can protect the cell from the
deleterious effects of calcium overload whic:h occurs under the ischemic conditio~.
~s Since lowering l{)P also ~avors an increase in oclJlar blood flow, the cornbination ~f
a calcium antagonist and an lOP-low~ring e:ompound will have a broader prote~tive
action than either one alone.
The calcium antagonists which are us~ul in the pres~nt in~ention include all
presently known calcium antagonists, especially thos~ which show a s~lecti~Jity
towards neuronal ~nd/or r~tinal vascular calcium channels. In pa~icular, it is b~tter
if the caleium antagonist do~s not significantly lower th~ systemic Plsod pressure
while exerting its blockade of calcium channels in optic nerv~ tissue, as that would
reduc~ the ocular perfusion pressure and tend to reduce ocular blood flow.
Fwther, those calcium antagonists which have a myocardial depressant action
2s wou.d be less pref~r~d due to their potential f~r causing a side ~Rect on th~ heart.
Such calcium antagonists can be typically divided into three chemical
classes: 1,4-dihydropyridines, such as nifedipinel nissldipine, nimodipine,
nicardipine, nitrendipine and ni.udipine; arylalkylamines, such as verapamil,
pr~nyl~mine, ~enidiline, bepridil, falipamil, tiapamil, gallopamil, and bencyclane; and
benzothiazepines, such as diltiazem, cinnarizine, flunarizine and lidoflazine.
21~.1Ql
W~ 93/23082 PCr/U~g3J/04505
Repr~sen~ative calciu~ an~agonists for each of the three chemical classes are
shown b~low in Structures (1) through ~111).
H~C C:H~
~c~ ftl3
C~3~C~H2 CH2-CH2--N--CH2-CH2~0CH3
OGH3
~1~ YE~AMiL
~--NO2 J~OCH9
H3COO~COOCH3 ~ CH
H3~ N C~3 H2C~2~CI 1 HCI
(11~ NIFEDIPII~IE (III)DILTIAZEM :~
Th~ preferred calcium antagonists ar~ th~ enantiomeric and racernic forms (whereapplicable) of: AE 0047, AHR 5360C, AHR 12234C, AHIR 16303B, AHR 16462B,
AJ 261~, AJ 3941, AQ-AH-208-CI, AR 12~56, alismol, amlodipine; anipamil,
o B 844-39~ Bay-e~927, Bay-k-9320, barnidipine, BBR 2160, b~sdil, benidipine,
bepridil, bisaramil, BMY 20014, BMY 20064, BN 50149, BN 50175, BN 50394,
BRL 3287A, buflom~dil, butoprozine? caroverine, CD 349, CERM 11956,
CGP 22442, CGP 267g7, C:t3P 28392, CGP 28727, CGP 32413, CG~ 19755,
Cl 951, cinnarlzine, CNS 2103, COR 28-22, (:;OR-2707C, COR 3752C, cronidipine,
s CRE 202, CRE 204, CRE 1005, CS 905, CV 159, D 2603, dagapamil, darodipine,
Wo g3/~3~82 2~3 1 ~ ~ 'CI/US93/04585
desmethylverapamil, DHM9, DHP 218, dicl~urime, diltiazem, dipe~ipine,
diprot~verine, dopropidil, dotarizine, EG 1û88, elgodipin~, emopamil, F~401,
fantofarone, FCE 24265, fedopamil, ~elodipinP, feniline, flordipin~, flunarizine,
fostidil, FPL 62129, FR 46171, FRC ~411, FRG 8~53, furaldipine, gallapamil,
(;OE 5057, GC)E ~584-A, GOE 93007, GYKI 46544, HA 1004, HA 1077
(cerebroarterial selective), HE-3-0346, HOE-166, Hoe 263, HP 406, israldipin~,
KB 27g6, KP 873, KT 362 (inhibs intracellular Ca), KW-304~ ~benidipine),
~ 3049-vascu3Oselective, lacidipin~, LAS 30356, LAS 30~98, LAS 30538,
LAS-Z077, LCB 2514, lidoflazin~, LU 49938, manidipine, MCI ~76, McN ~691,
McN 6186, MCN 6497, IVID 260792, MDL 143, MDL 12330A, MDL 16582A,
MI~L 72~67, m~pami, mepirodipine, mesudipine, minodipine, mioflazin~l MJ 14712,
MPC 1304, MPC 2101, N 20776, naltiazsrn, NB 81~, NC 1100, NC(: 70û,
NH 2250, NH 2716, N~ 7221 NP 252, NZ 105, nicardipine, ni~tiazem, nif~dipine,
nigludipine, niludipine, nilvadipine, nimodipinel nisoldipine, nitr~ndipin~
;)PC 13340, oxodipin~, P 0285, palonidipinel P 12681 PD 122860, pelanserin,
pe~h~xilinel PF 244l pirprofuroll pimozide, PN 200-110, prenylamine, R 71811, -~
Rec 1512288, Rec-15/2375, RGH 2970, riodipine, Ro 18-3981, Ro 40-~967,
ronipamilt RS ~3007, RU 43945, RWJ 22726, RWJ 26899, RVVJ 26902, ryanodine,
S 312-d, S12968, S11568, S 830327, SA 2572, SA 2995, SA 3212, sag~ndipine,
SC 30552, selodipine, s~motiadill SIM 608~1 SKF 96365l SIVI 6586, sornidipinel :;
SL 85.1016, SQ 31486l SQ 31765, SQ 31727l sa 323211 SQ 32324, S 33351,
SQ 33537, SR 33805, SUN 5647, SUN 60871 TA 3090 ~clentiazem~, taludipine,
ti~pamil, TN 871, TR 2957, trapidil, UK 516~6, UK 52831, UK 55444, verapamil,
vinigrol, vintoperoll W 787, WAS 4206, WK 269, WY 27S69, ~ 44644,
W'qf 44705l WY 46622l WY 47324, Y 19638, Y 208835, Y 22516, YC 114,
YM 15430-1, YM 161~1~, YS 035, and YS 161, as well as their pharmaceutically
acceptable salts. Most preferred are: bluflomedil, diltiazem, emopamil, felodipinel
flunarizine, israldipine, lidofla~ine, mioflazine, nimodipine, nifedipine, R-56865 and
~-58735.
The lOP-lowering compounds useful in the present invention includ~ all
pr~sently known lOP-lowering compounds, including miotics (e.g., pilocarpine,
wo 93/23082 2 1 3 1 1 ~ 1 P~/USg3/0~505
-7~
carbachol and acetyicholinesterase inhibitors); sympa~homimetics (e.g.,
epinephrine, dipivaiylepinephrine and para amino clonidine); beta-blockers (e.g.,
betaxolol, levobunolol and timolol~; and carbonic anhydrase inhibitors (e.~.,
acetazolamide, methazolamide ancl ethoxzolamide). The pr~ferred lOP-lowering
eompoLInds are: timolol, betaxolol, levobunoloi, car~eolol, pilocarpine, carbachol,
MK 927, MK 507, AL04414, AL04623, ALO4862, epinephrine, dipivalyl
epinephrine, a-methyl dipivalylepinephrine, apraclonidine, clonidine.
In general, an amount of a calcium antagonist between about 0.0001 and
~bout 10.0 p~rcen~ by weight (wt%) and an arnount ~ an lOP-l~wering compound
beh~een abou~ 0.00001 and about 10.0 wt%. It is preferred that an amount of a
calcium antagonist between about 0.001 ancl about 5.0 wt% is used and it is
especially preferred to us~ an amount between abo~t 0.01 and about 2.5 wt%. An
amount of an lOP-lowering compound between about 0.001 and abou~ 5.0 wt% is
pr~erred ~nd an arnount between about û.01 and about 2.~ ~% is especially
preferred. The ratio by weigh~ of calcium an~agonist to lOP-lowering compound isgenerally between about 100:1 to about 1:100, preferably between about 10:1 to
about 1:10.
The compositions of the present invention may additionally inc,lude
components to provide sustained release and/or comfort. Such components
inchJde high molecular weight, anionic mucomimetic polymers, gelling
polysaccharides and finely-divided drug carrier substrates. These components arediscusxed in great~r d~t~il in U.S. Patent No. 4,911,920 issu~d 27 March 1990,
and in EP 507 224 A1 (pubtished 7 :)otober 1992~. The entire oontents of that
patent and patent application are incorporated herein by reference.
2~i The high molecular weight, anionic mucomim~ic polymers useful in the
present invention have a molecLJlar weight between a~out 50,000 and 6 million
dal~ons The polym~rs ar~ char~cterized as having carboxylic acid functional
groups and preferably contain between 2 and 7 carbon atoms per functional growp.The gels which ~orm during preparatior, of the ophthalmic polymer dispersion havs
WO 93/23082 PCI /US93/045~5
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213~il
a viscosity betwe~n about ~,000 ~o about 300,000 ~entipoise (cps). Suitable
poiymers are carboxy vinyl polymers, preferably those called Carbom~rs, e.g.,
Carbopol~ (B.F. Goodrich Co., Cleveland, Ohio). Speoi~ically preferr~d are
Carbopol~ 934 and 940. Such polyrners will typi~lly be employed in an amount
be~ween ~bout 0.0~ and about 8.Q wt%, depending on the desired viscosity of the
~mposition. Pourable liquid compositions generally compris~ an amount o~ the
polymer between about 0.05 and about 2.0 wt/~. :
As used herein, the t~rm '~inely-divided drug carri~r substrate" (or "DCS"~
means finely-divided ~olids, colloidal particles, or soluble polymers and/or
poly~le~rolytes which are capable of setective adsorption or binding with drug
molecules. Examples of DCS in~lude, but arc not !imited to: finely divided silica,
such as furned ~ilica, silicates and bentonit~s; ion exchange resins, which can be
anionic, cationic or non-ionic in nature; and soluble polymers, such as, alginic ~cid,
pectin, soh~ble carrageenans, Carbopol(~, and polystyrene sulfonic acid. In
general, the DCS component is used at a level in the range of about 0.05 ~o about
10.0 wt%. For particulate DCS, the average particl~ size diameter ranges fr~m 1
to 20 microns. The amoun~ of DCS and its characteristics ~e.g., amount of cross-linking, pa~icle size) may be varied in order to produce th~ desired time-release
profile for the chosen drug.
Pre~rr~d DCS are the ion exchang0 r~sins. Some r~sins which ar~ used in
chro~natography make ideal DCS for binding drugs in the compositions o~ the
present invention. Such resins are readily availabls, for example, from F<ohm &
Haas (Philadelphia, Pennsylvania) und~r the name Amb~rlite~ and from Dow
Chemical Co. (Midland, Michigan) under ~he name Dowex~. Th~ averag~ particl~
~ize o~ ~he commeroially availabl~ forms of the resins is about 40 to 150 microns.
As th~ particl~ siz~ of the resin is critical, such commercially available particles are
most conveni~ntly reduced to a p~rticle size range of about 1.0 to 25 microns byball milling, according to known techniques. ~t Isast 9~% of the r3sulting
- spheroidal particles must have a diameter less than 20 microns. The ion exchange
resins will typically be present in an amount between abou~ 0.05 and about 10.0
213i:L01
WO 93/2308~ ^ P~/US~3/0~50~
g
wt% and will have an average particle size diameter between about 1 and about 20microns.
In addition to ~he above-described principal ingfedien~s, th~ anti-gl~ucom~ :
compositions of the present invention may further comprise various formlJlatory
s in~redients, such as antimicrabiai preservatives and tonici~y ag~nts. Exampies of
suitable antimicrobial preservatives includ~: benzall~on~um chioride, thimerosal,
~hlorobutanol, methyl paraben, propyl paraben, ph~nylethyl alcohol, edetate
disodium, sorbic acid, Onamer MO and other ag0nts equally well-known to those
skill~d in th~ art. Such preservativ~s, if utilized, will typically b~ employed in an
am~un~ betwe~n about 0.001 and about 1.0 vvt%. Examples o~ ~uitable agents
which may be utilized to adjust the tonicity or os.rnolaiity of th~ formulations includ~:
sodium chloride, potassium ~hloride, mannitol, dextrose, glycerin and propylen~ ;
~Iycol. Such agents, if utilized, will typically be ~mployed in an amount betwe~n
about 0.1 and about 10.0 wt%.
As will be appreciated by those skilled in the art, the compositions may be
formulated in various dosaQe forms suitable for topical ophthalmic delivery,
includin~ solutions, suspensions, emulsions, g~ls and erodible solid ocular inserts.
The compositions are preferably aqu OU5, have a pH betwe~n 3.5 to 8.0 and an
osmolality bet~ en 280 to 320 milliOsmoles per kilogram (rnOsm~kg~.
The compositions of the present invention may also comprise non-aqu~ous
formulations such as: substantially non-aqueous liquids substantially non-aqu@ous
s~mi-solid compDsitions and solid compositions or devicPs. The first class,
substantially non-aq-leous liquids, comprise a oombination of calcium channel
antagonist and lOP-lowering compound ("drug combinationi') dissolved or
suspended in one or more of th~ following: vegetable and mineral oils, such as,
tiquid petrolatum, corn oil, cas~or oil, sesame oil and peanut oil; triglycerides, such
as ~he capric/c3prylic triglycerides commonly used in foods and cosmetics; liquid
lanolin and lanolin derivative~; and perFluorohydrocarbons. The second class,
semi~solid cotnpositions, comprise a drug combination dissolv~d or suspend~d in
o o o o o o ~ o ~ o q r o O O O O O O
o ~ o ~ C` o
-10- 2131101
one or more of the following: various types of petrolatum, such as whit~, yellow,
red and so on; lanolin and lanolin derivatives; gelle~ mineral oil having a
hydrocarbon base, such as Pl~stibas~); petrolatum and ethylene carbonate
mixtures; petrolatum in cornbination with surfactants and polyglycol, such as
polyoxyl 40 stearate and polyethylene glycol.
The third class, solid compositions or devices, include non-erodible devices
which are inserted into the conjunctival sac of the eye and later removed, such as
the Alza-typ~ diffusion or osmotic pressure controll~d polymer membranes; and
bioerodible polymers which do not have to be removed from the conJunctivsl sac,
o such as ~ssentially anhydrous but water soluble polymers and resins (e.g.,
celluloses, polycarboxylic acids, and so on). E~pecially preferred are the
bio~rodible inserts described and detail~d in US 4,S40,408 (Lloyd) and US
4,730,013 (Bondi et al.), wherein drug combin~tions of the present invention would
ba entrained in a non-a~ueous matrix consisting essentially of poiyvinyl alcohcl.
15 . The entiro contents of thes~ two pat~nts ar~ incorporated herein by referenc~.
The present invention is alsa di3~cted to m*thods of treating glau~ma and
i, other oph~almic diseases and abnormalitl~s. The methods compris~ topi~ally
applying to the affe~ted eye(s) of the patient a therapeutically effective amount of a
composition ac~rding to th~ present inv~ntion. The fre~uency and amount of
dosa~e will b~ d~temlined by the clinician based on various clinical ~actors. The
methods will typically ~mpris~ topical appliGation of on~ or two drops ~or an
equiYalent ~molJnt of a solid or semi-solid dosage form) to the affected eye one to
t~vo times per day.
