`
`[19]
`
`[11] Patent Number:
`
`5,891,913
`
`Sallmann et al.
`
`[45] Date of Patent:
`
`Apr. 6, 1999
`
`US005891913A
`
`[54] OPHTHALMIC AND AURAL
`COMPOSITIONS CONTAINING
`
`[75]
`
`DICLOFENAC POTASSIUM
`..
`.
`Inventors: Altzred Sallmann, .Bottm1ngen; Gyorgy
`LZIJOS Kls, Triboltmgen, both of
`Switzerland; Wolfgang Blum, Weil am
`Rhein, Germany; Alica Huxley,
`Bjnnjngen, Switzerland
`
`[73] Assignee: Novartis Finance Corporation, New
`Y0Tk, N~Y~
`809 434
`’
`Sep. 28, 1995
`
`21 A 1. N ‘Z
`]
`pp
`0
`[
`[22]
`PCT Filed:
`ea
`
`§ 371 Date:
`
`Aug. 27, 1997
`
`§ 102(e) Date: Aug. 27, 1997
`PCT Pub. No.: W096/11003
`
`[87]
`
`PCT Pub Date: Apr‘ 18! 1996
`
`Foreign Application Priority Data
`[30]
`Oct. 10, 1994
`[EP]
`European Pat. Off.
`............ .. 94810589
`Sep. 18, 1995
`[EP]
`European Pat. Off.
`.............. 95810574
`[51]
`Int. Cl.6 ................................................. .. A61K 31/195
`[52] U.S. Cl.
`......................... .. 514/567; 514/912; 514/913
`[5s] Field of Search ..................................... 514/567, 912,
`514/913
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`
`9/1988 European Pat. Off.
`0306984A1
`3/1990 European Pat. Off.
`0390071A1
`592348 10/1993
`E
`P t. Off.
`2192539
`6/1986
`Ultllrfsepclealgngdom .
`
`.
`.
`.
`
`OTHER PUBLICATIONS
`
`Diclofenac—K (50 and 100)mg and placebo in the Acute
`Treatment of Migraine, C. Dahlof, et al., Cephalalgia 13, pp.
`117-123, 1993.
`Amoxicillin Comparative Double—Blind Study in Ent Infec-
`tions Clinical Evaluation of Diclofenac Potassium vs. Pla-
`cebo, Hospital Infantil Mexico, pp. 50-56, 1988. (English
`abstract).
`:::0?;“;::“;1::.I3121:t§::2§:1;::y.£1“N:::1%a2“2:$-
`parative Rndomized Trial with Nimesulide and Potassium
`Diclofenac, Oliveira, D.D., pp. 87-91, 1991.
`(English
`abstract).
`
`Primary Examiner—Zohreh Fay
`Attorney, Agent, or Firm—l\/lichael U. Lee
`
`[57]
`
`ABSTRACT
`-
`-
`-
`-
`-
`-
`°SIfi‘£h:1;?:;§;E1§§S:;°g
`giiofizjlsfcntplggirglflgl dfE§“E::
`medicament for treating inflammatory conditions of the eye,
`fer. treating glaueoma or foptreating. ear inflammatory eon-
`ditldene ind/or pamfale0ad1%0ns(0t1t1s)-1 asfwellhas the use
`o
`1c o enac potassium in t e preparation o a p armaceu-
`tical composition for the treatment of any inflammatory
`condition of the eye, for treating glaucoma or for treating ear
`inflammatory and/or painful conditions (otitis).
`
`4,960,799
`
`10/1990 Nagy ..................................... .. 514/567
`
`6 Claims, No Drawings
`
`Page 1 of 8
`
`LUPIN EX 1021
`
`LUPIN EX 1021
`
`Page 1 of 8
`
`
`
`5,891,913
`
`1
`OPHTHALMIC AND AURAL
`COMPOSITIONS CONTAINING
`DICLOFENAC POTASSIUM
`
`This application claims priority to European Patent
`Application No. 95/03844, filed on Sep. 28, 1995.
`The present invention describes an ophthalmic compo-
`sition comprising diclofenac potassium,
`the use of said
`composition as a medicament for treating inflammatory
`conditions of the eye, for treating glaucoma or for treating
`ear inflammatory and/or painful conditions (otitis); as well
`as the use of diclofenac potassium in the preparation of a
`pharmaceutical composition for treating any inflammatory
`condition of the eye, for treating glaucoma or for treating ear
`inflammatory and/or painful conditions (otitis).
`Hitherto, predominantly corticosteroids have been used
`for the treatment of relatively severe acute or chronically
`recurrent inflammatory symptoms in the eye. The immuno-
`suppressant action of these substances, however, conceals
`the risk of a deterioration in the clinical picture as a result of
`a bacterial or viral infection. Therefore, considerable efforts
`are still made,
`to develop potent non-steroidal anti-
`inflammatory agents and to introduce them into ophthalmo-
`logical therapy.
`EP 242 328 describes for example a medicament for the
`treatment of inflammations of the eye, which medicament
`comprises sodium 2-[(2,6-dichlorophenyl)amino]-phenyl
`acetate, known as diclofenac sodium.
`Diclofenac-potassium, is chemically described as potas-
`sium 2-[(2,6-dichlorophenyl)amino]-phenyl acetate.
`It
`is
`known as a non-steroidal anti-inflammatory drug (NSAID).
`A Norwegian publication, Cephalalgia 13, 117—123(1993),
`describes for example the use of diclofenac potassium in the
`acute treatment of migraine.
`A stabilized aqueous solution of pharmaceutically
`acceptable salts of 2-[(2,6-dichlorophenyl)amino]-phenyl
`acetic acid for ophthalmic use is disclosed in U.S. Pat. No.
`4,960,799. Diclofenac potassium is not specifically dis-
`closed in said application. Accordingly, all claims and
`working examples of said application disclose either
`diclofenac sodium or its free acid as a pharmaceutically
`active ingredient. Hence, said application is clearly directed
`towards the provision of a stable aqueous solution of a
`pharmaceutically acceptable salt of 2-[(2,6-dichlorophenyl)
`amino]-phenyl acetic acid containing an effective amount of
`a pharmaceutically acceptable salt of ethylenediamine tet-
`raacetic acid.
`
`that the potassium salt of
`Surprisingly it was found,
`2-[(2,6-dichlorophenyl)amino]-phenyl acetic acid,
`diclofenac potassium, is especially suitable to treat inflam-
`matory ocular processes in general. It has been demonstrated
`that for example the ocular penetration of diclofenac potas-
`sium is much superior in comparison to the corresponding
`diclofenac sodium. In addition to said advantage, pharma-
`cological studies show a much better topical tolerance, e.g.
`ocular tolerance, and efficacy of diclofenac potassium in
`comparison to diclofenac sodium and also a surprisingly
`short onset of action as well a long lasting duration of action
`e.g. in the eye.
`Therefore the present invention relates to an ophthalmic
`composition for treating inflammatory ocular conditions, for
`treating glaucoma or for treating ear inflammatory and/or
`painful conditions (otitis), which composition comprises a
`therapeutically effective amount of diclofenac potassium
`and a carrier.
`
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`2
`which composition comprises a therapeutically effective
`amount of diclofenac potassium and a carrier.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier and a stabilizer.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier and a solubilizer.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a stabilizer and a
`solubilizer.
`
`invention relates also to an ophthalmic
`The present
`composition, which comprises a therapeutically effective
`amount of diclotenac potassium, a carrier, a solubilizer, a
`stabilizer and a complexing agent.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a solubilizer, a
`stabilizer, a complexing agent and a tonicity enhancing
`agent.
`invention relates also to an ophthalmic
`The present
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a solubilizer, a
`stabilizer, a complexing agent, a tonicity enhancing agent
`and a buffer.
`
`invention relates also to an ophthalmic
`The present
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a solubilizer, a
`stabilizer, a complexing agent, a tonicity enhancing agent, a
`buffer and a preservative.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium and a carrier, and is further
`comprising one or more of the excipients selected from the
`group consisting of buffers, complexing agents,
`tonicity
`enhancing agents, preservatives and fillers.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier and a stabilizer,
`and is further comprising one or more of the excipients
`selected from the group consisting of buffers, complexing
`agents, tonicity enhancing agents, preservatives and fillers.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier and a solubilizer,
`and is further comprising one or more of the excipients
`selected from the group consisting of buffers, complexing
`agents, tonicity enhancing agents, preservatives and fillers.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a solubilizer and
`a stabilizer, and is further comprising one or more of the
`excipients selected from the group consisting of buffers,
`complexing agents, tonicity enhancing agents, preservatives
`and fillers.
`
`Another aspect of the present invention is the use of
`diclofenac potassium and a carrier in the preparation of a
`pharmaceutical composition for treating inflammatory ocu-
`lar conditions, for treating glaucoma or for treating ear
`inflammatory and/or painful conditions (otitis).
`The present invention relates also to the use of diclofenac
`potassium and a carrier in the preparation of a pharmaceu-
`tical composition for
`treating inflammatory ocular pro-
`cesses.
`
`invention relates also to an ophthalmic
`The present
`composition for treating inflammatory conditions of the eye,
`
`The present invention relates also to the use of diclofenac
`potassium, a carrier and a stabilizer in the preparation of a
`
`Page 2 of 8
`
`Page 2 of 8
`
`
`
`5,891,913
`
`3
`pharmaceutical composition for treating inflammatory ocu-
`lar conditions, for treating glaucoma or for treating ear
`inflammatory and/or painful conditions (otitis).
`The present invention relates also to the use of diclofenac
`potassium, a carrier, a stabilizer and a solubilizer in the
`preparation of a pharmaceutical composition for treating
`inflammatory ocular conditions, for treating glaucoma or for
`treating ear inflammatory and/or painful conditions (otitis).
`Still another aspect of the present invention is a method
`of treating inflammatory ocular conditions, which method
`comprises administering topically to the eye of a patient
`requiring such treatment a therapeutically effective amount
`of an ophthalmic composition comprising diclofenac potas-
`sium and a carrier.
`
`The present invention relates also to a method of treating
`inflammatory ocular conditions, which method comprises
`administering topically to the eye of a patient requiring such
`treatment a therapeutically effective amount of an oph-
`thalmic composition comprising diclofenac potassium, a
`carrier and a stabilizer.
`
`The present invention relates also to a method of treating
`inflammatory ocular conditions, which method comprises
`administering topically to the eye of a patient requiring such
`treatment a therapeutically effective amount of an oph-
`thalmic composition comprising diclofenac potassium, a
`carrier, a stabilizer and a solubilizer.
`In the present invention, treating inflammatory ocular
`conditions means,
`treating all ophthalmological diseases
`involving inflammatory processes, whatever the causes are.
`Examples for such causes are e.g. allergic or non-allergic
`inflammation, immune and non-immune processes, acute or
`chronic disease. Examples for such treatments of ocular
`inflammations are the inhibition of miosis during ocular
`surgery, prevention or treatment of ocular pain during these
`processes or consequent upon surgery,
`inhibition of
`photophobia, treatment of uveitis or ocular inflammation of
`any cause and the like. Post operative inflammations are for
`example, of the type associated with cataract removal or
`photorefractive surgery or incisional refractive surgery, tra-
`beculectomy and combined procedures thereof, painful eye-
`conditions (including photophobia and post-operative pain),
`pain associated with trauma or foreign bodies, prevention
`and treatment of macular edema (idiopathic or associated
`with surgical interventions or diabetes) and inhibition of
`miosis.
`
`According to the present invention an ophthalmic com-
`position may also be used for treating glaucoma in connec-
`tion with non-inflammatory induced elevated intraocular
`pressure associated with administered or endogenous glu-
`cocorticoids.
`
`According to the present invention an ophthalmic com-
`position may also be used for treating ear inflammatory
`and/or painful conditions (otitis).
`According to the present invention an ophthalmic com-
`position may preferably be used for treating inflammatory
`ocular conditions.
`
`According to the invention an ophthalmic composition is
`advantageously applied topically to the eye, especially in the
`form of a solution, a suspension, an ointment, a gel or a solid
`insert. Such compositions comprise the active ingredient, for
`example, in a range of from approximately 0.000001 to
`approximately 5.0% by weight, preferably from approxi-
`mately 0.001 to approximately 1.0% by weight, or more
`preferably in the range of from approximately 0.01 to
`approximately 0.5% by weight and most preferably in the
`range of from 0.025 to 0.1% by weight. The dose of the
`active ingredient may depend on various factors, such as
`
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`4
`mode of administration, requirement, age and/or individual
`condition. Analogously an above ophthalmic composition
`may be also topically applied to an ear.
`There are used for a corresponding ophthalmic compo-
`sition customary pharmaceutically acceptable excipients and
`additives known to the person skilled in the art, for example
`those of the type mentioned below, especially carriers,
`stabilizers, solubilizers,
`tonicity enhancing agents, buffer
`substances, preservatives,
`thickeners, complexing agents
`and other excipients. Examples of such additives and excipi-
`ents can be found in U.S. Pat. Nos. 5,134,124 and 4,906,613.
`Such compositions are prepared in a manner known per se,
`for example by mixing the active ingredient with the cor-
`responding excipients and/or additives to form correspond-
`ing ophthalmic compositions. The active ingredient is pref-
`erably administered in the form of eye drops, the active
`ingredient being conventionally dissolved, for example, in a
`carrier. The solution is, where appropriate, adjusted and/or
`buffered to the desired pH and, where appropriate, a
`stabilizer, a solubilizer or a tonicity enhancing agent
`is
`added. Where appropriate, preservatives and/or other excipi-
`ents are added to an ophthalmic composition.
`Carriers used in accordance to the present invention are
`typically suitable for topical or general administration, and
`are for example water, mixtures of water and water-miscible
`solvents, such as C1-
`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 hydrox-
`ypropyl starch, and also other synthetic products, such as
`polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl
`ether, polyethylene oxide, preferably cross-linked poly-
`acrylic 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.
`The solubilizers used for an ophthalmic composition of
`the present invention are, for example, tyloxapol, fatty acid
`glycerol poly-lower alkylene glycol esters, fatty acid poly-
`lower alkylene glycol esters, polyethylene glycols, glycerol
`ethers vitamin E and vitamin E derivatives, such as Vitamin
`E Tocopherol Polyethylene Glycol 1000 Succinate (TPGS)
`or mixtures of those compounds. A specific example of an
`especially preferred solubilizer is a reaction product of
`castor oil and ethylene oxide, for example the commercial
`products Cremophor EL® or Cremophor RH 40®. Reaction
`products of castor oil and ethylene oxide have proved to be
`particularly good solubilizers that are tolerated extremely
`well by the eye. Another preferred solubilizer is tyloxapol.
`The concentration used depends especially on the concen-
`tration of the active ingredient. The amount added is typi-
`cally sufficient
`to solubilize the active ingredient. For
`
`Page 3 of 8
`
`Page 3 of 8
`
`
`
`5,891,913
`
`5
`example, the concentration of the solubilizer is from 0.1 to
`5000 times the concentration of the active ingredient.
`According to the present invention lower alkylene means
`linear or branched alkylene with up to and including 7
`C-atoms. Examples are methylene, ethylene, 1,3-propylene,
`1,2-propylene, 1,5-pentylene, 2,5-hexylene or 1,7-
`heptylene.
`Lower alkylene is preferably linear or branched alkylene
`with up to and including 4 C-atoms.
`Examples of buffer substances are acetate, ascorbate,
`borate, hydrogen carbonate/carbonate, citrate, gluconate,
`lactate, phosphate, propionate and TRIS (tromethamine)
`buffers. Tromethamine and borate buffer are preferred buff-
`ers. The amount of buffer substance added is, for example,
`that necessary to ensure and maintain a physiologically
`tolerable pH range. The pH range is typically in the range of
`from 5 to 9, preferably from 6 to 8.2 and more preferably
`from 6.8 to 8.1.
`
`ionic
`for example,
`Tonicity enhancing agents are,
`compounds, such as alkali metal or alkaline earth metal
`halides, such as, for example, CaCl2, KBr, KCl, LiCl, Nal,
`NaBr or NaCl, or boric acid. Non-ionic tonicity enhancing
`agents are, for example, urea, glycerol, sorbitol, mannitol,
`propylene glycol, or dextrose. For example, sufficient tonic-
`ity enhancing agent is added to impart to the ready-for-use
`ophthalmic composition an osmolality of approximately
`from 50 to 1000 mOsmol, preferred from 100 to 400
`mOsmol, more preferred from 200 to 400 mOsmol and even
`more preferred from 280 to 350 mOsmol.
`Examples of preservatives are quaternary ammonium
`salts, such as cetrimide, benzalkonium chloride or benzoxo-
`nium chloride, alkyl-mercury salts of thiosalicylic acid, such
`as, for example, thiomersal, phenylmercuric nitrate, phe-
`nylmercuric acetate or phenylmercuric borate, parabens,
`such as,
`for example, methylparaben or propylparaben,
`alcohols, such as, for example, chlorobutanol, benzyl alco-
`hol or phenyl ethanol, guanidine derivatives, such as, for
`example, chlorohexidine or polyhexamethylene biguanide,
`or sorbic acid. Preferred preservatives are cetrimide, benza-
`lkonium chloride, benzoxonium chloride and parabens.
`Where appropriate, a sufficient amount of preservative is
`added to the ophthalmic composition to ensure protection
`against secondary contaminations during use caused by
`bacteria and fungi.
`The ophthalmic compositions may comprise further non-
`toxic excipients, such as, for example, emulsifiers, wetting
`agents or fillers, such as, for example,
`the polyethylene
`glycols designated 200, 300, 400 and 600, or Carbowax
`designated 1000, 1500, 4000, 6000 and 10 000. Other
`excipients that may be used if desired are listed below but
`they are not intended to limit in any way the scope of the
`possible excipients. They are especially complexing agents,
`such as disodium-EDTA or EDTA, antioxidants, such as
`ascorbic acid, acetylcysteine, cysteine, sodium hydrogen
`sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene or
`ot-tocopherol acetate; stabilizers, such as a cyclodextrin,
`thiourea,
`thiosorbitol, sodium dioctyl sulfosuccinate or
`monothioglycerol vitamin E and vitamin E derivatives, such
`as Vitamin E Tocopherol Polyethylene Glycol 1000 Succi-
`nate (TPGS); or other excipients, such as, for example,
`lauric acid sorbitol ester, triethanol amine oleate or palmitic
`acid ester. Preferred excipients are complexing agents, such
`as disodium-EDTA and stabilizers, such as a cyclodextrin.
`The amount and type of excipient added is in accordance
`with the particular requirements and is generally in the range
`of from approximately 0.0001 to approximately 90% by
`weight.
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`6
`A cyclodextrin as is referred to within the present inven-
`tion is either an (X-, [3- or y- cyclodextrin itself, a derivative
`thereof, e.g. a partially etherified derivative as e.g. a
`hydroxyalkyl ether or a mixture thereof. Examples of cyclo-
`dextrin derivatives are alkylated, hydroxyalkylated, car-
`boxyalkylated or alkyloxycarbonyl-alkylated (X-,
`[3- or y-
`cyclodextrins. Other typical examples are carbohydrate
`derivatives of cyclodextrins such as mono- or diglycosyl-ot-,
`[3- or y- cyclodextrin, mono- or dimaltosyl-ot-,
`[3- or y-
`cyclodextrin or panosylcyclodextrin. Another parameter
`which describes the substitution pattern of a cyclodextrin
`derivative is the degree of substitution (d.s.). Acyclodextrin
`is composed of several glucose units which have three free
`hydroxy groups per glucose. Accordingly the d.s. may vary
`from 0.125 up to 3. In the latter case all free (y-cyclodextrin
`has 24) hydroxy groups may be substituted, while in the
`former case only 1 may be substituted. Preferably the d.s.
`may vary from 0.125 to 1.5 and more preferably from 0.125
`to 0.5.
`
`Preferred cyclodextrins are [3- and y- ciclodextrin, deriva-
`tives and mixtures thereof.
`
`Strongly preferred cyclodextrins are hydroxypropyl-[3-
`ciclodextrin, hydroxypropyl-ycyclodextrin, dimethyl-[3-
`cyclodextrin and dimethyl-y- ciclodextrin.
`The amount of a cyclodextrin used in accordance with
`the present invention may preferably range from 0.01—20%
`by weight, more preferably from 0.1—15 % by weight and
`even more preferably from 1—10% by weight.
`The present
`invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a solubilizer and
`another therapeutically effective pharmaceutical agent
`which may be, for example, an antibiotic, an antiallergic, an
`anesthetic, another antiphlogistic, a corticosteroide, an agent
`suitable for lowering intra-ocular pressure, or another drug.
`Several animal models are used for the demonstration of
`
`the claimed therapeutic efficacy of the ophthalmic compo-
`sitions comprising diclofenac potassium. In each animal
`model several ophthalmic reference drugs are administered
`for comparison.
`In a first animal model, the ocular distribution and lens
`penetration of diclofenac potassium and diclofenac sodium
`is determined after multiple topical ocular administration of
`a corresponding eye drop composition. Hence 14C labelled
`eye drop material is topically administered to the eyes of
`chinchilla pigmented rabbits (5 instillations, 50 yl each,
`within 20 minutes). At regular intervals post-instillation
`(0.5 , 1.5, 2.0 hours), the animals are sacrificed and both eyes
`are removed. Said eyes are microdissected and the ocular
`distribution of the radioactivity is measured by a standard
`scintillation beta counting method. The highest concentra-
`tions are found in the cornea, and in descending order in the
`aqueous humor, in the iris ciliary body and in the vitreous.
`According to this experimental setup, the diclofenac potas-
`sium treated animals clearly displayed higher levels of
`radioactivity in the aforementioned areas than the diclofenac
`sodium treated animals.
`
`Another animal model is used for the comparison of the
`ocular anti-inflammatory efficacy of diclofenac potassium in
`comparison to diclofenac sodium, which model
`is the
`arachidonic acid induced uveitis in pigmented rabbits.
`Repeated instillations of arachidonic acid into the eye of
`rabbits induce an ocular inflammation, which inflammation
`significantly increases the flare level in the anterior chamber
`of rabbits. A laser cell flare meter (LCFM) is used for the
`quantification of said flare levels. This method is described
`by e.g. M. Kuchle et al., Ophthalmologe 91, 219(1994), and
`
`Page 4 of 8
`
`Page 4 of 8
`
`
`
`5,891,913
`
`7
`is a non-invasive method. It has been demonstrated, that the
`flare determination by LCFM reflects the amounts of pro-
`teins comprised in the aqueous humor. These proteins are
`commonly used as markers in assessing the degree of an
`inflammation. For the non-invasive evaluation of the effi-
`
`5
`
`cacy of an anti-inflammatory drug, said drugs are adminis-
`.
`.
`.
`.
`.
`tered by using two 1I1St1llaI10IlS. one. hour and 45 minutes
`before the induction of an arachidonic acid induced inflam-
`mation as described above. A control group of animals is
`treated with a single instillation of non-preserved saline 10
`.
`.
`.
`.
`.
`.
`(Unilarm®). The inflammation process is monitored during
`6 hours post-inflammation by the above described LCFM
`measurements.
`
`15
`
`In a further animal model the ocular anti-inflammatory
`efficacy of diclofenac potassium is determined with a trau-
`matic uveitis model. Uveitis is induced in said model by an
`argon laser iris photocoagulation in pigmented rabbits. Said
`iris photocoagulation is induced by 500 gm argon laser burns
`(power 750 mW, duration 0.1 sec). The inflammatory pro-
`cesses resulting therefrom are measured every 30 minutes 20
`after the laser induced photo-coagulation, by using the laser
`.
`.
`cell flare meter (LCFM) technique. For the evaluation of the
`efficacy of an anti-inflammatory drug, said drugs are again
`administered by two instillations, one hour and 45 minutes
`-
`-
`-
`-
`-
`-
`.
`.
`.
`.
`.
`.
`prior to the induction of an inflammation as described above. 25
`A control group of animals is treated with instillations of
`non-preserved saline (Unilarm®). Again the inflammation
`process is monitored during 6 hours.
`In addition to the non invasive LCFM evaluation of the
`above mentioned animal model an invasive evaluation is 30
`’
`carried out. Therefore the rabbits are sacrificed one hour and
`
`8
`EXAMPLE 2
`
`Formulation of diclofenac potassium eye drops (0.05%)
`
`di°1°fena°.p°taSSiuIT1
`benzalkonium chloride
`disodium edetate
`tyloxapol
`Y-CYC10deX§fin
`.
`tromethamfne
`hydrochloric acid 10%
`Sorbitol
`deion. water ad.
`
`0'50 mg/ml
`0.05 mg/ml
`10 mg/m1
`1.0 mg/ml
`20-0 mg/H11
`1'0 mg/ml
`1.3 mg/ml
`460 mg/ml
`1.00 ml
`
`EXAMPLE 3
`
`Formulation of non-preserved uni-dose diclofenac potas-
`sium eye drops (0.1%)
`
`diclofenac otassium
`disodium SSW,
`tyloxapol
`dimethyl-[5-Cyclodextrin
`tromethamine
`ydrochloric acid 10%
`h
`.
`.
`Sorbitol
`deion. water ad.
`
`1.00 m /ml
`1_0 In:/ml
`0.1 mg/ml
`40-0 mg/H11
`1.0 mg/ml
`1.3 mg/ml
`410 mg/ml
`1.00 ml
`
`EXAMPLE 4
`
`Formulation of oily eye drops
`
`'
`
`in regular intervals after which said eyes have been sub-
`jected to the traumatic uveitis by photocoagulation, and the
`aqueous humor of said rabbit eyes is sampled. The aqueous
`protein levels, cell counts and prostaglandins (PGE2, PGD2, 35 diclofenac potassium
`6-keto PGF10.) which represent the degree of an inflamma-
`benzalkonium chloride
`tion are biochemically investigated and quantified.
`0”‘/m°P0i’T RH 40 ®> (P°1Y°XY1 40 hydrogenated
`Another animal model is used for the induction of a
`31%d
`traumatic uveitis. It
`is the induction of a uveitis by the
`paracentesis of the anterior chamber of the rabbit eye. In 40
`analogy to the previously described laser induced uveitis
`model, drugs to be tested, are again administred prior to the
`paracentesis challenge. In this animal model, the animals are
`again sacrificed at regular intervals, and the inflammatory
`process is investigated by sampling the aqueous humor of 45
`the challenged rabbit eyes. The aqueous protein levels are
`again analyzed, quantified and then correlated with the
`degree of an inflammation.
`.
`.
`In all the aforementioned animal models, there is clear
`evidence that animals which are treated with diclofenac 50
`potassium benefit from a better efficacy compared to the
`.
`.
`.
`.
`animals treated with diclofenac sodium.
`
`EXAMPLE 5
`
`F0UI11l1at10Il Of an eye gel
`
`_
`
`_
`potasslum
`boric acid
`cremophor EL® (polyoxyl 35 castor oil)
`trorglethamine
`Car. Om“ 980
`deion. water ad.
`
`050 mg/ml
`0.1 mg/ml
`20-0 mg/ml
`100 ml
`'
`
`339135:
`1_g mg/g
`4.0 mg/g
`13-0 mg/g
`4'0 mg/g
`1.00 g
`
`Typical experimental procedures which illustrate the
`present invention, but are not intended to limit it in any way,
`are described below.
`
`55
`
`EXAMPLE 6
`
`EXAMPLE 1
`
`Formulation of an eye gel
`
`Formulation of diclofenac potassium eye drops (0.1%)
`
`diclofenac potassium
`thiomersal
`boric acid
`cremophor EL ® (polyoxyl 35 castor oil)
`tromethamine
`deion. water ad.
`
`1.00 mg/ml
`0.04 mg/ml
`19.0 mg/ml
`50.0 mg/ml
`6.0 mg/ml
`1.0 ml
`
`60
`
`05
`
`diclofenac-potassium
`benzalkonium chloride
`tyloxapol
`mannitol
`hydrochloric acid 10%
`disodium edetate
`chitosan
`deion. water ad.
`
`1.00 mg/g
`0.1 mg/g
`1.0 mg/g
`30.0 mg/g
`1.0 mg/g
`0.5 mg/g
`10.0 mg/g
`1.00 g
`
`Page 5 of 8
`
`Page 5 of 8
`
`
`
`9
`EXAMPLE 7
`
`Formulation of an eye ointment
`
`diclofenac potassium
`phenylethyl alcohol
`tyloxapol
`disodium edetate
`y-cyclodextrin
`deion. water
`cetylstearyl alcohol
`liquid paraflin
`white petrolatum
`wool fat
`
`1.00 mg/g
`5.0 mg/g
`1.0 mg/g
`0.5 mg/g
`20.0 mg/g
`140 mg/g
`22.0 mg/g
`207 mg/g
`462 mg/g
`141.5 mg/g
`
`EXAMPLE 8
`
`Formulation of diclofenac potassium eye drops (0.05%)
`
`diclofenac potassium
`cremophor RH ® (polyoxyl 40 hydrogenated castor oil)
`tromethamine
`disodium edetate
`sorbitol
`benzalkonium chloride
`hydrochloric acid 1N
`water for injections ad
`pH
`osmolality (mOsmol):
`
`0.5 mg/ml
`0.6 mg/ml
`1.0 mg/ml
`0.5 mg/ml
`49.0 mg/ml
`0.15 mg/ml
`5.1 mg/ml
`1.0 ml
`7.53
`317
`
`EXAMPLE 9
`
`Formulation of diclofenac sodium eye drops (0.1%)
`
`diclofenac sodium
`cremophor RH ® (polyoxyl 40 hydrogenated castor oil)
`tromethamine
`disodium edetate
`sorbitol
`benzalkonium chloride
`hydrochloric acid 1N
`water for injections ad
`pH
`osmolality (mOsmol):
`
`1.0 mg/ml
`0.6 mg/ml
`1.0 mg/ml
`0.5 mg/ml
`49.0 mg/l
`0.15 mg/ml
`5.52 mg/ml
`1.0 ml
`7.49
`308
`
`EXAMPLE 10
`
`Formulation of an eye drop vehicle
`
`cremophor RH ® (polyoxyl 40 hydrogenated castor oil)
`tromethamine
`disodium edetate
`sorbitol
`benzalkonium chloride
`hydrochloric acid 1N
`water for injections ad
`pH:
`osmolality (mOsmol):
`
`0.6 mg/ml
`1.0 mg/ml
`0.5 mg/ml
`49.0 mg/ml
`0.15 mg/ml
`5.0 mg/ml
`1.0 ml
`7.53
`301
`
`EXAMPLE 11
`
`Formulation of diclofenac potassium eye drops (0.1%)
`
`diclofenac potassium
`cremophor RH ® (polyoxyl 40 hydrogenated castor oil)
`tromethamine
`
`1.0 mg/ml
`0.6 mg/ml
`1.0 mg/ml
`
`Page 6 of 8
`
`5,891,913
`
`-continued
`
`disodium edetate
`sorbitol
`benzalkonium chloride
`hydrochloric acid 1N
`water for injections ad
`pH:
`osmolality (mOsmol):
`
`0.5 mg/ml
`49.0 mg/ml
`0.15 mg/ml
`5.7 mg/ml
`1.0 ml
`7.35
`314
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EXAMPLE 12
`
`Changes in aqueous flares (expressed as the area under the
`kinetic curves (AUC)) for the arachidonic acid induced
`uveitis model, carried out in pigmented rabbits.
`The drugs listed infra (including placebo) are applied
`topically (30 yl each) to the left eye of pigmented rabbits
`(chinchilla pigmented female rabbits) one hour before
`arachidonic acid instillations. Each opposite eye is instilled
`for control with 30 yl of the vehicle formulation of example
`10. Before the instillation of arachidonic acid, the animals
`are anesthetized with intramuscular injections of 35 mg/kg
`ketamine (Imalgene 1000®, Rhone Merieux) and 15 mg/kg
`xylazine (Rompun-Bayer). Arachidonic acid (0.5% aqueous
`solution, freshly prepared before use) is then instilled into
`both eyes of the rabbits with a Hamilton syringe (twice 50
`yl). A time interval of 5 minutes is kept between each
`instillation. The flares are then measured hourly, using an
`LCFM over a total period of 6 hrs after the arachidonic acid
`challenge. Before each measurement, the animals are freshly
`anesthetized with intramuscular injections of 35 mg/kg
`ketamine (Imalgene 1000®, Rhone Mérieux) and 15 mg/kg
`xylazine (Rompun-Bayer), in order to completely immobi-
`lize the eyes. The LCFM method is similar to a slit lamp
`microscopy examination. The laser beam of a Kowa
`FC-1000 LCFM is scanning vertically within a distance of
`0.6 mm towards the center of the anterior chamber. Each
`measurement lasts about 0.5 seconds. Such a measurement
`
`is repeated five times for each eye and the average of the
`photon counts is then calculated and plotted versus the
`observation time, which lasts in total 6 hours calculated from
`the induction of the inflammation. The results are summa-
`
`rized below, which show the integrated photon counts of the
`trea