United States Patent [19]
`Lehmussaari et al.
`
`I IIIII
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIU 111111 ~1111111111
`US005795913A
`5,795,913
`[ill Patent Number:
`[45] Date of Patent:
`*Aug. 18, 1998
`
`[54] OPHTHALMIC COMPOSITION
`
`[75]
`
`Inventors: Karl Lehmussaari: Eija Vartiainen;
`Timo Reunamaki; OUi Oksala. all of
`Tampere; Sakari Alaranta. Kangasala;
`Esko Pohjala. Tampere, all of Finland
`
`[73] Assignee: Santen Oy, Tampere. Finland
`
`[*] Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat No.
`5.710.182.
`
`[21] Appl. No.:
`
`535,033
`
`[22] PCT Filed:
`
`Mar. 29, 1995
`
`[86] PCTNo.:
`
`PCT/FI95/00167
`
`§ 371 Date: Mar. 15, 1996
`
`§ 102(e) Date: Mar. 15, 1996
`
`[87] PCT Pub. No.: W095/26712
`
`PCT Pub. Date: Oct. 12, 1995
`
`[30]
`
`Foreign Application Priority Data
`
`Mar. 31, 1994
`[SE]
`Sweden .................................. 9401109
`Int. Cl.6 ••••••••••••••••••••••••••••••••••••••••••••••••••••• A61K 31135
`[51]
`[52] U.S. Cl .............................................. 514/459; 514/912
`[58] Field of Search ...................................... 514/459. 912
`
`[56]
`
`References Cited
`
`FOREIGN PliTENT DOCUMENTS
`
`2839752 12/1995 Gennany .
`
`WO 9119481 1211991 WIPO.
`WO 9300887
`l/1993 WIPO.
`
`OTHER PUBLICATIONS
`
`Florence Thermes et al .. "Bioadhesion: The Effect of Poly(cid:173)
`acrylic Acid on the Ocular Bioavailability of Timolol''.
`1992. vol. 81. pp. 54-65. International Journal of Pharma(cid:173)
`ceutica.
`
`Primary Examiner-Zohreh Fay
`
`[57]
`
`ABSTRACT
`
`The present invention is directed to an ophthalmic compo(cid:173)
`sition in the form of a topical aqueous solution consisting
`essentially of
`an ophthalmologically active agent containing basic
`groups.
`an ion sensitive. hydrophilic polymer containing acidic
`groups in an amount of 0.004 to 1.5% by weight.
`at least one salt selected from the group of inorganic salts
`and buffers in a total amount of from 0.01 to 2.0% by
`weight.
`and optionally a wetting agent and a preservative, the ratio
`between salt and polymer being such that the solution
`exhibits a viscosity ofless than 1000 mpas. and the pH
`of the solution is 4.0 to 8.0. The composition contains
`a sufficient amount of polymer to provide for a con(cid:173)
`trolled absorption of the drug into the eye. its viscosity
`having been reduced to provide for better handling
`characteristics.
`
`10 Claims, 6 Drawing Sheets
`
`Page 1 of 11
`
`SENJU EXHIBIT 2007
`MYLAN v. SENJU
`IPR2016-00626
`
`

`
`U.S. Patent
`
`Aug. 18, 1998
`
`Sheet 1 of 6
`
`5,795,913
`
`~ N
`Q,)
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`Page 2 of 11
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`

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`VJ
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`
`Cl)
`
`6000
`
`-m-Tllli 0.25%, 440 cP
`---Tllli 0.25%, 7300 cP
`
`8000
`
`Fig. 2
`
`Shear rate (1/sec)
`20
`1t1
`
`15
`
`s
`I It P
`
`121
`
`10
`
`111
`
`0
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`
`Page 3 of 11
`
`

`
`U.S. Patent
`
`Aug. 18, 1998
`
`Sheet 3 of 6
`
`5,795,913
`
`4000 ~---------------------------------------~
`
`~ THH 0.25%, 7300 cP (PAA 0.95 mg/ml)
`c::J 1HH 0.25%, 440 cP (PAA 0.95 mg/ml)
`
`3000
`
`:::;::
`w
`(/)
`i z
`L5 2000
`~
`
`.€ C)
`c:
`
`1000
`
`0.5 h
`
`1.0 h
`
`THH = Timolol hemihydrate
`P AA = Carbo pol 941
`
`Fig. 3
`
`Page 4 of 11
`
`

`
`U.S. Patent
`
`Aug. 18, 1998
`
`Sheet 4 of 6
`
`5,795,913
`
`4000 - . - - - - - - - - - - - - - - - - - - - - - - - - - - - .
`
`~ THH 0.25%, PAA 2.0 mg/ml ( pH 6.9 )
`llllllllillilll THH 0.25%, PM 1.15 mg/ml (pH 6.9}
`
`3000
`
`::2:
`w
`U)
`I +
`~ 2000
`::2:
`
`.E 0') c
`
`1000
`
`0.5 h
`
`1.0 h
`
`THH = Timolol hemihydrate
`P AA = Carbopol 941
`
`Fig. 4
`
`Page 5 of 11
`
`

`
`U.S. Patent
`
`Aug. 18, 1998
`
`Sheet 5 of 6
`
`5,795,913
`
`7000,------------------------------------------~
`
`~ THH 0.5%, PAA 1.5 mg/ml (pH 7.5)
`lll!lll THH 0.5%, PAA 0.95 mg/ml ( pH 7.5)
`
`6000
`
`:2 5000
`w
`(f)
`-!..
`~ 4000
`~
`:2 3000
`
`~ c
`
`2000
`
`1000
`
`0.5 h
`
`1.0 h
`
`THH = Timolol hemihydrate
`P AA = Carbopol 941
`
`Fig. 5
`
`Page 6 of 11
`
`

`
`U.S. Patent
`
`Aug. 18, 1998
`
`Sheet 6 of 6
`
`5,795,913
`
`1..0
`cry
`
`0
`C")
`
`1..0
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`
`Page 7 of 11
`
`

`
`5.795.913
`
`1
`OPHTHALMIC COMPOSITION
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to an ophthalmic composi(cid:173)
`tion in the form of a topical aqueous solution for human and
`veterinary use, as well as the use of the solution. especially
`for the treatment of glaucoma and ocular hypertension.
`It is well known to use polymers alone or in combination
`with other polymers for the preparation of ophthalmic
`pharmaceuticals and artificial tear compositions. The inclu(cid:173)
`sion of the polymer aims at increasing the viscosity of the
`composition so as to provide for a longer contact time with
`the cornea of the eye, and, for example, in connection with
`ophthalmic drugs, to provide for a sustained release of the
`drug into the eye.
`For example, the U.S. Pat. Nos. 5.075.104 and 5.209.927
`relate to an ophthalmic gel composition and an ophthalmic
`liquid composition, respectively. The first mentioned com(cid:173)
`position includes 0.25 to 8% by weight of a carboxy vinyl
`polymer (polymer of carbomer type). the latter 0.05 to
`0.25% by weight, resulting in viscosities of the compositions
`ranging from 15000 to 300000. or 10 to 20000. respectively.
`In the publication WO 93/17664 high viscosity, polymer
`containing ophthalmic compositions are disclosed
`containing, in combination. carboxy vinyl polymers of the
`carbomer type, and cellulosic polymers. According to this
`disclosure lower polymer concentrations can be used while
`still achieving the desired higher viscosity. A wide range for
`the concentration of polymers is given, the broadest range
`indicated being 0.05 to 3% by weight of carbomer, and 0.05
`to 5.0% by weight of cellulose polymer. A similar two(cid:173)
`polymer system is described in the WO-publication WO
`91/1948L the system being such which gels when exposed
`to the pH and temperature conditions of the eye surface. In
`the said publication, an inclusion of up to 0.9% of salt is
`contemplated for the adjustment of the viscosity.
`There is also a number of publications relating to phar(cid:173)
`maceutically active ophthalmic compositions containing
`various polymers. i.a. carboxy vinyl polymers. at various
`concentrations. As tonicity regulating agents. usually non(cid:173)
`ionic polyols are suggested so as not to interfere with the gel
`structure (WO 93/00887, WO 90/13284). In the publication
`Int. J. Pharm.. 81 (1992) 59-65, aqueous compositions
`containing timolol maleate and 0.6% polyacrylic acid (MW
`250.000). as well as the salt of timolol base with 0.6%
`polyacrylic acid are described, containing mannitol as tonic-
`ity regulator. The viscosity measured at low shear rates is
`indicated as being 45 centipoise.
`In the DE-patent specification 28 39 752 ophthalmic gel
`compositions are described containing carboxy vinyl poly(cid:173)
`mers in an amount of 0.05 to 5.0% by weight and exhibiting
`viscosities of 1000 to 100.000 centipoise. According to this
`disclosure. a small amount of sodium chloride from 0.001 to 55
`0.5% by weight is added in order to prevent the gel from
`breaking down on the surface of the eye (see column 4. lines
`41 ff).
`
`50
`
`2
`formation of the polymer film on the cornea of the eye. but
`which composition is still fluid enough for ocular topical
`application. A further object of the invention is to provide an
`easy-to-use eye drop formulation with improved patient
`5 compliance.
`According to the invention it has now been shown that by
`raising the concentration of the polymer over a value where
`the composition normally is a gel rather than a liquid and by
`simultaneously lowering the viscosity thereof. it is possible
`10 to obtain a desired beneficial effect of the active agent in the
`eye, while simultaneously reducing any discomfort in the
`patient's eye, as compared to the administration of a corn(cid:173)
`position in gel form. The unbroken and even polymer film
`still being formed on the eye facilitates the binding and
`15 retaining of water on the surface of the eye, and thus
`provides for an additional wetting effect while providing for
`a better contact and thus a controlled absorption of active
`agent into the eye.
`According to the invention we have shown that it is the
`2° amount of polymer in the composition. rather than the
`viscosity of the composition as such, which are important
`from the point of view of obtaining good absorption of drug
`into the eye. This is especially evident from the tests
`described below. In the FIG. 3 it is shown. for example. that
`25 by using the same amount of polymer. in compositions that
`have different viscosities, the compositions provide for
`substantially the same absorption. According to the state of
`the art one would. however, had expected the composition
`with the higher viscosity to provide for the higher absorp-
`30 tion. These results are supported also by the results pre(cid:173)
`sented in the FIG. 4, which show that compositions, which
`contain different amounts of polymer, but have the same
`viscosities and pH's, the absorption is stronger form the
`composition with the higher polymer concentration.
`35 A further important beneficial effect is achieved by using,
`according to the invention, an ophthalmologically active
`agent which contains basic groups, such as amine groups.
`Such a basic agent participates in an ion exchange reaction
`or salt formation with a polymer containing acid groups,
`40 such as polyacrylic acid polymer. The increased retaining
`ionic forces between the polymer and active agent provides
`for a further improved delivery of the active agent. Due to
`the fact that the basic drug is well retained by the polymer.
`the dosage can be lowered and/or the daily number of
`45 administration of the drug can be reduced, if desired, with(cid:173)
`out the loss of activity, and consequently the side effects can
`be reduced as well.
`The present invention thus provides an ophthalmological
`composition in a liquid. easy-to-use form which provides for
`both an increased and prolonged absorption of active agent
`into the eye. The invention thus makes it possible to treat e.g.
`glaucoma and ocular hypertension using a once-a-day-only
`or less frequent regimen for administering the ophthalmo-
`logical active agent and to lower the dosage clearly below
`the dosages presently in use.
`More specifically. the object of the invention is an oph(cid:173)
`thalmological composition in the form of a topical aqueous
`solution consisting essentially of (%:s are of the total
`60 composition)
`an ophthalmologically active agent containing basic
`groups.
`an ion sensitive, hydrophilic polymer containing acidic
`groups in an amount of 0.004 to 1.5% by weight,
`at least one salt selected from the group of inorganic salts
`and buffers in a total amount of from 0.01 to 2.0% by
`weight.
`
`SUMMARY OF THE INVENTION
`
`The present invention is based on the discovery that the
`beneficial effect of ophthalmic compositions of the above
`type containing viscosity enhancing agents. is due to the
`concentration of the polymer present in the composition,
`rather than on the viscosity thereof. Thus one object of the 65
`invention is to provide an ophthalmic composition with a
`sufficiently high concentration of polymer to control the
`
`Page 8 of 11
`
`

`
`5.795.913
`
`3
`a wetting agent in an mount of 0 to 3.0% by weight.
`a preservative in an mount of 0 to 0.02% by weight, and
`water,
`the ratio between salt and polymer components being such
`that the solution exhibits a viscosity of less than 1000 mPas, 5
`and the pH of the solution is 4.0 to 8.0.
`
`4
`patholytic agent. such as a ~-blocker. carbonic anhydrase
`inhibitor. or an antibiotic. antiinflammatoric. antiallergic
`agent. etc. containing a basic group, or a combination
`thereof. Thus according to the invention. the eye drugs
`contemplated may contain a primary, secondary or tertiary
`amino group or organoammonium or amidine attached to a
`chain or a ring, or a nitrogen atom(s) can be a part in various
`basic heterocycles. such as imidazole, imidazoline. pyridine.
`piperidine or piperazine. Preferably an agent active against
`glaucoma or effective in the treatment of increased intraocu(cid:173)
`lar pressure is used. A particularly preferred group of com(cid:173)
`pounds is comprised of ~-blocking agents having a second(cid:173)
`ary amine function such as betaxolol. carteolol.levobunolol.
`metipranolol. pindolol. propranolol and timolol in base
`form. An especially advantageous mode of the invention is
`15 such where timolol is used as its easily crystallizable
`S-timolol hemihydrate.
`Other typical examples of basic drug molecules useful in
`eye therapy include tobramycin and norftoxacin
`(antimicrobial. antibacterial), cyclopentolate. tropicamide,
`20 atropine. phenylephrine, metaoxedrine (anticholinergic,
`mydriatic), pilocarpine. carbacol. ecothiopate (cholinergic),
`adrenaline, dipivefrin. dopamine (adrenergic). naphazoline,
`tetryzoline (vasoconstrictor), verapamil, nifedipine
`(vasodilator), apraclonidine, clonidine, medetomidine (a2-
`25 agonist), sezolamide (carbonic anhydrase inhibitor). cetiriz(cid:173)
`ine (antihistamine), as such or in their ester and prodrug
`forms.
`Especially contemplated in the invention is the use of a
`~-blocking agent. such as S-timolol. especially in the from
`of the hemihydrate. as the only drug, or as combined with
`e.g. the base form of pilocarpine.
`The amount of active agent in the final composition may
`vary. such as between 0.001 to 5% by weight, usually,
`however. between 0.01 to 0.5% by weight, and typically
`35 between 0.1 and 0.5% by weight. especially in the case of
`S-timolol hemihydrate.
`According to an advantageous embodiment of the
`invention. the composition contains in addition. in order to
`enhance the wetting effect thereof, a wetting agent. prefer(cid:173)
`ably a polyhydric alcohol. such as glycerol. The amount of
`wetting agent is generally at the most 3.0, such as of the
`order of 0.5 to 3.0% by weight.
`As preservatives, e.g. benzalkonium chloride, benzyl
`alcohol. mercury salts, thiomersal. chlorhexidine or the like,
`as such or in combination. The amount of preservative
`usually lies in the range of 0 to 0.02% by weight.
`An advantageous composition in the form of an aqueous
`solution consists essentially of the following components (%
`being % by weight of the total composition):
`timolol in the form of its hemihydrate in an amount of 0.1
`to 0.5% by weight, calculated as the free base,
`polyacrylic acid in an amount of 0.04 to 0.4% by weight
`glycerol in an amount of 0.5 to 2.5% by weight
`sodium phosphates in an amount of 0.01 to 1.5% by
`weight.
`a preservative in an amount of 0 to 0.02%, and
`water, the viscosity of the composition being less than 800
`centipoise and the pH of the composition being 6.5 to
`8.
`According to the invention, the term "consisting essen-
`tially of' is intended to mean that the composition contains
`only or essentially only the components listed in connection
`therewith. The compositions may however, in addition.
`contain substances, such as ophthalmologically acceptable
`65 adjuvants and additives of such a type and in such amounts
`as to have no essential influence on the characteristics of the
`composition.
`
`10
`
`BRIEF DESCRIYfiON OF THE DRAWINGS
`FIG. 1 is a graph of viscosity versus shear rate of the
`solutions described in Examples 1-3 herein;
`FIG. 2 is a graph of viscosity versus shear rate of the
`solutions compared in Study 1 described herein;
`FIG. 3 is a bar graph of concentration versus absorption
`time of the solutions compared in Study 1 described herein;
`FIG. 4 is a bar graph of concentration versus absorption
`time of the solutions used in study 4 described herein;
`FIG. 5 is a bar graph of concentration versus absorption
`time of the solutions used in study 5 described herein.
`FIG. 6 is a graph of viscosity versus shear rate of a
`solution in accordance with Example 1 taken at various
`times after storage at room temperature.
`
`DErAILED DESCRIYfiON OF THE
`INVENTION
`
`The ion-sensitive hydrophilic polymer to be used accord(cid:173)
`ing to the invention contains acid groups, and is typically a
`carboxy vinyl polymer, or hyaluronic acid. Typical repre(cid:173)
`sentatives of carboxy vinyl polymers are the polyacrylic acid
`polymers. known as carbomers. Carbomers are available at
`different molecular weights, typically ranging from e.g. 30
`450.000 to 4.000.000, and sold under the trade name
`Carbopol. e.g. Carbopol907. 910.934. 934P. 940.941.971.
`971P. 974. 974P, 980. and 981. preferably Carbopol941 and
`981.
`The polymer is preferably used in an amount of 0.01 to
`0.8. more preferably 0.01 to 0.4. and advantageously 0.04 to
`0.4% by weight.
`According to the invention it has been established that it
`is favourable both from the view point of efficacy of the
`product in the target site. and of ease of application, to 40
`reduce the viscosity of the composition to a level of less than
`1000 centipoise. suitably less than 800 mPas, when mea(cid:173)
`sured at 25° C. with a Brookfield LVDV-ill type viscometer
`at a shear rateD of 1.1 s-1
`• This object is achieved by adding
`to the composition a salt and/or a buffer in the specified 45
`amount. preferably in an amount of 0.01 to 1.5% by weight.
`As viscosity decreasing salts and buffers the following may
`be mentioned: sodium chloride. potassium chloride. sodium
`phosphates (monobasic and dibasic), sodium borate, sodium
`acetate. sodium citrate. equivalents or mixtures thereof. In
`case no salts are added. a formulation with an unacceptably
`high viscosity is obtained. - It is to be noted that the
`composition according to the invention still exhibits favour(cid:173)
`able non-newtonian properties when applied to the eye
`surface, despite the addition of salts.
`For some purposes. for example for appearance and 55
`storage purposes. the use of a buffering salt is preferred to
`the use of e.g. sodium or potassium chloride as the viscosity
`reducing agent.
`The pH of the composition is suitably from 5.0 to 8,
`preferably from 6.5 to 8.0. The pH of the composition is 60
`according to the invention adjusted solely by means of the
`amounts used of acidic polymer and basic active agent,
`respectively. and in such cases no additional pH-regulating
`agents are needed. This in turn means that the process for
`manufacturing the composition can be simplified.
`The ophthalmologically active agent is advantageously an
`antiglaucoma agent. a sympathomimetic agent. a sym-
`
`50
`
`Page 9 of 11
`
`

`
`5.795.913
`
`5
`The composition according to the invention is typically
`prepared in three stages. In the first step the polymer is
`dispersed in sterile water and sterilized by autodaving. In
`the second step. the other ingredients. namely the active
`ingredient(s). inorganic salt(s). tonicity regulating agent(s). 5
`preservative(s) and any other additives. are dissolved in
`sterile water and sterilized by filtration on a filter (pore size
`e.g. 0.2 llfll). In the third and last step the solution prepared
`in the two steps are combined aseptically and mixed until
`they form a homogenous solution with a low viscosity. The
`pH of the solution is usually adjusted by adjusting the
`relative amounts of active agent and polymer. Thereafter the
`composition is packaged in multi- or unit dose form.
`The following examples illustrate the invention in more 15
`detail. without limiting the same.
`
`10
`
`EXAMPLE 1
`
`6
`EXAMPLE 3
`
`The following composition was made:
`
`Composition
`
`S-Timolol hemihydrate
`Carbopol 981
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`2.56
`1.4
`0.62
`2.85
`23.0
`0.06
`to 1000 mL
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 6.9 and the viscosity of
`
`the solution was 70 centipoise (D=l.l s- 1). Viscosity vs.
`shear rate curve is shown in FIG. 1.
`
`EXAMPLE4
`
`The following composition was made:
`
`20
`
`The following composition was made:
`
`Composition
`
`S-TIIIlOlol hernihydrate
`Carbopol941
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`2.56
`0.95
`0.08
`1.80
`23.0
`0.06
`to IOOOmL
`
`Composition
`
`S-TtmOlol hemihydrate
`Carbopol 981
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`1.0
`0.65
`0.016
`0.32
`23.0
`0.06
`to 1000 mL
`
`25
`
`30
`
`Carbopol 941 was dispersed in 300 mL sterile water at
`room temperature. The solution was sterilized in an auto(cid:173)
`clave. The autoclaved solution was cooled to room tempera(cid:173)
`ture (solution 1). Benzalkonium chloride. glycerol. sodium 35
`phosphate monobasic and dibasic and timolol hemihydrate
`were dissolved in 700 mL sterile water at room temperature
`and sterilized by filtration on a filter with a pore size of 0.2
`J.UU (solution 2 ). In the final step the solutions prepared in the
`two previous steps (solution 1 and 2) were combined asep- 40
`tically and mixed until they formed a homogenous low
`viscous solution. The pH of the solution obtained was 7.4
`and its viscosity was 440 centipoise (D= 1.1 s-1
`). Thereafter
`the solution was packed in traditional eye drop bottles.
`
`45
`
`The viscosity vs. shear rate curve for the composition is
`shown in FIG. 1. It is to be noted that the shape of the curve
`shows still non-newtonian rheology despite the addition of
`salts.
`
`EXAMPLE2
`
`The following composition was made:
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was pH 6.6. The viscosity
`of the solution was 540 centipoise (D=l.l s-1
`).
`
`EXAMPLE 5
`
`The following composition was made:
`
`Composition
`
`S-TIIIlOiol hemihydrate
`Carbopol 941
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`2.56
`2.0
`1.40
`7.42
`16.0
`0.06
`to 1000 mL
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 6.9 and the viscosity
`50 was 600 centipoise (D=l.l s-1
`).
`
`EXAMPLE6
`
`The following composition was made:
`
`Composition
`
`S-TIIIlOiol hemihydrate
`Carbopol941
`Sodium chloride
`Glycerol
`Benzalkonil.Ull chloride
`Water for injection
`
`(g)
`
`2.56
`0.85
`0.9
`20.0
`0.06
`to IOOOmL
`
`55
`
`60
`
`Composition
`
`S-Timolol hemihydrate
`Carbopol 981
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`5.12
`3.0
`2.0
`10.0
`5.0
`om
`to 1000 mL
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 6.9 and the viscosity of 65
`the solution was 380 centipoise (D=l.l s-1
`). Viscosity vs.
`shear rate curve is shown in FIG. 1.
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 6.9 and the viscosity
`was 670 centipoise (D=l.l s-•).
`
`Page 10 of 11
`
`

`
`5.795.913
`
`7
`EXAMPLE?
`
`The following composition was made:
`
`Composition
`
`Clonidine (base)
`Carbopol 981
`Sodiwn phosphate monobasic
`Sodiwn phosphate dibasic
`Glycerol
`Benzalkonhnn chloride
`Water for injection
`
`(g)
`
`1.25
`0.70
`0.04
`0.6
`23.0
`0.06
`to 1000mL
`
`10
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 7.0 and the viscosity 15
`was 540 centipoise (D=l.l s-1
`).
`
`8
`intervals with a Brookfield LVDV-III type viscometer at
`room temperature. The viscosity vs. shear rate curves are
`shown in FIG. 6. The results show that the viscosity of the
`timolol-polyacrylic acid-solutiomremained stable even after
`5 one year of storage.
`We claim:
`1. Ophthalmic composition in the form of a topical
`aqueous solution consisting essentially of:
`an ophthalmologically active agent containing basic
`groups.
`an ion sensitive, hydrophilic polymer containing acidic
`groups in an amount of 0.004 to 1.5% by weight.
`at least one salt selected from the group of inorganic salts
`and buffers in a total amount of from 0.01 to 2.0% by
`weight,
`a wetting agent in an amount of 0 to 3.0% by weight.
`a preservative in an amount of 0 to 0.02% by weight. as
`well as
`water,
`the ratio between salt and polymer being such that the
`solution exhibits a viscosity of less than 1000 centipoise. and
`the pH of the solution is between about 4.0 and about 8.0.
`2. The composition of claim 1. wherein the polymer is
`25 present in an amount of from 0.01 to 0.8 by weight and is
`selected from the group consisting of carbopol 907. 910.
`934, 934P. 940, 941. 971. 971P. 974. 974P. 980 and 981.
`3. The composition of claim 1 wherein the wetting agent
`is glycerol.
`4. The composition of claim 3. wherein the amount of
`glycerol is 0.5 to 2.5% by weight.
`5. The composition of claim 1 or 2. wherein the sale is
`selected from the group consisting of sodium chloride.
`potassium chloride. sodium phosphates. sodium borate.
`35 sodium acetate, sodium citrate and mixtures thereof.
`6. The composition of claim 1 or 2. wherein the viscosity
`is less than 800 centipoise.
`7. The composition of claim 1 or 2. having a pH of 5.0 to
`8.0.
`8. The composition of claim 1. wherein the ophthalmo-
`logically active agent is selected from the group consisting
`of antiglaucoma agents, symphathoimimetic agents. sym(cid:173)
`patholytic agents. P-blockers, carbonic anhydrase inhibitors.
`antibiotics. anti.inftammatoric agents. antiallergic agents and
`mixtures thereof.
`9. The composition of claim 8. wherein the active agent
`is selected from the group consisting of betaxolol. carteolol.
`levobunolol. metipranolol. pindolol. propranolol and
`timolol. pilocarpine and mixtures thereof.
`10. The composition according to claim 1. consisting
`50 essentially of:
`timolol hemihydrate in an amount of 0.01 to 0.5% by
`weight;
`polyacrylic acid in an amount of 0.04 to 0.4% by weight;
`glycerol in an amount of 0.5 to 2.5% by weight.
`sodium phosphates in an amount of 0.01 to 1.5% by
`weight.
`a preservative in an amount of 0 to 0.02%. and
`water
`60 the viscosity of the solution being less than 800 centipoise
`and the pH of the solution being 6.5 to 8.
`
`EXAMPLES
`
`The following composition was made:
`
`Composition
`
`Pilocarpine (base)
`Carbopol 981
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Glycerol
`Benzalkonium chloride
`Water for injection
`
`(g)
`
`20.0
`3.0
`10.6
`0.53
`5.0
`0.10
`to 1000 mL
`
`20
`
`30
`
`The solution was prepared according to the Example 1.
`The pH of the solution obtained was 6.8 and the viscosity
`was 900 centipoise (D=l.1 s-1
`).
`By leaving out from the formulations (Examples 1-8) the
`benzalkonium chloride. corresponding unit-dose formula(cid:173)
`tions were obtained.
`Absorption of timolol into the rabbit eye (Study 1)
`An ophthalmic formulation (Example 1). which is a
`typical example of this invention, was instilled into a rabbit
`eye (n=6). The concentration of timolol in the aqueous 40
`humor was measured after Y2 and 1 hours using HPLC. The
`reference product contained the same amount of carbopol.
`timolol and preservative. benzalkonium chloride. but did not
`contain any inorganic salt(s). The viscosity of the reference
`product was much higher (7300 centipoise, D=l.1 s-1
`). The
`viscosity curves of the products are shown in F1G. 2.
`The timolol concentrations in the aqueous humor in
`rabbits are shown in F1G. 3. According to F1G. 3. the
`absorption of timolol in rabbits eye was equal despite the
`different viscosities.
`Absorption of timolol into the rabbit eye (Study 2 and 3)
`Timolol solutions were installed into a rabbit eye. The
`administered timolol solutions had the same pH and
`viscosity. but the solutions contained different amounts of
`polyacrylic acid (Carbopol 941). The concentration of
`timolol in the aqueous humor was measured after Y2 and 1 55
`hours using HPLC. The timolol concentrations in the aque(cid:173)
`ous humor in rabbits are shown in the F1G. 4 and 5.
`According to F1G. 4 and 5. the absorption of timolol in
`rabbit eye depend on the concentration of the polymer used.
`Stability of the timolol-polvacrylic acid solution
`An ophthalmic formulation (Example 1). which is a
`typical formulation of this invention, was stored at room
`temperature for 12 months. The viscosity of the timolol(cid:173)
`polyacrylic acid solution was measured after different time
`
`45
`
`* * * * *
`
`Page 11 of 11