U.S. patent application number 15/670684 was filed with the patent office on 2017-11-23 for treatment of ocular inflammatory diseases using laquinimod.
This patent application is currently assigned to Teva Pharmaceutical Industries, Ltd.. The applicant listed for this patent is Hussein Hallak, Joel Kaye, Nora Tarcic. Invention is credited to Hussein Hallak, Joel Kaye, Nora Tarcic.
Application Number | 20170333420 15/670684 |
Document ID | / |
Family ID | 49671002 |
Filed Date | 2017-11-23 |
United States Patent
Application |
20170333420 |
Kind Code |
A1 |
Kaye; Joel ; et al. |
November 23, 2017 |
TREATMENT OF OCULAR INFLAMMATORY DISEASES USING LAQUINIMOD
Abstract
Disclosed is a method for treating an ocular inflammatory
disease (OID), e.g., uveitis or conjunctivitis, comprising periodic
administration of a therapeutically effective amount of laquinimod
or a pharmaceutically acceptable salt thereof. Also provided is a
pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof for use in treating a
subject suffering from an OID, uveitis, bacterial conjunctivitis,
viral conjunctivitis, an inflammation of the orbital tissue, the
lacrimal apparatus, the eyelid, the cornea, the retina or the optic
pathway. This application also provides a method for treating a
subject suffering from an autoimmune disease-associated ocular
inflammation comprising periodic ocular administration to the
subject a therapeutically effective amount of laquinimod or a
pharmaceutically acceptable salt, and an ocular pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in treating an autoimmune disease-associated
ocular inflammation.
Inventors: |
Kaye; Joel; (Netanya,
IL) ; Hallak; Hussein; (East Jerusalem, IL) ;
Tarcic; Nora; (Modiin, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kaye; Joel
Hallak; Hussein
Tarcic; Nora |
Netanya
East Jerusalem
Modiin |
|
IL
IL
IL |
|
|
Assignee: |
Teva Pharmaceutical Industries,
Ltd.
Petach-Tikva
IL
|
Family ID: |
49671002 |
Appl. No.: |
15/670684 |
Filed: |
August 7, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15582162 |
Apr 28, 2017 |
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15670684 |
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13909403 |
Jun 4, 2013 |
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15582162 |
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61655526 |
Jun 5, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 37/06 20180101; A61K 9/0053 20130101; A61P 27/14 20180101;
A61K 9/0048 20130101; A61P 29/00 20180101; A61K 9/08 20130101; A61P
37/08 20180101; A61K 31/4704 20130101 |
International
Class: |
A61K 31/4704 20060101
A61K031/4704; A61K 9/00 20060101 A61K009/00; A61K 9/08 20060101
A61K009/08 |
Claims
1. A method of treating a subject suffering from an ocular
inflammatory disease, the method comprising periodic administration
to the subject of a therapeutically effective amount of laquinimod
or a pharmaceutically acceptable salt thereof effective to treat
the subject.
2. The method of claim 1, wherein the therapeutically effective
amount of laquinimod is effective to reduce a symptom of the ocular
inflammatory disease in the subject, induce clinical response,
induce or maintain clinical remission, inhibit disease progression,
inhibit a disease complication, reduce intraocular inflammation or
reduce retina tissue destruction in the subject.
3. The method of claim 1 or 2, wherein the ocular inflammatory
disease is uveitis, bacterial conjunctivitis, viral conjunctivitis,
or an inflammation of the orbital tissue, the lacrimal apparatus,
the eyelid, the cornea, the retina or the optic pathway.
4. The method of claim 3, wherein the ocular inflammatory disease
is conjunctivitis and the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to reduce a symptom of conjunctivitis in the subject.
5. The method of claim 3, wherein the ocular inflammatory disease
is uveitis and the therapeutically effective amount of laquinimod
or pharmaceutically acceptable salt thereof is effective to reduce
a symptom of uveitis in the subject.
6. The method of claim 5, wherein the uveitis is anterior uveitis,
intermediate uveitis, posterior uveitis, or diffuse uveitis.
7. The method of claim 3, wherein the ocular inflammatory disease
is an inflammation of the orbital tissue, the lacrimal apparatus,
the eyelid, the cornea, the retina or the optic pathway and the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reduce a symptom of the
inflammation in the subject.
8. The method of any one of claims 1-7, wherein the laquinimod or
pharmaceutically acceptable salt thereof is administered in the
form of a liquid or a gel.
9. The method of claim 8, wherein the concentration of laquinimod
or pharmaceutically acceptable salt thereof in the liquid or gel
5-100 mg/ml solution.
10. The method of claim 9, wherein the concentration of laquinimod
or pharmaceutically acceptable salt thereof is 10-15 mg/ml
solution.
11. The method of any one of claims 1-10, wherein the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is 0.05-4.0 mg per administration.
12. The method of claim 11, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
0.05-2.0 mg per administration.
13. The method of claim 12, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
about 0.1 mg per administration.
14. The method of claim 12, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
about 0.5 mg per administration.
15. The method of claim 1 or 2, wherein the ocular inflammatory
disease is allergic conjunctivitis or uveitis and wherein the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is at least 0.2 mg/day.
16. The method of claim 15, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
effective to reduce a symptom of the allergic conjunctivitis or
uveitis in the subject.
17. The method of claim 15 or 16, wherein the therapeutically
effective amount of laquinimod or pharmaceutically acceptable salt
thereof is effective to inhibit late ocular anaphylaxis in the
subject
18. The method of any one of claims 15-17, wherein the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reduce eosinophil
infiltration into the conjunctiva of the subject.
19. The method of claim 18, wherein the eosinophil infiltration
into the conjunctiva is measured by eosinophil density in the
conjunctiva.
20. The method of claim 19, wherein the eosinophil density is
reduced by at least 40% as compared to a subject not administered
laquinimod or pharmaceutically acceptable salt thereof.
21. The method of claim 20, wherein the eosinophil density is
reduced by at least 60% as compared to a subject not administered
laquinimod or pharmaceutically acceptable salt thereof.
22. The method of any one of claims 15-21, wherein the laquinimod
or pharmaceutically acceptable salt thereof is administered in the
form of a liquid or a gel.
23. The method of claim 22, wherein the concentration of laquinimod
or pharmaceutically acceptable salt thereof in the liquid or gel is
20-100 mg/ml solution.
24. The method of claim 23, wherein the concentration of laquinimod
or pharmaceutically acceptable salt thereof is 20-50 mg/ml
solution.
25. The method of any one of claims 15-24, wherein the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is 0.2-4.0 mg per administration.
26. The method of claim 25, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
0.2-2.0 mg per administration.
27. The method of claim 26, wherein the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
about 0.5 mg per administration.
28. The method of any one of claims 1-27, wherein the periodic
administration is once per day.
29. The method of any one of claims 1-28, wherein the periodic
administration is oral administration.
30. The method of any one of claims 1-29, wherein the periodic
administration is ocular administration.
31. The method of any one of claims 1-30, wherein the
pharmaceutically acceptable salt of laquinimod is laquinimod
sodium.
32. The method of any one of claims 1-31, wherein the subject is a
human.
33. A pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof for use in treating a
subject suffering from an ocular inflammatory disease.
34. A pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof for use in treating a
subject suffering from uveitis, bacterial conjunctivitis, viral
conjunctivitis, or an inflammation of the orbital tissue, the
lacrimal apparatus, the eyelid, the cornea, the retina or the optic
pathway.
35. A pharmaceutical composition for use in treating a subject
suffering from allergic conjunctivitis or uveitis comprising a unit
dose of 10 .mu.L of an aqueous pharmaceutical solution which
contains in solution at least 0.2 mg laquinimod or a
pharmaceutically acceptable salt thereof.
36. A method of treating a subject suffering from an autoimmune
disease-associated ocular inflammation, the method comprising
periodic ocular administration to the subject of a therapeutically
effective amount of laquinimod or a pharmaceutically acceptable
salt thereof effective to treat the subject.
37. An ocular pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof for use in treating an
autoimmune disease-associated ocular inflammation.
Description
[0001] This application claims benefit of U.S. Provisional
Application No. 61/655,526, filed Jun. 5, 2012, the entire content
of which is hereby incorporated by reference herein.
[0002] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] Ocular Inflammatory Disease ("OID") is a general term for
describing inflammation affecting one or more parts of the eye or
surrounding eye tissue. Uveitis is the inflammation of the uvea or
the uveal tract, which includes the iris, the ciliary body and the
choroid portions of the eye. Inflammation of the overlying retina,
called retinitis, or of the optic nerve, called optic neuritis, may
occur with or without accompanying uveitis. Anatomically, uveitis
may be classified as anterior, intermediate, posterior or diffuse,
depending on the portion of the uveal tract that is affected.
Anterior uveitis is localized primarily to the anterior segment of
the eye and includes iritis and iridocyclitis. Intermediate
uveitis, also called peripheral uveitis, is centered in the area
immediately behind the iris and lens in the region of the ciliary
body and pars plana, hence the alternate terms "cyclitis` and "pars
planitis." Posterior uveitis signifies any of a number of forms of
retinitis, choroiditis, or optic neuritis. Diffuse uveitis implies
inflammation involving all parts of the eye, including anterior,
intermediate, and posterior structures (The Merck Manual,
1999).
[0004] Inflammation from uveitis may result in a variety of other
eye conditions, including glaucoma, cataracts, and cystoid macular
edema, and ultimately may lead to permanent vision loss. Uveitis is
the third leading cause of blindness in the developed world. There
is no one root cause of uveitis or other OID. Causes range from
infections by certain bacteria, parasites, fungus, and viruses;
trauma; autoimmune disease; inducement by certain drugs such as
bisphosphonates or sulfaonamides; and inducement by certain
malignant cancers such as lymphoma.
[0005] Conjunctivitis is another OID that causes inflammation of
the conjunctival tissue. The conjunctiva is the thin, transparent
layer of tissue that covers the outside surface of the eye,
including the cornea and the visible sclera (the white part of the
eye), and also lines the eyelids. The conjunctiva secretes oils and
mucus and is responsible for moistening and lubricating the eye.
There are several types of conjunctivitis, some more severe than
others. Seasonal and perennial allergic conjunctivitis (SAC and
PAC) are generally associated with allergic reactions. The more
severe vernal and atopic keratoconjunctivitis (VKC and AKC) are
also associated with hypersensitivity to an allergen, but
inflammation occurs in both the conjunctiva and the cornea. VKC is
intermittent and often occurs seasonally, most commonly in summer,
while AKC does not have a seasonal component. Symptoms of SAC and
PAC include itching, swelling and tearing while symptoms for VKC
and AKC are more severe and include pain, visual loss and corneal
scarring.
[0006] Generally, allergic eye reactions such as that caused by OID
consist of two different phase reactions, early-phase reaction and
late phase reaction, and each reaction has different cell types
considered to be the major effector cells for production of the eye
disease. Early-phase reaction, which occurs with SAC and PAC, for
example, involves mast cells as the major effector cells, while
late-phase reaction, which occurs with VKC and AKC, for example,
involves eosinophils as the major effector cells.
[0007] Current therapies for allergic conjunctivitis include
anti-allergics with antihistamine and mast cell stabilizing
functions for treatment of SAC, steroids for PAC, and steroids
and/or cyclosporine A for AKC and VKC. There is a need for
additional treatment of OID.
SUMMARY OF THE INVENTION
[0008] Disclosed is a method of treating ocular inflammatory
disease (OID), including uveitis and conjunctivitis, using
laquinimod or a pharmaceutically acceptable salt thereof.
Laquinimod is a novel synthetic compound with high oral
bioavailability, which has been suggested as an oral formulation
for Relapsing Remitting Multiple Sclerosis (RRMS). Laquinimod and
its sodium salt form are described, for example, in U.S. Pat. No.
6,077,851.
[0009] This application provides a method of treating a subject
suffering from an ocular inflammatory disease (OID), the method
comprising periodic administration to the subject of a
therapeutically effective amount of laquinimod or a
pharmaceutically acceptable salt thereof effective to treat the
subject.
[0010] This application also provides a pharmaceutical composition
comprising laquinimod or a pharmaceutically acceptable salt thereof
for use in treating a subject suffering from an ocular inflammatory
disease.
[0011] This application also provides a pharmaceutical composition
comprising laquinimod or a pharmaceutically acceptable salt thereof
for use in treating a subject suffering from uveitis, bacterial
conjunctivitis, viral conjunctivitis, or an inflammation of the
orbital tissue, the lacrimal apparatus, the eyelid, the cornea, the
retina or the optic pathway.
[0012] This application also provides a pharmaceutical composition
for use in treating a subject suffering from allergic
conjunctivitis or uveitis comprising a unit dose of 10 .mu.L of an
aqueous pharmaceutical solution which contains in solution at least
0.2 mg laquinimod or a pharmaceutically acceptable salt
thereof.
[0013] This application also provides a method of treating a
subject suffering from an autoimmune disease-associated ocular
inflammation, the method comprising periodic ocular administration
to the subject a therapeutically effective amount of laquinimod or
a pharmaceutically acceptable salt thereof effective to treat the
subject.
[0014] This application also provides an ocular pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in treating an autoimmune disease-associated
ocular inflammation.
DETAILED DESCRIPTION OF THE INVENTION
[0015] This application provides for a method of treating a subject
suffering from an ocular inflammatory disease (OID), the method
comprising periodic administration to the subject of a
therapeutically effective amount of laquinimod or a
pharmaceutically acceptable salt thereof effective to treat the
subject.
[0016] In one embodiment, the ocular inflammatory disease is
uveitis, bacterial conjunctivitis, viral conjunctivitis, or an
inflammation of the orbital tissue, the lacrimal apparatus, the
eyelid, the cornea, the retina or the optic pathway. In an
embodiment, the OID is conjunctivitis. In another embodiment, the
conjunctivitis is bacterial conjunctivitis. In yet another
embodiment, the conjunctivitis is viral conjunctivitis.
[0017] In one embodiment, the OID is uveitis. In another
embodiment, the uveitis is anterior uveitis. In another embodiment,
the uveitis is intermediate uveitis. In another embodiment, the
uveitis is posterior uveitis. In yet another embodiment, the
uveitis is diffuse uveitis.
[0018] In one embodiment, the therapeutically effective amount of
laquinimod a pharmaceutically acceptable salt thereof is effective
to reduce a symptom of the ocular inflammatory disease in the
subject, induce clinical response, induce or maintain clinical
remission, inhibit disease progression, inhibit a disease
complication, reduce intraocular inflammation or reduce retina
tissue destruction in the subject. In another embodiment, the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reduce one or more symptoms
of the OID in the subject. In another embodiment, the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reverse the progression of
the OID. In another embodiment, the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
effective to induce a clinical response or induce or maintain
clinical remission in the subject suffering from the OID. In
another embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to inhibit disease progression or disease complication in the
subject suffering from the OID. In another embodiment, the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to decrease eosinophil
infiltration at the site of inflammation. In another embodiment,
the therapeutically effective amount of laquinimod or
pharmaceutically acceptable salt thereof is effective to reduce
intraocular inflammation. In yet another embodiment, the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reduce retina tissue
destruction in the subject.
[0019] In one embodiment of the present invention, the OID is
conjunctivitis and the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to reduce a symptom of conjunctivitis in the subject. In another
embodiment of the present invention, the OID is uveitis and the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is effective to reduce a symptom of uveitis
in the subject. In yet another embodiment of the present invention,
the ocular inflammatory disease is an inflammation of the orbital
tissue, the lacrimal apparatus, the eyelid, the cornea, the retina
or the optic pathway and the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to reduce a symptom of the inflammation in the subject.
[0020] In one embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered topically. In another
embodiment, administration of the laquinimod or pharmaceutically
acceptable salt thereof is ocular administration. In another
embodiment, administration of the laquinimod or pharmaceutically
acceptable salt thereof is oral administration. In another
embodiment the periodic administration is local administration. In
another embodiment, the laquinimod or pharmaceutically acceptable
salt thereof is administered to the affected eye of the
subject.
[0021] In one embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered in the form of a liquid or
a gel. In another embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered in liquid form. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered in a liquid eye drop. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered in gel form.
[0022] In one embodiment, the concentration of laquinimod or
pharmaceutically acceptable salt thereof in the liquid or gel is
0.5% (5 mg/ml)-10.0% (100 mg/ml). In another embodiment, the
concentration of laquinimod or pharmaceutically acceptable salt
thereof is 1.0% (10 mg/ml)-7.0% (70 mg/ml). In another embodiment,
the concentration of laquinimod or pharmaceutically acceptable salt
thereof is 1.0% (10 mg/ml)-5.0% (50 mg/ml). In another embodiment,
the concentration of laquinimod or pharmaceutically acceptable salt
thereof is about 1.0% (10 mg/ml). In another embodiment, the
concentration of laquinimod or pharmaceutically acceptable salt
thereof is about 5.0% (50 mg/ml). In an embodiment, the volume of
liquid or gel per administration is about 10 .mu.l. As used herein
"mg/ml" designates the amount (mg) of laquinimod or
pharmaceutically acceptable salt thereof per volume (ml) of
solution.
[0023] In another embodiment, the therapeutically effective amount
of laquinimod or pharmaceutically acceptable salt thereof is
0.05-4.0 mg per administration. In another embodiment, the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is 0.05-2.0 mg per administration. In
another embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is about 0.1
mg per administration. In another embodiment, the therapeutically
effective amount of laquinimod or pharmaceutically acceptable salt
thereof is about 0.5 mg per administration. In yet another
embodiment, the therapeutically effective amount of laquinimod or
pharmaceutically acceptable salt thereof is at least 0.02
mg/day.
[0024] In an embodiment, the periodic administration is 1-5 times a
day. In one embodiment, the periodic administration is once a day.
In another embodiment, the periodic administration is twice a day.
In another embodiment, the periodic administration is three times a
day. In yet another embodiment, the periodic administration is once
every 2 days.
[0025] In an embodiment of the invention, the laquinimod or
pharmaceutically acceptable salt thereof is administered once daily
for a period of 2 to 14 days. In another embodiment, the laquinimod
or pharmaceutically acceptable salt thereof is administered once
daily for a period of 5 to 14 days. In another embodiment, the
laquinimod or pharmaceutically acceptable salt thereof is
administered once daily for a period of 10 to 14 days. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered once daily for about 7 days.
[0026] In an embodiment of the present invention, the ocular
inflammatory disease is uveitis and the therapeutically effective
amount of laquinimod or pharmaceutically acceptable salt thereof is
at least 0.2 mg/day.
[0027] In another embodiment of the present invention, the ocular
inflammatory disease is allergic conjunctivitis and the
therapeutically effective amount of laquinimod or pharmaceutically
acceptable salt thereof is at least 0.2 mg/day. In another
embodiment, the OID is seasonal allergic conjunctivitis (SAC) or
perennial allergic conjunctivitis (PAC). In another embodiment, the
OID is atopic keratoconjunctivitis (AKC) or vernal
keratoconjunctivitis (VKC).
[0028] In one embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to reduce a symptom of the conjunctivitis in the subject. In
another embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is effective
to inhibit late ocular anaphylaxis in the subject. In another
embodiment, the therapeutically effective amount of laquinimod or
pharmaceutically acceptable salt thereof is effective to reduce
eosinophil infiltration in to the conjunctiva of the subject. In
yet another embodiment, the eosinophil infiltration into the
conjunctiva is measured by eosinophil density in the
conjunctiva.
[0029] In one embodiment, the eosinophil density is reduced by at
least 40% as compared to a subject not administered laquinimod or
pharmaceutically acceptable salt thereof. In another embodiment,
the eosinophil density is reduced by at least 45% as compared to a
subject not administered laquinimod or pharmaceutically acceptable
salt thereof. In another embodiment, the eosinophil density is
reduced by at least 50% as compared to a subject not administered
laquinimod or pharmaceutically acceptable salt thereof. In another
embodiment, the eosinophil density is reduced by at least 55% as
compared to a subject not administered laquinimod or
pharmaceutically acceptable salt thereof. In another embodiment,
the eosinophil density is reduced by at least 60% as compared to a
subject not administered laquinimod or pharmaceutically acceptable
salt thereof. In yet another embodiment, the eosinophil density is
reduced by at least 65% as compared to a subject not administered
laquinimod or pharmaceutically acceptable salt thereof.
[0030] In one embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered topically. In another
embodiment, administration of the laquinimod or pharmaceutically
acceptable salt thereof is ocular administration. In another
embodiment, administration of the laquinimod or pharmaceutically
acceptable salt thereof is oral administration. In another
embodiment the periodic administration is local administration. In
another embodiment, the laquinimod or pharmaceutically acceptable
salt thereof is administered to the affected eye of the
subject.
[0031] In one embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered in the form of a liquid or
a gel. In another embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is administered in liquid form. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered in a liquid eye drop. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered in gel form.
[0032] In one embodiment, the concentration of laquinimod or
pharmaceutically acceptable salt thereof in the liquid or gel is
2.0% (20 mg/ml)-10.0% (100 mg/ml). In another embodiment, the
concentration of laquinimod or pharmaceutically acceptable salt
thereof is 2.0% (20 mg/ml)-7.0% (70 mg/ml). In another embodiment,
the concentration of laquinimod or pharmaceutically acceptable salt
thereof is 2.0% (20 mg/ml)-5.0% (50 mg/ml). In another embodiment,
the concentration of laquinimod or pharmaceutically acceptable salt
thereof is about 5.0% (50 mg/ml). In an embodiment, the volume of
liquid or gel per administration is about 10 .mu.l. As used herein
"mg/ml" designates the amount (mg) of laquinimod or
pharmaceutically acceptable salt thereof per volume (ml) of
solution.
[0033] In one embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is 0.2-4.0
mg per administration. In another embodiment, the therapeutically
effective amount of laquinimod or pharmaceutically acceptable salt
thereof is 0.2-2.0 mg per administration. In yet another
embodiment, the therapeutically effective amount of laquinimod or
pharmaceutically acceptable salt thereof is about 0.5 mg per
administration.
[0034] In an embodiment, the periodic administration is 1-5 times a
day. In one embodiment, the periodic administration is once a day.
In another embodiment, the periodic administration is twice a day.
In another embodiment, the periodic administration is three times a
day. In yet another embodiment, the periodic administration is once
every 2 days.
[0035] In an embodiment of the invention, the laquinimod or
pharmaceutically acceptable salt thereof is administered once daily
for a period of 2 to 14 days. In another embodiment, the laquinimod
or pharmaceutically acceptable salt thereof is administered once
daily for a period of 5 to 14 days. In another embodiment, the
laquinimod or pharmaceutically acceptable salt thereof is
administered once daily for a period of 10 to 14 days. In another
embodiment, the laquinimod or pharmaceutically acceptable salt
thereof is administered once daily for about 7 days.
[0036] In one embodiment, the laquinimod or pharmaceutically
acceptable salt thereof is in a pharmaceutical composition which
comprises a pharmaceutically acceptable carrier. In another
embodiment, the pharmaceutical composition is in the form of a
tablet or capsule. In another embodiment, the pharmaceutical
composition is a liquid solution. In another embodiment, the liquid
solution is prepared by dissolving laquinimod or a pharmaceutically
acceptable salt thereof in a sterile pH-neutral solution. In one
embodiment, the pH-neutral solution is saline. In another
embodiment, the pH-neutral solution is phosphate buffered saline
(PBS). In another embodiment, the pH-neutral solution is sterile
water.
[0037] In one embodiment, the pharmaceutical composition is a gel.
In another embodiment, the pharmaceutically acceptable carrier is
hydrophilic. In another embodiment, the pharmaceutically acceptable
carrier comprises at least one gelling or suspension agent.
Examples of suitable gelling or suspension agents known in the art
include carbomers, modified cellulose derivatives,
naturally-occurring, synthetic or semi-synthetic gums such as
xanthan gum, acacia and tragacanth, modified starches, co-polymers
such as those formed between maleic anhydride and methyl vinyl
ether, colloidal silica and methacrylate derivatives sold under the
trade name EUDRAGIT.RTM. (available from Evonik Industries, Essen,
Germany) or a mixture thereof. In another embodiment, the
pharmaceutically acceptable carrier comprises at least one
surfactant or emulsifying agent compatible with any
pharmacologically active agents or pharmaceutically acceptable
components present. In one embodiment, the surfactants include
non-ionic, cationic and anionic surfactants. In another embodiment,
the surfactants include non-ionic surfactants such as sorbitan
fatty acid esters (SPANS.RTM.) and the corresponding
polyoxyethylene (POE) adducts (TWEENS.RTM.).
[0038] In an embodiment, the pharmaceutically acceptable salt of
laquinimod includes lithium, sodium, potassium, magnesium, calcium,
manganese, copper, zinc, aluminum and iron. Salt formulations of
laquinimod and the process for preparing the same are described in,
e.g., U.S. Patent Application Publication No. 2005/0192315 and PCT
International Application Publication No. WO 2005/074899, each of
which is hereby incorporated by reference into this application. In
one embodiment, the pharmaceutically acceptable salt of laquinimod
is laquinimod sodium.
[0039] In an embodiment of the invention, the method comprises
topically administering to the affected eye of the subject a 5.0%
(50 mg/ml) solution of laquinimod sodium once per day for a period
of 14 days. In another embodiment, the method comprises topically
administering to the affected eye of the subject a 5.0% (50 mg/ml)
solution of laquinimod sodium once per day for a period of 10
days.
[0040] In an embodiment, the therapeutically effective amount of
laquinimod or pharmaceutically acceptable salt thereof is 1.0-1.5
mg/day. In another embodiment, the therapeutically effective amount
of laquinimod or pharmaceutically acceptable salt thereof is 1.2
mg/day. In another embodiment, the therapeutically effective amount
of laquinimod or pharmaceutically acceptable salt thereof is at
least 0.2 mg/day.
[0041] In an embodiment of the invention, the subject is human.
[0042] This application also provides for a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in treating a subject suffering from an ocular
inflammatory disease.
[0043] This application also provides for a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in treating a subject suffering from uveitis,
bacterial conjunctivitis, viral conjunctivitis, or an inflammation
of the orbital tissue, the lacrimal apparatus, the eyelid, the
cornea, the retina or the optic pathway.
[0044] This application also provides for a pharmaceutical
composition for use in treating a subject suffering from allergic
conjunctivitis or uveitis comprising a unit dose of 10 .mu.L of an
aqueous pharmaceutical solution which contains in solution at least
0.2 mg laquinimod or a pharmaceutically acceptable salt thereof. In
an embodiment, the pharmaceutical composition is an ocular
pharmaceutical composition.
[0045] This application also provides for a pharmaceutical
composition comprising a therapeutically effective amount of
laquinimod or a pharmaceutically acceptable salt thereof for use in
treating a subject suffering from uveitis, bacterial
conjunctivitis, viral conjunctivitis, or an inflammation of the
orbital tissue, the lacrimal apparatus, the eyelid, the cornea, the
retina or the optic pathway. In an embodiment, the pharmaceutical
composition is an ocular pharmaceutical composition.
[0046] This application provides for a method of reducing
eosinophil density in the conjunctival tissue of a subject
comprising periodically administering to the subject an amount of
laquinimod or a pharmaceutically acceptable salt thereof effective
to reduce the eosinophil density in the conjunctival tissue of the
subject. This application also provides for a method of reducing
intraocular inflammation in a subject comprising periodically
administering to the subject an amount of laquinimod or a
pharmaceutically acceptable salt thereof effective to reduce
intraocular inflammation in the subject. This application also
provides for a method of reducing retina tissue destruction in a
subject comprising periodically administering to the subject an
amount of laquinimod or a pharmaceutically acceptable salt thereof
effective to reduce retina tissue destruction in the subject. In an
embodiment, the amount of laquinimod or pharmaceutically acceptable
salt thereof is a therapeutically effective amount. In another
embodiment, the administration is ocular administration.
[0047] This application also provides for a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in reducing eosinophil density in the
conjunctival tissue of a subject or for reducing intraocular
inflammation or destruction of retina tissue in a subject. In an
embodiment, the pharmaceutical composition comprises a
therapeutically effective amount of laquinimod of a
pharmaceutically acceptable salt thereof. In another embodiment,
the pharmaceutical composition is an ocular pharmaceutical
composition.
[0048] This application also provides a method of treating a
subject suffering from an autoimmune disease-associated ocular
inflammation, the method comprising periodic ocular administration
to the subject of a therapeutically effective amount of laquinimod
or a pharmaceutically acceptable salt thereof effective to treat
the subject.
[0049] This application also provides an ocular pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof for use in treating an autoimmune disease-associated
ocular inflammation.
[0050] All combinations of the various elements described herein
are within the scope of the invention.
Definitions
[0051] "Ocular inflammatory diseases" or "OID" as used herein means
the inflammation affecting one or more parts of the eye or
surrounding eye tissue other than inflammation resulting from an
autoimmune disease. OID may include, but is not limited to,
inflammation of the orbital tissues, the lacrimal apparatus, the
eyelid, the conjunctiva (conjunctivitis), the cornea, the retina, a
component of the optic pathway, e.g., the optic nerve, and a
component of the uveal tract (uveitis), i.e., the iris, ciliary
body and choroid. Specific examples of OID include uveitis, acute
conjunctivitis, viral conjunctivitis, nongonococcal bacterial
conjunctivitis, adult gonococcal conjunctivitis, inclusion
conjunctivitis, seasonal allergic conjunctivitis, chronic
conjunctivitis, granular conjunctivitis, perennial allergic
conjunctivitis, episcleritis, scleritis, atopic
keratoconjunctivitis, and vernal keratoconjunctivitis.
[0052] Unlike the use of the term OID herein, the literature may
use the term in a less definite manner to refer to ocular
inflammation generally, and often including ocular inflammation
secondary to an underlying systemic inflammatory disease different
from inflammation which represents localized pathologic process
without systemic involvement (Gordon, 2006; Rothova et al., 1992;
Optometric Clinical Practice Guideline, 2002.) For example,
conjunctivitis may result from primary involvement of the
conjunctival tissue or may occur secondary to other systemic
conditions that produce conjunctival inflammation (Optometric
Clinical Practice Guideline, 2002.) In one study conducted by
Rothova et al., systemic disease which could be considered to be
causally related to ocular inflammation was diagnosed in 26% of the
865 uveitis patients observed (Rothova et al.). However, as used
herein OID specifically excludes ocular inflammation which results
from an underying, systemic, autoimmune disease.
[0053] As used herein "autoimmune disease-associated ocular
inflammation" is the inflammation affecting one or more parts of
the eye or surrounding eye tissue secondary to an autoimmune
disease, and is specifically excluded from the definition of OID
herein.
[0054] Autoimmune diseases contemplated by the present invention
include either cell-mediated disease (e.g., T-cell) or antibody
mediated (e.g., B-cell) disorders. Such disorders can be inter alia
arthritic conditions, demyelinating diseases and inflammatory
diseases. For Example, autoimmune diseases contemplated herein
include multiple sclerosis, autoimmune hemolytic anemia, autoimmune
oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis,
Crohn's disease, chronic immune thrombocytopenic purpura, colitis,
contact sensitivity disease, diabetes mellitus, Grave's disease,
Guillain-Barre's syndrome, Hashimoto's disease, idiopathic
myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris,
rheumatoid arthritis, and systemic lupus erythematosus.
[0055] "Administering to the subject" means the giving of,
dispensing of, or application of medicines, drugs, or remedies to a
subject to relieve, cure, or reduce the symptoms associated with a
condition, e.g., a pathological condition. The route of
administration can be, e.g., topical. Routes of administration can
also be classified by whether the effect is local (e.g., in topical
administration) or systemic (e.g., in enteral or parenteral
administration). "Local administration" as used herein shall mean
administration of a compound or composition directly to where its
action is desired, and specifically excludes systemic
administration. "Topical administration" of a compound or
composition as used herein shall mean application of the compound
or composition to body surfaces such as the skin or mucous
membranes such as eyes. "Ocular administration" as used herein
shall mean application of a compound or composition to the eye of a
subject or to the skin around the eye (periocular skin) of a
subject, i.e., local administration. Examples of ocular
administration include topical administration directly to the eye,
topical application to the eye lid or injection into a portion of
the eye or eye socket. In addition, an "ocular pharmaceutical
composition" as used herein means a pharmaceutical composition
formulated for ocular administration.
[0056] An "amount" or "dose" of laquinimod as measured in
milligrams refers to the milligrams of laquinimod acid present in a
preparation, regardless of the form of the preparation.
[0057] "Unit dose" as used herein is the amount of a compound or
composition to be administered to the subject in a single
administration. The unit dose disclosed herein can be administered
once daily, twice daily, three times daily, four times daily, five
times daily, every other day, weekly, twice weekly, three times
weekly, four times weekly, five times weekly or six times
weekly.
[0058] "About" in the context of a numerical value or range means
.+-.10% of the numerical value or range recited or claimed.
[0059] As used herein, "treating" encompasses, e.g., inducing
inhibition, regression, or stasis of a disease, disorder or
condition, or ameliorating or alleviating a symptom of a disease,
disorder or condition. "Ameliorating" or "alleviating" a condition
or state as used herein shall mean to relieve or lessen the
symptoms of that condition or state. "Inhibition" of disease
progression or disease complication in a subject as used herein
means preventing or reducing the disease progression and/or disease
complication in the subject.
[0060] As used herein, "effective" as in an amount effective to
achieve an end, i.e., "therapeutically effective amount", means the
quantity of a component that is sufficient to yield an indicated
therapeutic response without undue adverse side effects (such as
toxicity, irritation, or allergic response) commensurate with a
reasonable benefit/risk ratio when used in the manner of this
disclosure. For example, an amount effective to reduce
inflammation. The specific effective amount will vary with such
factors as the particular condition being treated, the physical
condition of the patient, the type of mammal being treated, the
duration of the treatment, the nature of concurrent therapy (if
any), and the specific formulations employed and the structure of
the compounds or its derivatives.
[0061] A "salt" is salt of the instant compounds which have been
modified by making acid or base salts of the compounds. The term
"pharmaceutically acceptable salt" in this respect, refers to the
relatively non-toxic, inorganic and organic acid or base addition
salts of compounds of the present invention. A pharmaceutically
acceptable salt of laquinimod as used in this application includes
lithium, sodium, potassium, magnesium, calcium, manganese, copper,
zinc, aluminum and iron. Salt formulations of laquinimod and the
process for preparing the same are described, e.g., in U.S. Pat.
No. 7,589,208 and PCT International Application Publication No. WO
2005/074899, which are hereby incorporated by reference into this
application.
[0062] Laquinimod can be administered in admixture with suitable
pharmaceutical diluents, extenders, excipients, or carriers
(collectively referred to herein as a pharmaceutically acceptable
carrier) suitably selected with respect to the intended form of
administration and as consistent with conventional pharmaceutical
practices. The unit will be in a form suitable for topical
administration. Laquinimod can be administered alone but is
generally mixed with a pharmaceutically acceptable carrier. As used
herein, "pharmaceutically acceptable carrier" refers to a carrier
or excipient that is suitable for use with humans and/or animals
without undue adverse side effects (such as toxicity, irritation,
and allergic response) commensurate with a reasonable benefit/risk
ratio. It can be a pharmaceutically acceptable solvent, suspending
agent or vehicle, for delivering the instant compounds to the
subject.
[0063] General techniques and compositions for making dosage forms
useful in the present invention are described in the following
references: Modern Pharmaceutics, Chapters 9 and 10 (Banker &
Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets
(Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical
Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical
Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985);
Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones,
Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David
Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous
Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the
Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);
Pharmaceutical Particulate Carriers: Therapeutic Applications:
Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,
1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood
Books in the Biological Sciences. Series in Pharmaceutical
Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds); Modern
Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40
(Gilbert S. Banker, Christopher T. Rhodes, Eds). These references
in their entireties are hereby incorporated by reference into this
application.
[0064] It is understood that where a parameter range is provided,
all integers within that range, including tenths thereof, are also
provided by the invention. For example, "5-10%" includes 5.0%,
5.1%, 5.2%, 5.3%, 5.4% etc. up to 10.0%.
[0065] Immunomodulatory agents have been suggested for treating
certain ocular inflammatory diseases (Foster 2003; Mishra 2011;
Shah 1992). However, not all immunomodulatory agents are
appropriate for OID. For example, fingolimod (Gilenya.RTM. from
Novartis AG), an immunomodulatory agent, is known to pose a risk of
macular edema in patients with a history of uveitis. (Sergott,
2011) The effects of laquinimod on OID have not been previously
reported.
[0066] In addition, in accordance with the present invention, a
therapeutically effective amount of laquinimod or a
pharmaceutically acceptable salt thereof is delivered to a subject
via ocular administration. As discussed in Example 2 to follow, not
all amounts of laquinimod or a pharmaceutically acceptable salt
thereof are "therapeutically effective amounts". A therapeutically
effective amount or means for determining a therapeutically
effective amount for ocular/local administration of laquinimod have
not been previously reported.
[0067] This invention will be better understood by reference to the
Experimental Examples which follow, but those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention as described more fully in the
claims which follow thereafter.
EXPERIMENTAL EXAMPLES
Example 1: Evaluation of Efficacy Following Daily Topical
Administration of Laquinimod in S-Antigen-Induced Experimental
Autoimmune Uveitis in Rats (EAU Model)
General.
[0068] A 1% (10 mg/ml) and a 5% (50 mg/ml) solution of laquinimod
sodium were prepared in sterile water. Dissolution of laquinimod
powder was achieved by shaking, stirring, or low-speed vortex. The
solutions were stored for up to 2 weeks at 2-8.degree. C. and up to
24 hours at room temperature. Laquinimod solutions were prepared
under light protection and were protected from light for the
duration of the experiment. Cyclosporine A was used as a reference
material at a concentration of 25 mg/kg/j (Fluka). One 100 mg/4 ml
in olive oil dose was prepared every 2 days and stored at room
temperature.
Animals and Animal Husbandry.
[0069] Thirty two (32) female albino Lewis rats, approximately 8
weeks old, were used for this study. All rats were held in
observation for at least 3 days to monitor for signs of ill health
or ocular abnormalities. Only healthy animals were accepted for use
in this study. The rats were housed under identical environmental
conditions, with a relative humidity of 55%.+-.10%, continuous
ventilation, and an automatic hour light/dark cycle. Environmental
conditions were continuously controlled and recorded. Animals had
free access to food and water.
Materials and Methods.
[0070] Thirty two female albino Lewis rats were randomly divided
into four (4) groups of eight (8) rats. Ocular inflammation was
induced at Day 1 by injection of 100 .mu.l of human S-antigen (100
.mu.g) in Freud's complete adjuvant (4 mg/ml) into the footpad of
each rat, and an intraperitoneal injection of 1 .mu.g/100 .mu.l
pertussis toxin. Disease onset was typically observed between Days
9 and 12 after immunization, and the disease state peaked around
Days 16 to 18. The study was halted when at least 60% of the
vehicle group showed signs of inflammation.
[0071] Beginning on Day 7 until the end of the study, each animal
group was treated with a test solution in both eyes as shown in
Table 1:
TABLE-US-00001 TABLE 1 Group Treatment Frequency 1 1% Laquinimod
Once Daily (10 .mu.l) 2 5% Laquinimod Once Daily (10 .mu.l) 3
Vehicle Once Daily (10 .mu.l) 4 Cyclosporine A (25 mg/kg) Once
Daily per os (1 ml/kg)
[0072] Both eyes of each rat were examined with a slit-lamp at
baseline and then every 2 days from Day 10 to the end of the study.
Fifteen minutes prior to each examination, 10 .mu.l of Mydriaticum
(0.5% tropicamide) was instilled for papillary dilatation.
[0073] Immediately after euthanasia (i.e., at Day 16), both
eyeballs of all rats of each group were enucleated and prepared for
histological examination. They were fixed in Bouin-Hollande
solution, dehydrated, and embedded in paraffin wax. They were then
cut into eight sections, approximate five to seven micrometers
thick and stained with Trichome of Masson. The retinal thickness
and cell infiltration were evaluated and scored using the scale
shown in Table 2:
TABLE-US-00002 TABLE 2 No tissue destruction and with any features
in a score from 1-7, 0 limited to total destruction of the various
layers of the retina Slight cellular infiltration without
destruction of retina 1 Destruction of the outer segments of rods
and cones 2 Destruction of the outer nuclear layer 3-4 Destruction
of the inner nuclear layer 5-6 Destruction of the ganglion layer
7
Results.
Animal Body Weight.
[0074] Animal body weight was measured and recorded before
induction and treatment then at the end of the study. At baseline
(treatment), mean body weight per group was between 198 and 202
grams, with a standard deviation of between .+-.5 grams and 11
grams. At the end of the study (Day 16), mean body weight per group
was between 202 grams and 209 grams, with a standard deviation of
.+-.9 grams. There were no relevant differences in body weight
between test material, vehicle, and reference animal group.
Ocular Evaluation.
[0075] The effect of test material and reference material on ocular
inflammation was measured with slit lamp evaluation and scored
using the clinical scoring as shown in Table 3:
TABLE-US-00003 TABLE 3 No sign of inflammation, normal iris
dilatation after instillation with a 0 mydriatic drug Discrete
inflammation in iris and conjunctiva 1 Dilatation of iris and
conjunctival vessels 2 Hyperhemia in iris associated with the
Tyndall effect in anterior 3 chamber Same signas as score 3, but
add 1 point each if syncehcia, fibrin, or 4-6 hypopion (cell
deposit in the inferior anterior chamber) were observed
[0076] In EAU rats, laquinimod showed a therapeutic effect on
ocular inflammation. The 1% laquinimod solution administered once
per day reduced intraocular inflammation compared with the vehicle
group. The mean clinical score at Day 16 was 1.3.+-.2.1, compared
with the vehicle group which was 4.8.+-.1.3. The 5% laquinimod
solution administered once per day significantly reduced
intraocular inflammation compared with the vehicle group. The mean
clinical score at Day 16 was 0.6.+-.1.5 compared with the vehicle
group, which was 4.8.+-.1.3. Six out of eight of the rats tested
demonstrated no intraocular inflammation. As expected, cyclosporine
A, the reference material, administered once per day at 25 mg/kg,
demonstrated complete inhibition of intraocular inflammation, with
a mean clinical score at Day 16 of 0.0.+-.0.0. Data for the slit
lamp test is summarized in Table 4.
[0077] Histological examination of the eyeballs revealed that 1%
laquinimod administered once per day suppressed uveitis. The mean
histologic grade using the scale set forth in paragraph above was
1.2.+-.2.2 versus 5.8.+-.2.3 for the vehicle group. Only four eyes
out of sixteen showed a significant destruction of the retina
associated with infiltration of inflammatory cells. The 5%
laquinimod administered once per day significantly reduced
posterior uveitis as assessed by histological grading. The mean
histologic grade for this group was 0.7.+-.1.9. Only two eyes (from
two different animals) out of sixteen showed a destruction of the
retina associated with infiltration of inflammatory cells. As
expected, the mean histologic grade for cyclosporine A (25 mg/kg)
once per day was 0.0.+-.0.0, thereby totally protecting the retina
from destruction. Summary data from the histological evaluation is
shown in Table 5.
[0078] The 1% and 5% laquinimod solutions reduced the clinical
signs of ocular inflammation. The reduced EAU clinical scores
correlated well with the decrease in the retinal damage and immune
cell infiltration as assessed by histology.
TABLE-US-00004 TABLE 4 Slit Lamp Ocular Evaluation of Both Eyes in
Albino Rats. Base- Day Day Day Day Treatment line 10 12 14 16 1%
Laquinimod Mean 0.0 0.1 0.1 0.8 1.3 SD 0.0 0.3 0.3 1.8 2.1
Incidence % 0.0 6.3 6.3 18.8 31.3 5% Laquinimod Mean 0.0 0.0 0.0
0.3 0.6 SD 0.0 0.0 0.0 1.3 1.5 Incidence % 0.0 0.0 0.0 6.3 12.5
Vehicle Mean 0.0 0.1 0.3 2.4 4.8 (sterile water) SD 0.0 0.5 1.0 2.3
1.3 Incidence % 0.0 6.3 6.3 56.3 93.8 Cyclosporine A Mean 0.0 0.0
0.0 0.0 0.0 (25 mg/kg/day) SD 0.0 0.0 0.0 0.0 0.0 per os Incidence
% 0.0 0.0 0.0 0.0 0.0
TABLE-US-00005 TABLE 5 Histological Ocular Evaluation of Both Eyes
in Albino Rats. Treatment Day 16 1% Laquinimod Mean 1.2 SD 2.2 5%
Laquinimod Mean 0.7 SD 1.9 Vehicle (sterile water) Mean 5.8 SD 2.3
Cyclosporine A (25 mg/kg/day) Mean 0.0 per os SD 0.0
Example 2: Evaluation of Ocular Active Anaphylaxis Reduction
Following Topical Ocular Administration of Laquinimod in Mice (Late
Phase) Using Ovalbumin Model
General.
[0079] Laquinimod solutions were prepared as in Example 1.
Animals and Animal Husbandry.
[0080] Forty (40) male Balb/c albino mice were used for this
experiment. The mice were about 7-8 weeks old upon ordering, and
were held in observation for at least three (3) days to monitor for
signs of ill health or ocular abnormalities. Only healthy animals
were accepted for use in this study. The rats were housed under
identical environmental conditions, with a relative humidity of
55%.+-.10%, continuous ventilation, and an automatic 12 hour
light/dark cycle. Environmental conditions were continuously
controlled and recorded. Animals had free access to food and
water.
Materials and Methods.
[0081] Forty (40) Balb/c albino mice were randomly allocated to
five groups of eight animals each. Only the right eyes of each
animal were used in this study. Animals were grouped as shown in
Table 6:
TABLE-US-00006 TABLE 6 Group Treatment Sensitize/Challenge 1
Vehicle (sterile water) No 2 Vehicle (sterile water) Yes 3 1%
Laquinimod Yes 4 5% Laquinimod Yes 5 1% Prednisolone Yes
Sensitization.
[0082] On Days 1 and 8, animals in groups 2-5 were injected once
intraperitoneally with 0.2 ml of a mixture comprising 5 .mu.g/ml
ovalbumin and 15 mg/ml alum in phosphate buffered saline (PBS; pH
7.3-7.4). Animals of group 1 received a mock sensitization
comprising 0.2 ml intraperitoneal injection of PBS only on Days 1
and 8.
Treatment Regimen.
[0083] Laquinimod or controls were delivered into the right
conjunctival sac as follows: [0084] From Day 8 to Day 17, animals
were dosed four times daily with 10 .mu.l of either 1% laquinimod,
5% laquinimod, or vehicle. Reference Group 5 was dosed with the
same regimen, but starting on Day 15. (**Note: Due to a technical
error, four mice from Group 1 (negative vehicle) were not dosed on
Day 8 and one mouse from Group 1 (negative vehicle) was not dosed
on Day 11. This was deemed not to be a critical error that would
affect the outcome of the study so the study was continued). [0085]
On Day 18, animals were dosed five times during a three hour period
before the second challenge (3 h, 2 h, 1 h, 40 min., and 10
min.).
Challenge.
[0086] Allergic conjunctivitis was achieved by a single
administration on Day 15 (30 minutes before the treatment regimen)
and Day 18 (2 hours after 40 minute treatment) with 10 .mu.l of 5
mg/ml ovalbumin in PBS, pH 7.3-7.4 to the right eyes of all rats in
groups 2 through 5. Group 1 was mock challenged with 10 .mu.l PBS
only.
[0087] On Day 19 (12 h to 24 h after challenge), rats were
euthanized using an intraperitoneal injection of pentobarbital.
Right eyelids and eyeballs were immediately fixed in Bouin-Hollande
solution for 24 hours and embedded in paraffin wax. Fixed samples
were cut vertically into 5 to 7 micrometer thick sections with a
microtome in two different regions--the bulbar conjunctiva and the
fornix and palpebral conjunctiva. Three sections per region were
selected for analysis based on the quality of the sectioning. The
selected sections were stained with May-Grunwald/acid Giemsa.
[0088] After staining, digital images using 200.times.
magnifications were taken with a Leica light microscope. Total area
of subconjunctival tissue was measured automatically using the
Leica Application Suite (LAS) software. Eosinophils were counted
throughout the whole conjunctiva in each of the three sections per
sample. The density per square millimeter of eosinophils stained
with acid Giemsa was calculated for each specimen. The average cell
density per eye was calculated from the results of the six
sections.
Results.
Animal Body Weight.
[0089] All animals showed normal body weight variation during the
study, except for Group 5 (prednisolone), which showed a slight
body weight loss between Day 15 and Day 19 (about -4%). This weight
loss is commonly observed during chronic corticosteroid treatments.
Vehicle groups 1 and 2 showed a 2% and 3% weight gain,
respectively, while treatment groups 3 and 4 showed a 4% and 1%
weight gain, respectively.
Evaluation of Eosinophil Infiltration.
[0090] Conjunctival challenge with ovalbumin in sensitized mice
triggers a late phase reaction of anaphylaxis characterized by
eosinophil infiltration into the subconjunctival tissue. Eosinophil
densities are summarized in Table 7:
TABLE-US-00007 TABLE 7 Eosinophil density Density Inhibition of
Eosinophil Treatment (cells/mm2) Infiltration vs. Vehicle 1%
Laquinimod Mean 117.5 48% SD 112.3 5% Laquinimod Mean 72.5 68% SD
57.6 Pred Forte .RTM. Reference Mean 23.1 90% SD 16.9 Vehicle
(sterile water) positive Mean 225.4 -- control SD 188.4 Vehicle
(sterile water) negative Mean 47.1 -- control SD 16.0
[0091] Topical ocular challenge with ovalbumin in sensitized mice
induced a late phase reaction characterized by a significant
eosinophil infiltration in to the conjunctival tissues. As shown
above, topical administration of 1% prednisolone induced a
significant decrease by 90% of the eosinophil density, with a Mann
& Whitney-U test p value of 0.0008. Multiple topical
administrations of 1% laquinimod reduced eosinophil density by 48%
in comparison with positive control; however, this could not be
shown to be statistically significant. Multiple topical
administrations of 5% laquinimod showed a statistically significant
68% reduction in eosinophil density over the vehicle group, with a
Mann & Whitney-U test p value of 0.0023.
Conclusion.
[0092] Under experimental conditions, multiple topical
administrations of laquinimod inhibited the late ocular anaphylaxis
reaction in mice, with a statistically significant effect at a dose
of 5%. No adverse clinical effect was observed in
laquinimod-treated mice.
Example 3: Dose Conversion Between Species
[0093] The National Institutes of Health (NIH) provides a table of
Equivalent Surface Area Dosage Conversion Factors below (Table 8)
which provides conversion factors that account for surface area to
weight ratios between species.
TABLE-US-00008 TABLE 8 Equivalent Surface Area Dosage Conversion
Factors To Mouse Rat Monkey Dog Man 20 g 150 g 3 kg 8 kg 60 kg From
Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3
Dog 6 4 12/3 1 1/2 Man 12 7 3 2 1
[0094] In the examples 4-9 below, the administration of the
composition is once daily. The administration can be repeated daily
for a period of one, two, three or four days, up to 14 days, or
longer as necessary.
Example 4: Laquinimod for Treating Uveitis
[0095] A laquinimod composition as described herein is administered
to the eye of a subject suffering from uveitis. The administration
of the composition is effective to treat the subject suffering from
uveitis. The administration of the composition is also effective to
reduce intraocular inflammation in the subject. The administration
of the composition is also effective to reduce retina tissue
destruction in the subject.
Example 5: Laquinimod for Treating Bacterial Conjunctivitis
[0096] A laquinimod composition as described herein is administered
to a subject suffering from bacterial conjunctivitis. The
administration of the composition is effective to treat the subject
suffering from bacterial conjunctivitis. The administration of the
composition is also effective to reduce intraocular inflammation in
the subject.
Example 6: Laquinimod for Treating Viral Conjunctivitis
[0097] A laquinimod composition as described herein is administered
to a subject suffering from viral conjunctivitis. The
administration of the composition is effective to treat the subject
suffering from viral conjunctivitis. The administration of the
composition is also effective to reduce intraocular inflammation in
the subject.
Example 7: Laquinimod for Treating Inflammation in the Eye
[0098] A laquinimod composition as described herein is administered
to a subject suffering from an inflammation of the orbital tissue,
the lacrimal apparatus, the eyelid, the cornea, the retina or the
optic pathway in the eye. The administration of the composition is
effective to treat the subject suffering from the inflammation. The
administration of the composition is also effective to reduce
intraocular inflammation in the subject.
Example 8: Laquinimod for Treating Allergic Conjunctivitis
[0099] A laquinimod composition as described herein is administered
to a subject suffering from allergic conjunctivitis at 0.2 mg-0.5
mg laquinimod/day. The administration of the composition is
effective to treat the subject suffering from allergic
conjunctivitis. The administration of the composition is also
effective to reduce intraocular inflammation in the subject. The
administration of the composition is also effective to inhibit late
ocular anaphylaxis in the subject. The administration of the
composition is also effective reduce eosinophil infiltration into
the conjunctiva of the subject.
Example 9: Laquinimod for Treating OID
[0100] A laquinimod composition as described herein is administered
to a subject suffering from an OID. The administration of the
composition is effective to treat the subject suffering from the
OID. The administration of the composition is also effective to
reduce intraocular inflammation in the subject.
Example 10: Comparing Ocular and Oral Administration of Laquinimod
for Treating Uveitis
Methods.
[0101] Laquinimod eye drops (1% and 5%) and oral laquinimod (OD)
daily (QD) were administered to albino rats. The animals were dosed
for 7 days once 30-40% of the animals have developed the disease.
Cyclosporine (PO, QD) was used as positive control.
[0102] Disease was induced as follows: Day 1, 100-.mu.L human
S-antigen (100 .mu.g in Freud's complete adjuvant (4 mg/mL H37Ra))
injection in footpad+1 .mu.g/100 .mu.L pertussis toxin
intraperitoneal injection.
Results.
[0103] Response to treatment were assessed by clinical score based
on the following scale: [0104] 0--No sign of inflammation, normal
iris dilatation after instillation with a mydriatic drug. [0105]
1--Discrete inflammation in iris and conjunctiva. [0106]
2--Dilatation of iris and conjunctival vessels. [0107]
3--Hyperhemia in iris associated or not with the Tyndall effect in
anterior chamber.
[0108] 4-7--+1 point was added if synechia, myosis, fibrin, or
hypopion (cell deposit in the inferior anterior chamber) were
observed.
[0109] Results are summarized in Table 9 below:
TABLE-US-00009 Dose % Inhibition of clinical score on Day 16 CyA
74% 1% PO Laquinimod 24% 5% PO laquinimod 39% 1% Laquinimod eye
drops -75% 5% Laquinimod eye drops 31%
[0110] Results for Histological analysis is shown in Table 10
below:
TABLE-US-00010 Histological ocular evaluation (scale 0-7) Treatment
Both Eyes/Day 19 % Inhibition Vehicle Mean 3.0 N/A (1x/day for 7
days; SD 1.6 1 mL/kg; per os) Laquinimod Mean 2.8 7.00% (1%; 1x 10
.mu.l SD 1.5 instillation/day for 7 days in both eyes) Laquinimod
Mean 1.8 40.00% (5%; 1x 10 .mu.l SD 1.7 instillation/day for 7 days
in both eyes) Laquinimod Mean 2.3 23.00% (1%; 1x/day for 7 SD 1.7
days; 1 mL/kg; per os) Laquinimod Mean 1.2 60.00% (5%; 1x/day for 7
SD 1.6 days; 1 mL/kg; per os) Cyclosporin A Mean 1.3 57.00% (1x/day
for 7 days; 25 mg/kg/ SD 1.7 day; per os)
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