(12) United States Patent
`Miyagi et al.
`
`US006281224B1
`US 6,281,224 B1
`*Aug. 28, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) PRANOPROFEN EYEDROPS CONTAINING
`ORGANIC AMINE
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`(75) Inventors: Shogo Miyagi, Kobe; Yoshihide
`Horibe, Higashiosaka, both of (JP)
`
`(73) Assignee: Santen Pharmaceutical Co., Ltd.,
`Osaka (JP)
`
`(*) Notice:
`
`This patent issued on a continued pros
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the tWenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`08/945,198
`Apr. 16, 1996
`
`(21) Appl. No.:
`(22) PCT Filed:
`
`(86) PCT No.:
`
`PCT/JP96/01035
`
`§ 371 Date:
`
`Oct. 20, 1997
`
`§ 102(e) Date: Oct. 20, 1997
`
`(87) PCT Pub. No.: WO96/32941
`
`PCT Pub. Date: Oct. 24, 1996
`Foreign Application Priority Data
`
`(30)
`
`Apr. 20, 1995
`
`(JP) ................................................. .. 7094723
`
`(51) Int. Cl.7 ................................................... .. A61K 31/44
`(52) U.S. Cl. ................ ..
`514/291; 514/912
`(58) Field of Search .................................... .. 514/291, 912
`
`4,725,586 * 2/1988 Lindstrom et al. .................. .. 514/54
`4,829,083
`5/1989 Doulakas.
`4,829,088
`5/1989 Doulakas.
`5,414,011
`5/1995 Fu 6181..
`
`FOREIGN PATENT DOCUMENTS
`
`59-89616
`61-12617
`62242617
`62242618
`1-29170
`2-286627
`5-186349
`7-17863
`60-184013
`WO 87/00753
`
`5/1984 (JP).
`1/1986 (JP).
`10/1987 (JP).
`10/1987 (JP).
`6/1989 (JP).
`11/1990 (JP).
`7/1993 (JP).
`1/1995 (JP).
`9/1995 (JP).
`2/1987 (WO).
`
`* cited by examiner
`
`Primary Examiner—Zohreh Fay
`(74) Attorney, Agent, or Firm—Frishauf, HoltZ, Goodman,
`Langer & Chick, PC.
`(57)
`ABSTRACT
`
`An ophthalmic solution containing 0.01 to 0.5 Weight % of
`pranoprofen and 0.1 to 5.0 Weight % of an organic amine,
`such as tromethamine or 4-(2-hydroXyethyl)-1-(2
`sulfoethyl)piperaZine. Such solution has a desirable stability
`and does not cause undue irritation When administered to
`eyes to treat an in?ammatory disease such as keratocon
`junctivitis.
`
`19 Claims, No Drawings
`
`

`
`US 6,281,224 B1
`
`1
`PRANOPROFEN EYEDROPS CONTAINING
`ORGANIC AMINE
`
`TECHNICAL FIELD
`The present invention relates to a pranoprofen ophthalmic
`solution containing an organic amine, and the ophthalmic
`solution is characterized in that a change in the composition
`thereof does not occur, the stability is excellent and irritation
`is little.
`
`BACKGROUND TECHNIQUES
`Pranoprofen is an acidic non-steroidal anti-in?ammatory
`drug Which is a propionic acid derivative, is useful for
`in?ammatory diseases in the ophthalmic ?eld such as kera
`toconjunctivitis in an extraocular area and an anterior seg
`ment of the eye, and has been put into practice in the form
`of an ophthalmic soluton. Pranoprofen can stimulate the
`eyes and, therefore, a variety of attempts have been made to
`suppress the irritation in order to prepare ophthalmic solu
`tions. For example, there have been proposed a method by
`addition of boric acid (Japanese Laid-open Patent Publica
`tion No. 60-184013), a method by addition of carbonate
`(Japanese Laid-open Patent Publication No. 5-186349) and
`a method by addition of acetate ion (Japanese Laid-open
`Patent Publication No. 7-17863)to reduce such irritation.
`On the other hand, an attempt at preparing ophthalmic
`solutions and intraocular Irrigating solutions containing an
`organic amine have been also made. For example, in a case
`of an ophthalmic solution containing sulfa drugs, there has
`been disclosed a method for making it possible to solubiliZe
`sulfa drugs and enhancing the preserative properties by
`addition of an alkanolamine such as monoethanolamine,
`diethanolamine or triethanolamine in ophthalmic solutions
`containing a sulfa drug and, thereby, (Japanese Patent Pub
`lication No. 1-29170, Japanese Laid-open Patent Publication
`No. 59-89616 and Japanese Laid-open Patent Publication
`No. 61-12617). In addition, there have been also disclosed
`diclofenac sodium ophthalmic solutions containing
`tromethamine or a homologue thereof having 10 or less
`carbon atoms as preseratives and a stabiliZing agent
`(Japanese Laid-open Patent Publication No. 62-242617,
`Japanese Laid-open Patent Publication No. 62-242618), and
`intraocular irrigating solutions containing chondroitin sul
`fate in Which 4-(2-hydroxyethyl)-1-(2-sulfoethyl)piperaZine
`(hereinafter referred to as “HEPES”) is formulated (PCT
`WO87/00753 and US. Pat. No. 4725586).
`HoWever, there has not been reported yet preparations of
`ophthalmic solutions containing pranoprofen as an active
`ingredient and in Which an organic amine is formulated.
`It is an interesting theme to ?nd ophthalmic solutions
`containing pranoprofen as an active ingredient, Which has an
`excellent stability and little irritation to eyes.
`An object of the present invention is to provide oph
`thalmic solutions containing pranoprofen as an active
`ingredient, Which has no change in the composition, an
`excellent stability and little irritation to eyes.
`In order to ?nd pranoprofen ophthalmic solutions having
`an excellent stability and little irritation to eyes, the present
`inventors studied extensively. As a result, the present inven
`tors found that ophthalmic solutions Which have no change
`in the composition, an excellent stability and little Irritation
`to eyes can be prepared by addition of an organic amine such
`as tromethamine or HEPES.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`SUMMARY OF THE INVENTION
`The present invention relates to an ophthalmic solution
`containing pranoprofen as an active ingredient, in Which an
`
`65
`
`2
`organic amine is formulated (hereinafter referred to as “the
`present ophthalmic solution”).
`Preferred organic amines used in the present ophthalmic
`solution is alkanolamines such as tromethamine,
`monoethanolamine, diethanolamine and triethanolamine;
`sulfoalkyl piperaZines such as HEPES, 1,4-bis(2-sulfoethyl)
`piperaZine (hereinafter referred to as “PIPES”), 1,4-bis(3
`sulfopropyl)piperaZine (hereinafter referred to as “PIPPS”)
`and 1,4-bis(4-sulfobutyl)piperaZine (hereinafter referred to
`as “PIPBS”); sulfoalkyl alkylenediamines such as N,N‘-bis
`(3-sulfopropyl)ethylenediamine (hereinafter referred to as
`“EDPS”). Tromethamine and HEPES are particularly pref
`erable.
`The concentration of the organic amine to be used can be
`appropriately selected and, in a case of tromethamine and
`HEPES, 0.1 to 5.0%, inter alia, 0.5 to 2.5%, particularly
`2.0% is preferable.
`The concentration of pranoprofen Which is an active
`ingredient in the present ophthalmic solution to be used can
`be appropriately selected depending upon symptoms and
`0.01 to 0.5%, particularly 0.1% is preferable.
`Additionally, preseratives are formulated in the present
`ophthalmic solution, if necessary. Presertives Widely used in
`the ophthalmic solutions can be used and, in particular,
`benZalkonium chloride is preferable and the concentration
`thereof to be used is preferably 0.002 to 0.01%, more
`preferably 0.005%.
`The pH of the present ophthalmic solution can be in a
`range Which is acceptable to ophthalmic preparations, and a
`range of 6.5 to 8.5 is preferable and a range of 7.6 to 8.0 is
`particularly preferable in vieWpoint of the eye irritating
`properties.
`As used herein, the concentration of each ingredient in the
`present invention is expressed as % by Weight (W/v).
`Pranoprofen is useful for in?ammatory diseases in the
`ophthalmic ?eld such as keratoconjunctivitis in an extraocu
`lar area and an anterior segment of the eye, and has been put
`into practice in the form of an ophthalmic solution. Prano
`profen causes ocular pain because of irritation to eyes. In
`order to suppress the irritation, a variety of attempts have
`been made (Japanese Laid-open Patent Publication No.
`60-184013, Japanese Laid-open Patent Publication No.
`5-186349, Japanese Laid-open Patent Publication No.
`7-17863). Further, there is a demand for development of
`ophthalmic solutions having reduce irritating properties.
`On the other hand, there have been disclosed sulfa drug
`containing ophthalmic solutions Which contain an organic
`amine (Japanese Patent Publication No. 1-29170, Japanese
`Laid-open Patent Publication No. 59-89616, Japanese Laid
`open Patent Publication No. 61-12617), diclofenac sodium
`ophthalmic solutions (Japanese Laid-open Patent Publica
`tion No. 62-242617, Japanese Laid-open Patent Publication
`No. 62-242618) and intraocular irrigating solution contain
`ing chondroitin sulfate (PCT WO87/00753, US. Pat. No.
`4,725,586). HoWever, heretofore there has been no report on
`pranoprofen ophthalmic solutions containing an organic
`amine.
`Then, in order to ?nd pranoprofen ophthalmic solutions
`having an excellent stability and little irritation to eyes, the
`present inventors extensively studied preparations contain
`ing an organic amine.
`As a result, as detailed data Will be shoWn in the Examples
`hereinbeloW and the section entitled “Effect of the
`invention”, it Was found that the present ophthalmic solution
`has no change in the composition, a high pranoprofen
`
`Page 2
`
`

`
`US 6,281,224 B1
`
`3
`remaining rate, no pH change, and reduced eye irritation
`properties and, thus, is useful as an ophthalmic solution
`having pranoprofen as an active ingredient.
`A general process for preparation of the present oph
`thalmic solution is as folloWs: An organic amine is added to
`sterile puri?ed Water, and pranoprofen is added thereto While
`stirring to completely dissolve it. To this is added a presera
`tive to dissolve it, the pH is adjusted With hydrochloric acid
`or sodium hydroxide, and the solution is ?nally steriliZed by
`?ltration to obtain the present ophthalmic solution.
`In addition, isotonic agents such as sodium chloride and
`concentrated glycerin, non-ionic surfactants such as poly
`oxyethylene sorbitan monooleate (hereinafter referred to as
`
`4
`carbonate, acetic acid, potassium dihydrogenphosphate,
`sodium dihydrogenphosphate dihydrate, disodium hydro
`genphosphate dodecahydrate, sodium chloride, polysorbate
`80, sodium edetate and benZalkonium chloride at the values
`shoWn in Table 1.
`
`The ?gures for each ingredient shoWn in Table 1 are
`expressed as % by Weight (W/v) and the appearance of each
`of the preparations are shoWn as the state before steriliZation
`by ?ltration based on the folloWing criteria:
`
`10
`
`<<appearances>> +:cloudy, —:colorless and clear
`
`TABLE 1
`
`Reference
`Preparation
`
`Reference
`Preparation
`
`Reference
`Preparation
`
`% by Weight (W/v)
`Reference
`Reference
`Preparation
`Preparation
`5
`
`1.6
`
`0.8
`
`—
`
`—
`
`—
`
`1.6
`
`0.8
`
`—
`
`—
`
`—
`
`—
`
`—
`
`0.36
`
`—
`
`—
`
`—
`
`—
`
`0.035
`
`0.72
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`0.31
`
`—
`
`—
`
`—
`
`2.5
`
`0.72
`
`—
`0.1
`0.01
`0.1
`0.005
`
`—
`
`7.6
`
`—
`—
`—
`0.1
`0.005
`
`+
`
`7.6
`
`0.18
`0.1
`0.01
`0.1
`0.005
`
`—
`
`7.6
`
`—
`0.1
`0.01
`0.1
`0.005
`
`—
`
`7.6
`
`0.59
`0.1
`0.01
`0.1
`0 005
`
`—
`
`7.6
`
`Boric acid
`
`Sodium borate
`
`Sodium carbonate
`
`Acetic acid
`
`Potassium
`
`dihydrogenphosphate
`
`Sodium
`
`dihydrogenphosphate
`dihydrate
`
`Disodium
`
`hydrogenphosphate
`dodecahydrate
`
`Sodium chloride
`Polysorbate 80
`Sodium edetate
`Pranoprofen
`Benzalkonium chloride
`
`Appearances
`
`pH
`
`“polysorbate 80”), stearic polyoxyl 40 and polyoxyethylene
`hydrogenated castor oil, stabiliZing agents such as sodium
`edetate and sodium citrate can be added thereto together
`With the organic amine, as necessary.
`The folloWing examples for formulating the preparations
`of the present ophthalmic solution are for better understand
`ing of the present invention but do not limit the scope
`thereof.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`Preparation Example
`Reference Example
`Boric acid (1.6 g), sodium borate (0.8 g), polysorbate 80
`(0.1 g) and sodium edetate (0.01 g) Were added to sterile
`puri?ed Water (80 ml), and pranoprofen (100 mg) Was added
`thereto While stirring to completely dissolve it To this Was
`added benZalkonium chloride (5 mg) to dissolve it, an
`appropriate amount of hydrochloric acid or sodium hydrox
`ide Was added thereto to adjust the pH to 7.6, sterile puri?ed
`Water Was added thereto to a total volume of 100 ml. The
`resulting colorless and clear solution Was ?nally steriliZed
`by ?ltration to obtain a 0.1% pranoprofen ophthalmic solu
`tion as reference preparation 1.
`Then, reference preparations 2 to 5 Were prepared accord
`ing to the similar manner as that described above by ?xing
`the concentration of pranoprofen at 0.1% and setting the
`concentrations of boric acid, sodium borate, sodium
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`As apparent from Table 1, In the preparations containing
`boric acid, sodium borate and benZalkonium chloride, a
`change in the composition occurred and cloudiness Was
`observed unless polysorbate 80 and sodium edentate Were
`formulated. In addition, When this cloudy liquid Was steril
`iZed by ?ltration, the content of pranoprofen Was decreased.
`
`EXAMPLE
`
`Tromethamine (2 g) Was added to sterile puri?ed Water
`(80 ml), and pranoprofen (100 mg) Was added thereto While
`stirring to completely dissolve it. To this Was added benZa
`lkonium chloride (5 mg) to dissolve it, an appropriate
`amount of hydrochloric acid or sodium hydroxide Was added
`to adjust the pH to 7.6, sterile puri?ed Water Was added to
`a total volume of 100 ml. The resulting colorless and clear
`solution Was ?nally steriliZed by ?ltration to obtain a 0.1%
`pranoprofen ophthalmic solution as preparation 1.
`Then, preparations 2 to 9 Were prepared according to the
`similar manner as that described above by ?xing the con
`centrations of pranoprofen and benZalkonium chloride at
`0.1% and 0.005%, respectively, and setting the concentra
`tions of tromethamine, HEPES, sodium chloride, polysor
`bate 80 and sodium edetate at the values shoWn in Table 2.
`The ?gures for each ingredient in Table 2 are expressed as
`% by Weight (W/v) and the appearance of each of the
`preparations are shoWn as the state before steriliZation by
`?ltration based on the folloWing criteria:
`<<appearances>> +: cloudy, —: colorless and clear
`
`Page 3
`
`

`
`US 6,281,224 B1
`
`TABLE 2
`
`% by Weight (W/v)
`Preparation 1 Preparation 2 Preparation 3 Preparation 4 Preparation 5 Preparation 6 Preparation 7 Preparation 8 Preparation 9
`
`Tromethamine
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.5
`
`0.5
`
`1.0
`
`—
`
`HEPES
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`2.0
`
`Sodium chloride
`
`Polysorbate 80
`
`Sodium edetate
`
`Pranoprofen
`Benzalkonium
`chloride
`
`Appearances
`
`pH
`
`—
`
`—
`
`—
`
`0.1
`0.005
`
`—
`
`—
`
`—
`
`0.1
`0.005
`
`—
`
`0.1
`
`—
`
`0.1
`0.005
`
`—
`
`0.1
`
`—
`
`0.1
`0.005
`
`—
`0.1
`0.01
`0.1
`0.005
`
`—
`0.1
`0.01
`0.1
`0.005
`
`0.68
`0.1
`0.01
`0.1
`0 005
`
`0.45
`0.1
`0.01
`0.1
`0.005
`
`0.5
`0.1
`0.01
`0.1
`0 005
`
`—
`
`7.6
`
`—
`
`8.0
`
`—
`
`7.6
`
`—
`
`8.0
`
`7.6
`
`7.6
`
`7.6
`
`7.6
`
`7.6
`
`As apparent from Table 2, in the preparations containing
`tromethamine and benzalkonium chloride, cloudiness Was
`not recognized and colorless and clear solutions Were
`obtained regardless of inclusion of polysorbate 80 and
`sodium edetate and, thus, it Was found that the present
`ophthalmic solution does not cause a change in the compo
`sition.
`
`Effect of the Invention
`Preparation properties test
`1) Stability test I (Effect on the remaining rate of
`pranoprofen)
`In order to study the stability of the present ophthalmic
`solution, the remaining rate of pranoprofen Which is an
`active ingredient Was measured.
`(Test procedures)
`An ophthalmic solution Was ?lled into an eyedropper
`made of polyethylene, Which Was stored at a temperature of
`40° C. and humidity of 75% for tWo months, and the amount
`of pranoprofen in the solution Was measured quantitatively
`by high performance liquid chromatography.
`(Results)
`Table 3 shoWs an example of the remaining rates of
`pranoprofen in preparations (preparation 1, preparation 2,
`preparation 3 and preparation 4) containing tromethamine
`and a preparation (reference preparation 1) containing boric
`acid.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`TABLE 3
`
`Remaining rate
`
`45
`
`Preparation 1
`Preparation 2
`Preparation 3
`Preparation 4
`Reference preparation 1
`
`98.6%
`99.9%
`98.7%
`100.2%
`94.9%
`
`As apparent from Table 3, in the preparations containing
`tromethamine, the remaining rate Was 98% or higher under
`the aforementioned conditions and no effect on the remain
`ing rate of pranoprofen Was recognized.
`2) Stability test II (Effect on pH at storage)
`In order to study the stability of the present ophthalmic
`solution, a pH change at storage Was measured by the
`folloWing procedures.
`(Test procedures)
`An ophthalmic solution Was ?lled into an eyedropper
`made of polyethylene, Which Was stored at a temperature of
`60° C. for tWo Weeks, and the pH of the solution Was
`measured.
`(Results)
`Table 4 shoWs an example of pH changes in the prepa
`rations (preparation 1, preparation 2, preparation 3, prepa
`
`50
`
`55
`
`60
`
`65
`
`ration 4 and preparation 5) containing tromethamine and a
`preparation (reference preparation 3) containing sodium
`carbonate and potassium dihydrogenphosphate.
`
`TABLE 4
`
`pH
`Before storage —> After storage
`
`Preparation 1
`Preparation 2
`Preparation 3
`Preparation 4
`Preparation 5
`Reference preparation 3
`
`7.6 —> 7.6
`8.0 —> 8.0
`7.6 —> 7.6
`8.0 —> 8.0
`7.6 —> 7.6
`7.6 —> 9.0
`
`As apparent from Table 4, in the preparations containing
`tromethamine, no pH change Was recognized under the
`aforementioned conditions.
`From the results 1) and 2), it Was made clear that the
`present ophthalmic solution has an excellent stability.
`3) Eye stimulating test
`In order to study the safety of the present ophthalmic
`solution, the irritating properties in human eyes Were mea
`sured by the folloWing procedures.
`(Test procedures)
`The eyes of 5 to 10 healthy male humans Were instilled
`With the present ophthalmic solution, the degree of irritation
`Was evaluated based on the criteria shoWn in Table 5 and an
`average of the scores Was adopted as an index for a degree
`of stimulation.
`
`TABLE 5
`
`Degree of stimulation
`
`Score
`
`Sensation of no stimulation
`Sensation of Weak stimulation
`Sensation of stimulation
`Sensation of strong stimulation
`
`0
`1
`2
`3
`
`(Results)
`Table 6 shoWs an example of degrees of irritation in the
`preparations (preparation 1, preparation 2, preparation 3,
`preparation 5 and preparation 9) containing tromethamine, a
`preparation (reference preparation 4) containing acetic acid
`and disodium hydrogenphosphate dodecahydrate, and a
`preparation (reference preparation 5) containing sodium
`dihydrogenphosphate dihydrate and disodium hydrogen
`phosphate dodecahydrate.
`
`Page 4
`
`

`
`US 6,281,224 B1
`
`7
`
`TABLE 6
`
`Degree of stimulation
`
`Preparation 1
`Preparation 2
`Preparation 3
`Preparation 5
`Preparation 9
`Reference preparation 4
`Reference preparation 5
`
`0.6
`0.4
`1.0
`0.0
`0.25
`1.8
`1.6
`
`As apparent from Table 6, a degree of stimulation Was 1
`or less and little ocular irritation Was recognized in the
`preparations containing tromethamine or HEPES and, thus,
`it Was made clear that the present ophthalmic solution is an
`ophthalmic solution having little ocular irritation.
`As described above, the present ophthalmic solution is an
`ophthalmic solution having no change in the composition,
`an excellent stability and little irritation to eyes and, thus, is
`useful as an ophthalmic solution containing pranoprofen as
`an active ingredient.
`
`INDUSTRIAL APPLICABILITY
`
`According to the present invention, there is provided an
`ophthalmic solution having pranoprofen as an active
`ingredient, Which has no change in the composition, an
`excellent stability and little irritation to eyes.
`What is claimed is:
`1. An ophthalmic solution comprising an effective oph
`thalmic amount of pranoprofen as an active ingredient, an
`amount of benZalkonium chloride effective as a
`preservative, and an amount of tromethamine effective to
`keep the solution stable and clear and loWers eye irritation,
`said tromethamine being in a concentration of 1 to 2.5% by
`Weight.
`2. The ophthalmic solution according to claim 1, Wherein
`the pranoprofen is in a concentration of 0.01 to 0.5% by
`Weight of.
`3. The ophthalmic solution according to claim 1, Wherein
`the tromethamine is in a concentration of 2.5% by Weight.
`4. The ophthalmic solution according to claim 1, Wherein
`the tromethamine is in a concentration 2.0% by Weight.
`5. The ophthalmic solution according to claim 1, Wherein
`the pranoprofen is in a concentration of 1.0% by Weight.
`6. The ophthalmic solution according to claim 1, Wherein
`the benZalkonium chloride is in a concentration of 0.002 to
`0.01% by Weight.
`
`8
`7. The ophthalmic solution according to claim 1, Wherein
`the benZalkonium chloride is in a concentration of 0.005%
`by Weight.
`8. The ophthalmic solution according to claim 1, Which
`has a pH of 6.5 to 8.5.
`9. The ophthalmic solution according to claim 1, Which
`has a pH of 7.6 to 8.0.
`10. A stable and clear ophthalmic solution for decreasing
`eye irritation comprising 0.01 to 0.5% by Weight of
`pranoprofen, 1 to 2.5% by Weight of tromethamine and
`0.002 to 0.01% by Weight of benZalkonium chloride, and
`having a pH of 6.5 to 8.5.
`11. A stable and clear ophthalmic solution for decreasing
`eye irritation comprising 0.1% by Weight of pranoprofen, 1
`to 2.5% by Weight of tromethamine and 0.005% by Weight
`of benZalkonium chloride, and having a pH of 7.6 to 8.0.
`12. The ophthalmic solution according to claim 1, Which
`further comprises
`an isotonic agent selected from the
`group consisting of sodium chloride and glycerin; (ii) a
`surfactant selected from the group consisting of polyoXy
`ethylene sorbitan monooleate, stearic polyoXyl 40 and poly
`oXyethylene hydrogenated castor oil; and (iii) a stabilizing
`agent selected from the group consisting of sodium edetate
`and sodium citrate.
`13. The ophthalmic solution according to claim 1,
`Wherein the pranoprofen is in a concentration of 0.01 to
`0.5% by Weight and the benZalkonium chloride is in a
`concentration of 0.002 to 0.01% by Weight.
`14. The ophthalmic solution according to claim 1,
`Wherein the tromethamine is in a concentration of 1% by
`Weight.
`15. The ophthalmic solution according to claim 1,
`Wherein the tromethamine is in a concentration of 2% by
`Weight.
`16. The ophthalmic solution according to claim 10,
`Wherein the tromethamine is in a concentration of 1 by
`Weight.
`17. The ophthalmic solution according to claim 10,
`Wherein the tromethamine is in a concentration of 2.5% by
`Weight.
`18. The ophthalmic solution according to claim 11,
`Wherein the tromethamine is in a concentration of 1 by
`Weight.
`19. The ophthalmic solution according to claim 11,
`Wherein the tromethamine is in a concentration of 2.5% by
`Weight.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
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