WO1995018604A1

WO1995018604A1 - Topical treatment of ocular photophobia

Info

Publication number: WO1995018604A1
Application number: PCT/IB1995/000003
Authority: WO
Inventors: Troy Albert Reaves, Jr.
Original assignee: Ciba-Geigy Ag
Priority date: 1994-01-11
Filing date: 1995-01-03
Publication date: 1995-07-13
Also published as: ZA95134B; AU1249395A; IL112256A0

Abstract

The use of a non-steroidal antiinflammatory agent in the preparation of an ophthalmic pharmaceutical composition for the prevention, treatment or control of ocular photophobia is described.

Description

TOPICAL TREATMENT OF OCULAR PHOTOPHOBIA
This invention relates to the use of a non-steroidal antiinflammatory agent in a therapeutically effective amount in the preparation of an ophthalmic pharmaceutical composition in combination with an ophthalmically acceptable carrier for treating or preventing ocular photophobia of a mammal; to a method for the topical prevention, control and treatment of ocular photophobia resulting from a variety of ocular conditions, ocular examinations and ocular surgery; and particularly to the topical ophthalmic use of a nonsteroidal anti-inflammatory agent for the treatment of ocular photophobia in mammals.

Photophobia is an abnormal visual intolerance to light, in particular to strong light. Ocular photophobia as used herein denotes photophobia of ocular origin, such as photophobia associated with various ocular disorders, ocular examination procedures or ocular surgery.

Ocular disorders resulting in ocular photophobia comprise allergic conditions such as acute seasonal allergic conjunctivitis, keratoconjunctivitis, keratitis sicca, keratouveitis, chronic non-infectious conjunctivitis, infectious conjunctivitis, uveitis, iridocyclitis, iritis, and disruptions to the blood-aqueous-barrier.

Ocular examination procedures resulting in ocular photophobia involve ocular
examinations by various ophthalmological techniques, such as dilated eye exams.

Surgical procedures resulting in ocular photophobia comprise extracapsular cataract
extraction, phacoemulsification cataract extraction, laser capsulotomy, epikeratophakia,
penetrating keratoplasty, lamellar keratoplasty, automated lamellar keratoplasty, incisional
keratotomy, radial keratotomy, astigmatic keratotomy, photorefractive keratectomy,
phototherapeutic keratectomy, conjunctival flaps, pterygium excision, prosthokerato
plasty, trabeculectomy, laser trabeculoplasty, laser iridectomy, and cyclodestructive
procedures. The photorefractive keratectomy or phototherapeutic keratectomy is per
formed with one or more frequencies of laser energy involving excimer and/or intra
stromal lasers.

Systemic administration of certain non-steroidal antiinflammatory agents has been
reported to influence ocular sensitivity to light (photophobia).

Photophobia has been reported as a potential side effect for systemically administered benoxaprofen (British Med. J. 284,1784, June 12,1982). On the other hand photophobia associated with migraine headache is reduced with ketorolac administered intramuscularly (Ann. Emerg. Med. Ll/8,919-924,1992); similarly for diclofenac sodium administered orally (J. Int. Med. Res. (UK) 15/1,44-48,1987).

The present invention relates to the use of a non-steroidal antiinflammatory agent in the preparation of an ophthalmic pharmaceutical composition for treating or preventing ocular photophobia of a mammal.

The present invention provides a method for the prevention, treatment or control of ocular photophobia associated with diseases and disorders of the eye. The present invention also provides a safe and effective method for the prevention, treatment or control of ocular photophobia associated with ocular surgical procedures and with ocular examinations.

Ocular photophobia as used herein refers to photophobia of ocular origin, that is photophobia due to photophobia-inducing ocular disorders or diseases or due to photophobia-inducing ocular surgical, traumatic and examination procedures.

Photophobia-inducing ocular disorders as used herein refer to allergic conditions such as acute seasonal allergic conjunctivitis, keratoconjunctivitis, keratitis sicca, keratouveitis, chronic non-infectious conjunctivitis, infectious conjunctivitis, uveitis, iridocyclitis, iritis and to disruptions to the blood-aqueous-barrier. Ocular photophobia as used herein refers preferably to allergic conditions such as acute seasonal allergic conjunctivitis, kerato
conjunctivitis, keratitis sicca, keratouveitis, chronic non-infectious conjunctivitis and
infectious conjunctivitis, and more preferably to acute seasonal allergic conjunctivitis.

These and other objects are accomplished in accordance with the present invention which
provides a method of treating or controlling ocular photophobia which comprises
administering topically to the affected eye of a mammal, including a human host, a
therapeutically effective amount of an ophthalmic composition of a nonsteroidal ocularly
suitable anti-inflammatory drug in a pharmaceutical acceptable carrier.

The present method can be safely used to substantially reduce the ocular photophobia
resulting from various causes as discussed hereinabove. Thus, the method of the present
invention would eliminate a significant ocular problem and offers readily apparent advantages over the inconveniences afforded by conventional methods of alleviating the discomfort of photophobia, i. e., sunglasses or eye bandages.

The foregoing and other aspects, advantages and objects of the invention may be more fully appreciated by reference to the following detailed description.

More particularly, the present invention relates to the use of a non-steroidal antiinflammatory agent in a therapeutically effective amount in the preparation of an ophthalmic pharmaceutical composition in combination with an ophthalmically acceptable carrier for treating or preventing ocular photophobia of a mammal.

The present invention relates to a method of treating ocular photophobia in mammals which comprises administering topically to the eye of a mammal in need thereof a therapeutically effective amount of an ophthalmic composition of an ocularly suitable non-steroidal antiinflammatory drug in combination with an ocularly acceptable carrier.

Suitable non-steroidal antiinflammatory agents are those well-known in the art, including fenamates, oxicams, arylacetic acids, arylpropionic acids and the like, preferably indomethacin, sulindac, diclofenac, suprofen, oxaprozin, naproxen, flurbiprofen, etodolac, ketorolac, ketoprofen, meclofenamic acid, tenidap, piroxicam, tolmetin, and ophthalmically acceptable salts thereof. Preferred salts are alkali metal salts, such as the sodium or potassium salt, and ammonium salts, such as the tromethamine and diethylammonium
salts.

Preferred non-steroidal antiinflammatory agents are indomethacin, diclofenac, piroxicam,
flurbiprofen, suprofen, ketorolac and ophthalmically acceptable salts thereof. More
preferred non-steroidal antiinflammatory agents are indomethacin, diclofenac, piroxicam,
flurbiprofen and ophthalmically acceptable salts thereof. Highly preferred is diclofenac
and ophthalmically acceptable salts thereof. Strongly preferred is diclofenac sodium.

Such non-steroidal antiinflammatory agents can be administered as solutions, gels,
suspensions, dispersions, ointments or creams using suitable ophthalmic carriers
well-known to those skilled in the art.

Concentration of active ingredient ranges from about 0.001% to about 5%, preferably
about 0.01% to about 2%, depending on the compound and formulation involved.

The non-steroidal antiinflammatory agent is preferably administered in the form of a sterile aqueous solution or suspension, preferably hypotonic or isotonic, and having a pH ranging from about 4.0 to 9.7, preferably from about 4.5 to 7.5 and more preferably from 6.0 to 7.5.

The formulations are prepared using carriers well-known in the art. For example, suitable formulations of diclofenac and salts thereof are described in U. S. patents 4,960,799 and 4,829,088, which are incorporated herein by reference.

Examples of suitable carriers are especially water, mixtures of water and water-miscible solvents, such as Cl-to C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5 % by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products,

such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, poly
ethylene oxide, preferably cross-linked polyacrylic acid, such as neutral Carbopol, or
mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as
methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral
Carbopol, or mixtures thereof The concentration of the carrier is, for example, from 1 to
100 000 times the concentration of the active ingredient.

Examples of commercial ophthalmic preparations suitable in the instant invention are
diclofenac sodium 0.1% sterile ophthalmic solution (Voltaren Ophthalmic, Ciba-Vision
Ophthalmics, U. S. A.), flurbiprofen sodium 0.03% sterile ophthalmic solution (Ocufen,
Allergan Medical Optics, U. S. A.), suprofen 1% sterile ophthalmic solution (Profenal,
Alcon Surgical, Inc., U. S. A.) and ketorolac tromethamine 0.5% sterile ophthalmic solution
(Acular, Allergan, Inc., U. S. A.).

Typically, one drop (about 25-50 u. l) of the ophthalmic solution is administered to the eye of a patient in need thereof about two to eight times a day. For surgical procedures, the ophthalmic solution is administered 30 to 60 minutes before surgery, and again right after surgery and administration is continued as required.

The photophobia of patients exposed to ambient room light, a penlight, daylight or other source of light stimulation is rated as none, mild, moderate or severe in order to determine the elimination or reduction of photophobia on treatment with the non-steroidal antiinflammatory agent in comparison to patients administered placebo vehicle only.

The use of topically administered non-steroidal antiinflammatory agents to significantly reduce photophobia associated with ocular disorders, ocular examinations, ocular trauma (e. g. corneal abrasions, removal of foreign bodies), retinal detachment surgery and ocular surgery represents an innovative medicinal approach to treating and/or controlling ocular photophobia which has been treated until now only by prescribing the use of eyeglasses, preferably sunglasses.

The following examples are presented for illustrative purposes and are not intended to limit the scope of the invention.

The diclofenac sodium 0.1% ophthalmic solution (DSOS) used in the following studies is prepared substantially according to U. S. patent 4,960,799.

The formulation is as follows:
Material Amount Per ml
Diclofenac Sodium 1.00 mg
Tromethamine, U. S. P. 9.36 mg
Sorbic Acid, N. F. 2.00 mg
Boric Acid, N. F. 14.25 mg
Edetate Disodium, U. S. P. 1.00 mg
Polyoxyl 35 Castor Oil, N. F. 50.00 mg
Purified Water, U. S. P. qs 1 ml
The placebo vehicle ophthalmic solution (PVOS) used in the following studies is:
Material Amount Per ml
Tromethamine, U. S. P. 9.36 mg
Sorbic Acid, N. F. 2.00 mg
Boric Acid, N. F. 14.25 mg
Edetate Disodium, U. S. P. 1.00 mg
Polyoxyl 35 Castor Oil, N. F. 50.00 mg
Purifie Water, U. S. P. qs 1 ml
Examples
Clinical Study 1: A prospective, randomized, double-masked, parallel group comparison study of diclofenac sodium 0.1% ophthalmic solution (DSOS) with its placebo vehicle ophthalmic solution (PVOS) is performed.

Patients with clinically documented acute seasonal allergic conjunctivitis are enrolled for clinical evaluation. The study procedures involve one drop of DSOS or PVOS immediately following the enrollment examination and then every two hours for a maximum of eight doses daily for two days and then every four to six hours for a maximum of four doses daily for the next twelve days. Twenty patients (DSOS=10; PVOS=10) are evaluated at 30 minutes following the first dose and then after two, seven and fourteen days of masked treatment. Patients in both treatment
groups display photophobia of varying severity when enrolled into the study. On average, patients that received PVOS experienced little change in their photophobia severity score
while patients that received DSOS experienced significant improvement.

In DSOS treated
patients, improvement in the mean photophobia score from baseline is observed as early
as 30 minutes after the first dose is administered to the eye and continued throughout the
fourteen days of treatment.

Clinical Study 2: A prospective, randomized, double-masked, fellow-eye comparison
study of diclofenac sodium 0.1% ophthalmic solution (DSOS) with its placebo vehicle
ophthalmic solution (PVOS) is performed. Patients with bilateral myopia that are
scheduled for bilateral radial keratotomy surgery are enrolled for clinical evaluation. The
study procedures involve one drop of DSOS or PVOS 30 to 60 minutes before surgery,
one drop after surgery, and one drop six hours after surgery into the specified eyes.

Twenty-one patients (DSOS=21 eyes; PVOS=21 eyes) are evaluated prior to the first dose,
at 5,2,4 and 6 hours after surgery, and again at either 24 or 48 hours after surgery. Both eyes of all patients are without photophobia symptoms prior to surgery and then experienced a significant postsurgical photophobia that peaks by one hour after surgery. On average, eyes that received PVOS experience little change in their photophobia severity score over the next 24 to 48 hours while eyes that receive DSOS experience significant improvement for up to 24 hours after surgery. In the DSOS treated eyes, the improvement in photophobia is observed as early as 1.5 hours after surgery and continues through at least 24 hours postsurgically.

Clinical Study 3: A prospective, randomized, double-masked, parallel-group comparison study of diclofenac sodium 0.1% ophthalmic solution (DSOS) with its placebo vehicle ophthalmic solution (PVOS) is performed. Patients with myopia that are scheduled for unilateral radial keratotomy surgery are enrolled for clinical evaluation. The study procedures involve one drop of DSOS or PVOS 30 to 60 minutes before surgery, one drop after surgery, and one drop six hours after surgery into the specified eyes. Forty-five patients (DSOS=24; PVOS=21) are evaluated prior to the first dose, at 0.5,1,1.5,2,4 and 6 hours after surgery, and again at 24 hours after surgery. Patients in both treatment groups are without photophobia symptoms prior to surgery and then experience a significant postsurgical photophobia that peaks by two hours after surgery.

On average, eyes that receive PVOS experience little change in their photophobia severity score over the next 24 hours while eyes that receive DSOS experience significant improvement for up to 24 hours after surgery. In the DSOS treated eyes, the improvement in photophobia
is observed as early as 4 hours after surgery and continues through at least 24 hours postsurgically.

Clinical Study 4: A prospective, randomized, double-masked, parallel-group comparison
study of diclofenac sodium 0.1% ophthalmic solution (DSOS) with its placebo vehicle
ophthalmic solution (PVOS) is performed. Patients with myopia that are scheduled for
unilateral excimer laser photorefractive keratectomy surgery are enrolled for clinical
evaluation. The study procedures involve two drops given 5 minutes apart of DSOS or
PVOS after surgery and then one drop every six hours to allow for four daily doses in the
surgically-treated eye until the cornea is completely reepithelialized. Thirty-two patients
(DSOS=16; PVOS=16) are evaluated prior to the first dose, at 0.5,1,1.5,2,4,12,18 and
24 hours after surgery. Daily followup examinations are scheduled until corneal
reepithelialization is complete.

Patients in both treatment groups are without photophobia
symptoms prior to surgery and then experience a significant postsurgical photophobia that
peaks by two to four hours after surgery. On average, eyes that receive PVOS experience little change in their photophobia severity score over the next 48 hours while eyes that receive DSOS experience significant improvement for up to 48 hours after surgery. In the
DSOS treated eyes, the improvement in photophobia is observed as early as 4 hours after surgery and continues through at least 48 hours postsurgically.

Clinical Studv 5: A prospective, randomized, double-masked, parallel-group comparison study of diclofenac sodium 0.1% ophthalmic solution (DSOS) with its placebo vehicle ophthalmic solution (PVOS) is performed. Twenty normal or patient volunteers (40 healthy eyes) undergoing bilateral pupil dilatation for routine fundus examination are enrolled for clinical evaluation. All eyes have pupil dilatation using 1 drop of tropicamide (1.0 %) and 1 drop of phenylephrine (2.5 %). In addition 1 eye of each patient received 2 drops of the PVOS in a random order 5 minutes after the instillation of the above dilating drops. Light sensitivity and pupil size are measured 30,60,90 and 120 minutes after instillation of the dilating drops. Photophobia is assessed by the patient on a verbal rating scale (VRS) and visual analogue scale (VAS).

For a more objective assessment neutral density filters of increasing strengths are placed in front of the eye until the photosensitivity on the VAS scale is reduced to zero. A statistically significant difference is noticed over the entire observation period in favor of DSOS as compared to PVOS.

Claims

CLAIMS 1. The use of a non-steroidal antiinflammatory agent in a therapeutically effective amount in the preparation of an ophthalmic pharmaceutical composition in combination with an ophthalmically acceptable carrier for treating or preventing ocular photophobia of a mammal.

2. The use according to claim 1 wherein the antiinflammatory agent is selected from the group consisting of a fenamate, an oxicam, an arylacetic acid and an arylpropionic acid, and ophthalmically acceptable salts thereof.

3. The use according to claim 1 wherein the antiinflammatory agent is selected from the group consisting of indomethacin, sulindac, diclofenac, suprofen, oxaprozin, naproxen, flurbiprofen, etodolac, ketorolac, ketoprofen, meclofenamic acid, piroxicam, tenidap and tolmetin, and ophthalmically acceptable salts thereof.

4. The use according to claim 1 wherein the pharmaceutical composition is a sterile solution or suspension having a pH ranging from about 4.0 to 9.7, preferably from about 4.5 to 7.5 and more preferably from 6.0 to 7.5.

5. The use of a non-steroidal antiinflammatory drug selected from the group consisting of diclofenac, piroxicam, flurbiprofen, suprofen, ketorolac, indomethacin and ophthalmically acceptable salts thereof, in the preparation of an aqueous ophthalmic solution or suspension comprising a therapeutically effective amount of said non-steroidal antiinflammatory drug and an ophthalmically acceptable carrier, for preventing or treating ocular photophobia of a human host.

6. The use according to claim 5 wherein said non-steroidal antiinflammatory agent is diclofenac or an ophthalmically acceptable salt thereof.

7. The use according to claim 5 wherein the non-steroidal antiinflammatory agent is diclofenac sodium.

8. The use according to claim 1 for treating ocular photophobia resulting from acute seasonal allergic conjunctivitis, keratoconjunctivitis, keratitis sicca, keratouveitis, chronic non-infectious conjunctivitis, infectious conjunctivitis, uveitis, iridocyclitis, iritis, disruptions to the blood-aqueous-barrier, ocular trauma, retinal detachment surgery and dilated ocular examination.

9. The use according to claim 1 for treating ocular photophobia resulting from ocular surgery.

10. The use according to claim 9 wherein said ocular surgery is selected from the group including extracapsular cataract extraction, phacoemulsification cataract extraction, laser capsulotomy, epikeratophakia, penetrating keratoplasty, lamellar keratoplasty, automated lamellar keratoplasty, incisional keratotomy, radial keratotomy, astigmatic keratotomy, conjunctival flaps, pterygium excision, prosthokeratoplasty, trabeculectomy, laser trabeculoplasty, laser iridectomy and cyclodestructive procedures.

11. The use according to claim 9 wherein said ocular surgery is selected from the group of photorefractive keratectomy and phototherapeutic keratectomy.

12. The use according to claim 11 wherein said photorefractive keratectomy or phototherapeutic keratectomy is performed with one or more frequencies of laser energy involving excimer and/or intrastromal lasers.

13. A method of treating or preventing ocular photophobia which comprises administering topically to the eye of a mammal in need thereof a therapeutically effective amount of an ophthalmic pharmaceutical composition of a non-steroidal antiinflammatory agent in combination with an ophthalmically acceptable carrier.

14. The method of claim 13 wherein the antiinflammatory agent is selected from the group consisting of a fenamate, an oxicam, an arylacetic acid and an arylpropionic acid, and ophthalmically acceptable salts thereof.

15. The method according to claim 13 wherein the antiinflammatory agent is selected from the group consisting of indomethacin, sulindac, diclofenac, suprofen, oxaprozin, naproxen, flurbiprofen, etodolac, ketorolac, ketoprofen, meclofenamic acid, piroxicam, tenidap and tolmetin, and ophthalmically acceptable salts thereof.

16. The method according to claim 13 wherein the pharmaceutical composition is a sterile solution or suspension having a pH of about 6.0 to 7.5.

17. The method according to claim 13 of preventing or treating ocular photophobia which comprises administering topically to the eye of a human host in need thereof a therapeutically effective amount of an aqueous ophthalmic solution or suspension of a nonsteroidal antiinflammatory drug selected from the group consisting of diclofenac, piroxicam, flurbiprofen, suprofen, ketorolac, indomethacin, and ophthalmically acceptable salts thereof in an ophthalmically acceptable carrier.

18. The method according to claim 17 wherein said non-steroidal antiinflammatory agent is diclofenac or an ophthalmically acceptable salt thereof.

19. The method according to claim 17 wherein the non-steroidal antiinflammatory agent is diclofenac sodium.

20. The method according to claim 13 of treating ocular photophobia resulting from acute seasonal allergic conjunctivitis, keratoconjunctivitis, keratitis sicca, keratouveitis, chronic non-infectious conjunctivitis, infectious conjunctivitis, uveitis, iridocyclitis, iritis, disruptions to the blood-aqueous-barrier, retinal detachment surgery and dilated ocular examination.

21. The method according to claim 13 of treating ocular photophobia resulting from ocular surgery.

22. The method according to claim 21 wherein said ocular surgery is selected from the group including extracapsular cataract extraction, phacoemulsification cataract extraction, laser capsulotomy, epikeratophakia, penetrating keratoplasty, lamellar keratoplasty, automated lamellar keratoplasty, incisional keratotomy, radial keratotomy, astigmatic keratotomy, conjunctival flaps, pterygium excision, prosthokeratoplasty, trabeculectomy, laser trabeculoplasty, laser iridectomy, and cyclodestructive procedures.

23. The method according to claim 21 wherein said ocular surgery is selected from the group of photorefractive keratectomy and phototherapeutic keratectomy.

24. The method according to claim 23 wherein said photorefractive keratectomy or phototherapeutic keratectomy is performed with one or more frequencies of laser energy involving excimer and/or intrastromal lasers.