U.S. patent application number 11/390874 was filed with the patent office on 2006-08-24 for methods of treating dry eye disorders.
Invention is credited to Daniel A. Gamache.
Application Number | 20060189541 11/390874 |
Document ID | / |
Family ID | 32030872 |
Filed Date | 2006-08-24 |
United States Patent
Application |
20060189541 |
Kind Code |
A1 |
Gamache; Daniel A. |
August 24, 2006 |
Methods of treating dry eye disorders
Abstract
Inhibitors of cytokine synthesis in nonimmune, resident ocular
surface cells are useful for treating dry eye disorders and other
disorders requiring the wetting of the eye.
Inventors: |
Gamache; Daniel A.;
(Arlington, TX) |
Correspondence
Address: |
ALCON
IP LEGAL, TB4-8
6201 SOUTH FREEWAY
FORT WORTH
TX
76134
US
|
Family ID: |
32030872 |
Appl. No.: |
11/390874 |
Filed: |
March 28, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10650006 |
Aug 26, 2003 |
7026296 |
|
|
11390874 |
Mar 28, 2006 |
|
|
|
60412463 |
Sep 20, 2002 |
|
|
|
Current U.S.
Class: |
514/20.8 ;
514/256; 514/275; 514/406 |
Current CPC
Class: |
A61K 38/08 20130101;
A61K 31/192 20130101; A61K 31/416 20130101; A61K 31/616 20130101;
A61K 31/551 20130101; A61P 43/00 20180101; A61P 27/02 20180101;
A61K 31/506 20130101; A61K 31/505 20130101 |
Class at
Publication: |
514/016 ;
514/256; 514/275; 514/406 |
International
Class: |
A61K 38/08 20060101
A61K038/08; A61K 31/506 20060101 A61K031/506; A61K 31/4162 20060101
A61K031/4162 |
Claims
1-7. (canceled)
8. A method for the treatment of dry eye which comprises
administering to a mammal a composition comprising a
pharmaceutically acceptable carrier and a pharmaceutically
effective amount of a c-jun N-terminal kinase inhibitor.
9. The method of claim 8 wherein the pharmaceutically effective
amount of the c-jun N-terminal kinase inhibitor is 0.001-1.0%
(w/w).
10. The method of claim 8 wherein the composition is topically
administered to the eye.
11. The method of claim 8 wherein the dry eye is associated with
refractive surgery.
Description
[0001] This application is a continuation of U.S. Ser. No.
10/650,006, filed Aug. 26, 2003, which claims priority to U.S.
Provisional Application, U.S. Ser. No. 60/412,463, filed Sep. 20,
2002.
[0002] The present invention is directed to the treatment of dry
eye disorders. In particular, the present invention is directed to
the use of certain cytokine synthesis inhibitors in the treatment
of dry eye and other disorders requiring the wetting of the eye in
mammals.
BACKGROUND OF THE INVENTION
[0003] Dry eye, also known generically as keratoconjunctivitis
sicca, is a common ophthalmological disorder affecting millions of
Americans each year. The condition is particularly widespread among
post-menopausal women due to hormonal changes following the
cessation of fertility. Dry eye may afflict an individual with
varying severity. In mild cases, a patient may experience burning,
a feeling of dryness, and persistent irritation such as is often
caused by small bodies lodging between the eye lid and the eye
surface. In severe cases, vision may be substantially impaired.
Other diseases, such as Sjogren's disease and cicatricial
pemphigoid manifest dry eye complications.
[0004] Although it appears that dry eye may result from a number of
unrelated pathogenic causes, all presentations of the complication
share a common effect, that is the breakdown of the pre-ocular tear
film, which results in dehydration of the exposed outer surface and
many of the symptoms outlined above (Lemp, Report of the National
Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The
CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
[0005] Practitioners have taken several approaches to the treatment
of dry eye. One common approach has been to supplement and
stabilize the ocular tear film using so-called artificial tears
instilled throughout the day. Other approaches include the use of
ocular inserts that provide a tear substitute or stimulation of
endogenous tear production.
[0006] Examples of the tear substitution approach include the use
of buffered, isotonic saline solutions, aqueous solutions
containing water soluble polymers that render the solutions more
viscous and thus less easily shed by the eye. Tear reconstitution
is also attempted by providing one or more components of the tear
film such as phospholipids and oils. Phospholipid compositions have
been shown to be useful in treating dry eye; see, e.g., McCulley
and Shine, Tear film structure and dry eye, Contactologia, volume
20(4), pages 145-49 (1998); and Shine and McCulley,
Keratoconjunctivitis sicca associated with meibomian secretion
polar lipid abnormality, Archives of Ophthalmology, volume 116(7),
pages 849-52 (1998). Examples of phospholipid compositions for the
treatment of dry eye are disclosed in U.S. Pat. Nos. 4,131,651
(Shah et al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980
and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et
al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371,108
(Korb et al.) and 5,578,586 (Glonek et al.). U.S. Pat. No.
5,174,988 (Mautone et al.) discloses phospholipid drug delivery
systems involving phospholipids, propellants and an active
substance.
[0007] Another approach involves the provision of lubricating
substances in lieu of artificial tears. For example, U.S. Pat. No.
4,818,537 (Guo) discloses the use of a lubricating, liposome-based
composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses
compositions containing glycerin and propylene glycol for treating
dry eye.
[0008] Although these approaches have met with some success,
problems in the treatment of dry eye nevertheless remain. The use
of tear substitutes, while temporarily effective, generally
requires repeated application over the course of a patient's waking
hours. It is not uncommon for a patient to have to apply artificial
tear solution ten to twenty times over the course of the day. Such
an undertaking is not only cumbersome and time consuming, but is
also potentially very expensive. Transient symptoms of dry eye
associated with refractive surgery have been reported to last in
some cases from six weeks to six months or more following
surgery.
[0009] Aside from efforts directed primarily to the alleviation of
symptoms associated with dry eye, methods and compositions directed
to treatment of the dry eye condition have also been pursued. For
example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex
steroids, such as conjugated estrogens, to treat dry eye conditions
in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)
discloses the use of finely divided calcium ion compositions to
stimulate pre-ocular tear film production; and U.S. Pat. No.
4,966,773 (Gressel et al.) discloses the use of microfine particles
of one or more retinoids for ocular tissue normalization.
[0010] Some recent literature reports suggest that patients
suffering from dry eye syndrome disproportionately exhibit the
hallmarks of excessive inflammation in relevant ocular tissues,
such as the lacrimal and meibomian glands. The use of various
compounds to treat dry eye patients, such as steroids [e.g. U.S.
Pat. No. 5,958,912; Marsh, et al., Topical nonpreserved
methylprednisolone therapy for keratoconjunctivitis sicca in
Sjogren syndrome, Ophthalmology, 106(4): 811-816 (1999);
Pflugfelder, et al. U.S. Pat. No. 6,153,607], cytokine release
inhibitors (Yanni, J. M.; et. al. WO 0003705 A1), cyclosporine A
[Tauber, J. Adv. Exp. Med. Biol. 1998, 438 (Lacrimal Gland, Tear
Film, and Dry Eye Syndromes 2), 969], and 15-HETE (Yanni et. al.,
U.S. Pat. No. 5,696,166), has been disclosed.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to methods for the
treatment of dry eye and other disorders requiring the wetting of
the eye, including symptoms of dry eye associated with refractive
surgery such as LASIK surgery. According to the methods of the
present invention, certain cytokine synthesis inhibitors are
administered to a patient suffering from dry eye or other disorders
requiring wetting of the eye. The cytokine synthesis inhibitors are
preferably administered topically to the eye.
BRIEF DESCRIPTION OF THE DRAWING
[0012] FIG. 1 shows the inhibition of hyperosmolarity-induced
cytokine production from human corneal epithelial cells in vitro by
SP-600125 and dexamethasone.
DETAILED DESCRIPTION OF THE INVENTION
[0013] According to the present invention, inhibitors of cytokine
synthesis by nonimmune resident ocular surface cells, including
corneal and conjunctival epithelial and stromal cells, are
administered to a patient suffering from dry eye. The compounds
suitable for use in the present invention inhibit the synthesis of
pro-inflammatory cytokines in nonimmune resident ocular surface
cells by interfering with specific effectors of signaling cascades
in these cells. Effectors of cytokine synthesis targeted for
inhibition in the treatment of dry eye include mitogen-activated
kinases (MAP kinase, p38 kinase), c-jun N-terminal kinase (JNK) and
I-kappa kinase (IKK). Also, inhibitors of enzymes which convert
precursors of the pro-inflammatory cytokines IL-1.beta. (ICE, IL-1
converting enzyme) and TNF.alpha. (TACE, TNF-alpha converting
enzyme) to the active species or inhibit the translation of
cytokine mRNA provide dry eye therapy. Cytokines promote further
synthesis of pro-inflammatory cytokines through activation of Janus
family tyrosine kinase (JAK) and signal transducers and activators
of transcription (STAT) and, therefore, inhibitors of JAKs and
STATs provide treatment of dry eye. Inhibitors of activator
protein-1 (AP-1) suppress cytokine synthesis in ocular surface
cells and provide dry eye therapy. Additionally, ligands of
retinoid X receptors (RXR) are known to suppress cytokine synthesis
in epithelial cells and are suitable for use in the present
invention.
[0014] The classes of cytokine synthesis inhibitors identified
above are known.
[0015] Inhibitors of MAP kinases (p38) include
(5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole)
["SB-220025"].
[0016] Inhibitors of JNK include anthra[1,9-cd]pyrazol-6(2H)-one
["SP-600125"], CEP-1347, SB-203580, SB-202190, and SPC0009766.
Other examples of JNK inhibitors include those disclosed in WO
00/75118; WO 00/35906; WO 00/35909; WO 00/35921; WO 00/64872; WO
01/12621; WO 01/23378; WO 01/23379; WO 01/23382; WO 01/47920; WO
01/91749; WO 02/46170; and WO 02/62792.
[0017] Additional known inhibitors of JNK include SPC 0009766; CEP
1347; SB 203580; and SB 202190. CEP 1347 has the following
structure: ##STR1## The chemical name for CEP 1347 is
(9S,10R,12R)-5,16-bis[(ethylthio)methyl]-2,3,9,10,11,12-hexahydro-10-hydr-
oxy-9-methyl-1
-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzo-
diazocine-10-carboxylic acid, methyl ester. SB 203580 has the
chemical structure: ##STR2## The chemical name for SB 203580 is
4-[5-(4-fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-1H-imidazol4-yl]-pyrid-
ine. SB 202190 has the chemical structure: ##STR3## The chemical
name for SB 202190 is
4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-phenol.
[0018] Inhibitors of ICE include pralnacasan (HMR3480/VX-740). TNF
mRNA translation inhibitors include
(D)Arginyl-(D)Norleucyl-(D)Norleucyl-(D)Arginyl-(D)Norleucyl-(D)Norleucyl-
-(D)Norleucyl-Glycine-(D)Tyrosine-amide,acetate salt ["RDP58"].
[0019] NFkB inhibitors include
2-chloro-N-[3,5-di(trifluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidine--
5-carboxamide ["SP-100030"], and triflusal.
[0020] AP-1 inhibitors include SP-100030. RXR agonists include
bexarotene.
[0021] Preferred cytokine synthesis inhibitors for use in the
present invention are JNK inhibitors and AP-1 inhibitors.
[0022] According to the methods of the present invention, a
composition comprising one or more of the specified cytokine
synthesis inhibitors and a pharmaceutically acceptable carrier for
topical ophthalmic administration or implantation into the
conjunctival sac or anterior chamber of the eye is administered to
a mammal in need thereof. The compositions are formulated in
accordance with methods known in the art for the particular route
of administration desired.
[0023] The compositions administered according to the present
invention comprise a pharmaceutically effective amount of one or
more of the specified cytokine synthesis inhibitors. As used
herein, a "pharmaceutically effective amount" is one which is
sufficient to reduce or eliminate signs or symptoms of dry eye or
other disorders requiring the wetting of the eye. Generally, for
compositions intended to be administered topically to the eye in
the form of eye drops or eye ointments, the total amount of
cytokine synthesis inhibitor will be about 0.001 to 1.0% (w/w).
[0024] Preferably, the compositions administered according to the
present invention will be formulated as solutions, suspensions and
other dosage forms for topical administration. Aqueous solutions
are generally preferred, based on ease of formulation, as well as a
patient's ability to easily administer such compositions by means
of instilling one to two drops of the solutions in the affected
eyes. However, the compositions may also be suspensions, viscous or
semi-viscous gels, or other types of solid or semi-solid
compositions. Suspensions may be preferred for cytokine synthesis
inhibitors which are sparingly soluble in water.
[0025] The compositions administered according to the present
invention may also include various other ingredients, including but
not limited to surfactants, tonicity agents, buffers,
preservatives, co-solvents and viscosity building agents.
[0026] Various tonicity agents may be employed to 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
and/or mannitol may be added to the composition to approximate
physiological tonicity. Such an amount of tonicity agent will vary,
depending on the particular agent to be added. In general, however,
the compositions will have a tonicity agent in an amount sufficient
to cause the final composition to have an ophthalmically acceptable
osmolality (generally about 150-450 mOsm, preferably 250-350
mOsm).
[0027] An appropriate buffer system (e.g., sodium phosphate, 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 6-7.5.
[0028] Compositions formulated for the treatment of dry eye-type
diseases and disorders may also comprise aqueous carriers designed
to provide immediate, short-term relief of dry eye-type conditions.
Such carriers can be formulated as a phospholipid carrier or an
artificial tears carrier, or mixtures of both. As used herein,
"phospholipid carrier" and "artificial tears carrier" refer to
aqueous compositions which: (i) comprise one or more phospholipids
(in the case of phospholipid carriers) or other compounds, which
lubricate, "wet," approximate the consistency of endogenous tears,
aid in natural tear build-up, or otherwise provide temporary relief
of dry eye symptoms and conditions upon ocular administration; (ii)
are safe; and (iii) provide the appropriate delivery vehicle for
the topical administration of an effective amount of one or more of
the specified cytokine inhibitors. Examples or artificial tears
compositions useful as artificial tears carriers include, but are
not limited to, commercial products, such as Tears Naturale.RTM.,
Tears Naturale II.RTM., Tears Naturale Free.RTM., and Bion
Tears.RTM. (Alcon Laboratories, Inc., Fort Worth, Tex.). Examples
of phospholipid carrier formulations include those disclosed in
U.S. Pat. Nos. 4,804,539 (Guo et al.), 4,883,658 (Holly), 4,914,088
(Glonek), 5,075,104 (Gressel et al.), 5,278,151 (Korb et al.),
5,294,607 (Glonek et al.), 5,371,108 (Korb et al.), 5,578,586
(Glonek et al.); the foregoing patents are incorporated herein by
reference to the extent they disclose phospholipid compositions
useful as phospholipid carriers of the present invention.
[0029] Other compounds designed to lubricate, "wet," approximate
the consistency of endogenous tears, aid in natural tear build-up,
or otherwise provide temporary relief of dry eye symptoms and
conditions upon ocular administration the eye are known in the art.
Such compounds may enhance the viscosity of the composition, and
include, but are not limited to: monomeric polyols, such as,
glycerol, propylene glycol, ethylene glycol; polymeric polyols,
such as, polyethylene glycol, hydroxypropylmethyl cellulose
("HPMC"), carboxy methylcellulose sodium, hydroxy propylcellulose
("HPC"), dextrans, such as, dextran 70; water soluble proteins,
such as gelatin; and vinyl polymers, such as, polyvinyl alcohol,
polyvinylpyrrolidone, povidone and carbomers, such as, carbomer
934P, carbomer 941, carbomer 940, carbomer 974P.
[0030] Other compounds may also be added to the ophthalmic
compositions of the present invention to increase the viscosity of
the carrier. Examples of viscosity enhancing agents include, but
are not limited to: polysaccharides, such as hyaluronic acid and
its salts, chondroitin sulfate and its salts, dextrans, various
polymers of the cellulose family; vinyl polymers; and acrylic acid
polymers. In general, the phospholipid carrier or artificial tears
carrier compositions will exhibit a viscosity of 1 to 400
centipoises ("cps").
[0031] Topical ophthalmic products are typically packaged in
multidose form. Preservatives are thus required to prevent
microbial contamination during use. Suitable preservatives include:
benzalkonium chloride, chlorobutanol, benzododecinium bromide,
methyl paraben, propyl paraben, phenylethyl alcohol, edetate
disodium, sorbic acid, polyquaternium-1, or other agents known to
those skilled in the art. Such preservatives are typically employed
at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the
present invention will be sterile, but typically unpreserved. Such
compositions, therefore, generally will not contain
preservatives.
[0032] The preferred compositions of the present invention are
intended for administration to a human patient suffering from dry
eye or symptoms of dry eye. Preferably, such compositions will be
administered topically. In general, the doses used for the above
described purposes will vary, but will be in an effective amount to
eliminate or improve dry eye conditions. Generally, 1-2 drops of
such compositions will be administered from once to many times per
day.
[0033] A representative eye drop formulation is provided in Example
1 below.
EXAMPLE 1
[0034] TABLE-US-00001 Ingredient Amount (% w/w) Cytokine synthesis
inhibitor 0.001-1.0 Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium
Chloride 0.75 Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl
q.s., pH = 7.4 Purified Water q.s. 100%
[0035] The above composition is prepared by the following method.
The batch quantities of boric acid, sodium chloride, disodium
edetate, and polyquaternium-1 are weighed and dissolved by stirring
in 90% of the batch quantity of purified water. The pH is adjusted
to 7.4.+-.0.1 with NaOH and/or HCl. The batch quantity of the
cytokine synthesis inhibitor as a stock solution is measured and
added. Purified water is added to q.s. to 100%. The mixture is
stirred for five minutes to homogenize and then filtered through a
sterilizing filter membrane into a sterile recipient.
EXAMPLE 2
Inhibition of Hyperosmolarity-Induced Cytokine Production from
Human Corneal Epithelial Cells in vitro.
[0036] The ocular tear film in dry eye is abnormally hyperosmolar,
which is irritating to ocular surface cells. Treatment of human
conjunctival epithelial cells with a hypertonic media elicits the
production of pro-inflammatory cytokines. A selective JNK
inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one, was evaluated for
inhibition of hyperosmolarity-induced cytokine secretion from the
transformed human corneal epithelial cell line, CEPl-17. CEPl-17
cells were grown in complete isotonic Keratinocyte Growth Medium
(iso KGM) and plated in 48-well plates in iso KGM without
hydrocortisone (iso KGM-HC). When the cells reached confluence,
they were pre-treated for 1 hour with the compound at the indicated
concentration in iso KGM-HC. The cells were then stimulated by
hypertonic KGM-HC for 6 hours (additional 80 mM NaCl added in iso
KGM-HC) in the presence of the compound. Aliquots of the
supernatants were assayed for IL-6, IL-8 by ELISA. Cytokine release
was normalized by the amount of double stranded DNA (dsDNA)
extracted from the cells. Percent inhibition of cytokine production
was calculated by comparison with cytokine levels in
vehicle-treated cells. The results are shown in FIG. 1.
Hyperosmolarity significantly induced IL-6 and IL-8 production from
CEPl-17 cells under the conditions described. Dexamethasone
significantly inhibited secretion of each cytokine at 100 nM.
Anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) dose-dependently
inhibited both IL-6 (IC.sub.50=12.6 .mu.M) and IL-8 (IC.sub.50=3.7
.mu.M) production.
[0037] This invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its special or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *