United States Patent [19J
`Sallmann et al.
`
`[54] OPHTHALMIC AND AURAL
`COMPOSITIONS CONTAINING
`DICLOFENAC POTASSIUM
`
`[75]
`
`Inventors: Alfred Sallmann, Bottmingen; Gyiirgy
`Lajos Kis, Triboltingen, both of
`Switzerland; Wolfgang Blum, Weil am
`Rhein, Germany; Alica Huxley,
`Binningen, Switzerland
`
`[73] Assignee: Novartis AG, Basel, Switzerland
`
`[21] Appl. No.: 09/223,198
`
`[22]
`
`Filed:
`
`Dec. 30, 1998
`
`Related U.S. Application Data
`
`[62]
`
`Division of application No. 08/809,434, Aug. 27, 1997, Pat.
`No. 5,891,913, which is a continuation of application No.
`PCT/EP95/03844, Sep. 28, 1995.
`
`[30]
`
`Foreign Application Priority Data
`
`Oct. 10, 1994
`Sep. 18, 1995
`
`[EP]
`[EP]
`
`European Pat. Off. .............. 94810589
`European Pat. Off ............... 95810574
`
`Int. CI? ................................................... A61K 31/195
`[51]
`[52] U.S. Cl. ........................... 514/567; 514/912; 514/913
`[58] Field of Search ..................................... 514/567, 912,
`514/913
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,960,799 10/1990 Nagy ....................................... 514/567
`
`FOREIGN PATENT DOCUMENTS
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006107343A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,107,343
`Aug. 22, 2000
`
`3/1990 European Pat. Off ..
`0390071A1
`592348 10/1993 European Pat. Off ..
`2192539
`6/1986 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Diclofenac-K (50 and lOO)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(cid:173)
`tions Clinical Evaluation of Diclofenac Potassium vs. Pla(cid:173)
`cebo, Hospital Infantil Mexico, pp. 50--56,1988. (English
`abstract).
`
`The Treatment of Upper Respiratory Trace and Ear Inflam(cid:173)
`matory Non-Infectious Conditions with NSAID A Com(cid:173)
`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-R. Scott Meece; Robert J.
`Gorman, Jr.
`
`[57]
`
`ABSTRACT
`
`The present invention describes an ophthalmic composition
`comprising diclofenac potassium, the use of said composi(cid:173)
`tion as a medicament for treating inflammatory conditions of
`the eye, for treating glaucoma or for treating ear inflamma(cid:173)
`tory 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).
`
`0306984A1
`
`9/1988 European Pat. Off ..
`
`7 Claims, No Drawings
`
`LUPIN EX1009, Page 1
`
`

`
`6,107,343
`
`1
`OPHTHALMIC AND AURAL
`COMPOSITIONS CONTAINING
`DICLOFENAC POTASSIUM
`
`This is a divisional of application Ser. No. 08/809,434,
`filed Aug. 27, 1997, now U.S. Pat. No. 5,891,913 which is
`a continuation of PCT/EP95/03844, filed Sep. 28, 1995.
`The present invention describes an ophthalmic compo(cid:173)
`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(cid:173)
`suppressant action of these substances, however, conceals
`the risk of a deterioration in the clinical picture as a result of 20
`a bacterial or viral infection. Therefore, considerable efforts
`are still made, to develop potent non-steroidal anti(cid:173)
`inflammatory agents and to introduce them into ophthalmo(cid:173)
`logical therapy.
`EP 242 328 describes for example a medicament for the 25
`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(cid:173)
`sium 2-[(2,6-dichlorophenyl)amino ]-phenyl acetate. It is 30
`known as a non-steroidal anti-inflammatory drug (NSAlD).
`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 35
`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(cid:173)
`closed in said application. Accordingly, all claims and
`working examples of said application disclose either 40
`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 45
`a pharmaceutically acceptable salt of ethylenediamine tet(cid:173)
`raacetic acid.
`Surprisingly it was found, that the potassium salt of
`2-[(2,6-dichlorophenyl)amino ]-phenyl acetic acid,
`diclofenac potassium, is especially suitable to treat inflam- 50
`matory ocular processes in general. It has been demonstrated
`that for example the ocular penetration of diclofenac potas(cid:173)
`sium is much superior in comparison to the corresponding
`diclofenac sodium. In addition to said advantage, pharma(cid:173)
`cological studies show a much better topical tolerance, e.g. 55
`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 60
`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.
`The present invention relates also to an ophthalmic
`composition for treating inflammatory conditions of the eye,
`
`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
`5 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
`10 composition, which comprises a therapeutically effective
`amount of diclofenac potassium, a carrier, a stabilizer and a
`solubilizer.
`The present invention relates also to an ophthalmic
`composition, which comprises a therapeutically effective
`15 amount of diclofenac 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.
`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, a tonicity enhancing agent
`and a buffer.
`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, 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(cid:173)
`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(cid:173)
`tical composition for treating inflammatory ocular pro-
`65 cesses.
`The present invention relates also to the use of diclofenac
`potassium, a carrier and a stabilizer in the preparation of a
`
`LUPIN EX1009, Page 2
`
`

`
`6,107,343
`
`3
`pharmaceutical composition for treating inflammatory ocu(cid:173)
`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 5
`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 10
`comprises administering topically to the eye of a patient
`requiring such treatment a therapeutically effective amount
`of an ophthalmic composition comprising diclofenac potas(cid:173)
`sium and a carrier.
`The present invention relates also to a method of treating 15
`inflammatory ocular conditions, which method comprises
`administering topically to the eye of a patient requiring such
`treatment a therapeutically effective amount of an oph(cid:173)
`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(cid:173)
`thalmic composition comprising diclofenac potassium, a 25
`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 30
`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 35
`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
`photo-refractive surgery or incisional refractive surgery,
`trabeculectomy and combined procedures thereof, painful 40
`eye-conditions (including photophobia and post-operative
`pain), pain associated with trauma or foreign bodies, pre(cid:173)
`vention and treatment of macular edema (idiopathic or
`associated with surgical interventions or diabetes) and inhi(cid:173)
`bition of miosis.
`According to the present invention an ophthalmic com(cid:173)
`position may also be used for treating glaucoma in connec(cid:173)
`tion with non-inflammatory induced elevated intraocular
`pressure associated with administered or endogenous glu(cid:173)
`cocorticoids.
`According to the present invention an ophthalmic com(cid:173)
`position may also be used for treating ear inflammatory
`and/or painful conditions (otitis).
`According to the present invention an ophthalmic com(cid:173)
`position may preferably be used for treating inflammatory 55
`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 60
`example, in a range of from approximately 0.000001 to
`approximately 5.0% by weight, preferably from approxi(cid:173)
`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 65
`range of from 0.025 to 0.1% by weight. The dose of the
`active ingredient may depend on various factors, such as
`
`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(cid:173)
`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(cid:173)
`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(cid:173)
`responding excipients and/or additives to form correspond(cid:173)
`ing ophthalmic compositions. The active ingredient is pref(cid:173)
`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
`20 stabilizer, a solubilizer or a tonicity enhancing agent is
`added. Where appropriate, preservatives and/or other excipi(cid:173)
`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
`to C7 -alkanols, vegetable oils or
`solvents, such as C1 -
`mineral oils comprising from 0.5 to 5% by weight
`hydroxyethylcellulose,
`ethyl
`oleate,
`carboxymethylcellulose, polyvinyl-pyrrolidone and other
`non-toxic water-soluble polymers for ophthalmic uses, such
`as, for example, cellulose derivatives, such as
`methylcellulose,
`alkali metal
`salts of
`carboxyme thy lcellulose, hydroxymethy lcellulose,
`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(cid:173)
`ypropyl starch, and also other synthetic products, such as
`polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl
`ether, polyethylene oxide, preferably cross-linked poly(cid:173)
`acrylic acid, such as neutral Carbopol, or mixtures of those
`polymers. Preferred carriers are water, cellulose derivatives,
`45 such as methylcellulose, alkali metal salts of
`carboxyme thy lcellulose, hydroxymethy lcellulose,
`hydroxyethylcellulose, methylhydroxypropylcellulose and
`hydroxypropylcellulose, neutral Carbopol, or mixtures
`thereof. The concentration of the carrier is, for example,
`50 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(cid:173)
`lower alkylene glycol esters, polyethylene glycols, glycerol
`ethers 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(cid:173)
`tration of the active ingredient. The amount added is typi(cid:173)
`cally sufficient to solubilize the active ingredient. For
`example, the concentration of the solubilizer is from 0.1 to
`5000 times the concentration of the active ingredient.
`
`LUPIN EX1009, Page 3
`
`

`
`6,107,343
`
`5
`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(cid:173)
`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.
`Tonicity enhancing agents are, for example, ionic
`compounds, such as alkali metal or alkaline earth metal
`halides, such as, for example, CaC12 , 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 25
`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(cid:173)
`nium chloride, alkyl-mercury salts of thiosalicylic acid, such
`as, for example, thiomersal, phenylmercuric nitrate, phe(cid:173)
`nylmercuric acetate or phenylmercuric borate, parabens,
`such as, for example, methylparaben or propylparaben,
`alcohols, such as, for example, chlorobutanol, benzyl alco(cid:173)
`hol or phenyl ethanol, guanidine derivatives, such as, for
`example, chlorohexidine or polyhexamethylene biguanide,
`or sorbic acid. Preferred preservatives are cetrimide, benza(cid:173)
`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(cid:173)
`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-hydroxy-toluene or
`a-tocopherol acetate; stabilizers, such as a cyclodextrin,
`thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or
`monothioglycerol; or other excipients, such as, for example,
`lauric acid sorbitol ester, triethanol amine oleate or palmitic
`acid ester. Preferred exipients 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.
`A cyclodextrin as is referred to within the present inven(cid:173)
`tion is either an a-, ~- or y-cyclodextrin itself, a derivative
`thereof, e.g. a partially etherified derivative as e.g. a
`hydroxy alkyl ether or a mixture thereof. Examples of cyclo-
`
`6
`dextrin derivatives are alkylated, hydroxyalkylated, car(cid:173)
`boxyalkylated or alkyloxycarbonyl-alkylated a-, ~- or
`y-cyclodextrins. Other typical examples are carbohydrate
`derivatives of cyclodextrins such as mono- or diglycosyl-a-,
`5 ~- or y-cyclodextrin, mono- or dimaltosyl-a-, ~- or
`y-cyclodextrin or panosyl-cyclodextrin. 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
`10 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
`15 to 0.5.
`Preferred cyclodextrins are ~- and y-cyclodextrin,
`derivatives and mixtures thereof.
`Strongly preferred cyclodextrins are hydroxypropyl-~­
`cyclodextrin, hydroxypropyl-y-cyclodextrin, dimethyl-~-
`20 cyclodextrin and dimethyl-y-cyclodextrin.
`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
`30 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(cid:173)
`sitions comprising diclofenac potassium. In each animal
`35 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
`40 a corresponding eye drop composition. Hence 14C labelled
`eye drop material is topically administered to the eyes of
`chinchilla pigmented rabbits (5 instillations, 50 ,ul each,
`within 20 minutes). At regular intervals post-instillation
`(0.5, 1.5, 2.0 hours), the animals are sacrificed and both eyes
`45 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(cid:173)
`tions are found in the cornea, and in descending order in the
`aqueous humor, in the iris ciliary body and in the vitreous.
`50 According to this experimental setup, the diclofenac potas(cid:173)
`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
`55 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
`60 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
`is a non-invasive method. It has been demonstrated, that the
`65 flare determination by LCFM reflects the amounts of pro(cid:173)
`teins comprised in the aqueous humor. These proteins are
`commonly used as markers in assessing the degree of an
`
`LUPIN EX1009, Page 4
`
`

`
`6,107,343
`
`7
`inflammation. For the non-invasive evaluation of the effi(cid:173)
`cacy of an anti-inflammatory drug, said drugs are adminis(cid:173)
`tered by using two instillations one hour and 45 minutes
`before the induction of an arachidonic acid induced inflam(cid:173)
`mation as described above. A control group of animals is 5
`treated with a single instillation of non-preserved saline
`(Unilarm®). The inflammation process is monitored during
`6 hours post-inflammation by the above described LCFM
`measurements.
`In a further animal model the ocular anti-inflammatory 10
`efficacy of diclofenac potassium is determined with a trau(cid:173)
`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 ,urn argon laser burns 15
`(power 750 mW, duration 0.1 sec). The inflammatory pro(cid:173)
`cesses resulting therefrom are measured every 30 minutes
`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 20
`administered by two instillations, one hour and 45 minutes
`prior to the induction of an inflammation as described above.
`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
`carried out. Therefore the rabbits are sacrificed one hour and
`in regular intervals after which said eyes have been sub(cid:173)
`jected to the traumatic uveitis by photocoagulation, and the 30
`aqueous humor of said rabbit eyes is sampled. The aqueous
`protein levels, cell counts and prostaglandins (PGE2, PGD2,
`6-keto PGF1a) which represent the degree of an inflamma-
`tion~~t~!~c~:=~:l:0:~e~~ig:~=~ ~~~ ~~a~~~~~t.ion of a 35
`traumatic uveitis. It is the induction of a uveitis by the
`paracentesis of the anterior chamber of the rabbit eye. In
`analogy to the previously described laser induced uveitis
`model, drugs to be tested, are again administered 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
`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
`potassium benefit from a better efficacy compared to the
`animals treated with diclofenac sodium.
`Typical experimental procedures which illustrate the 50
`present invention, but are not intended to limit it in any way,
`are described below.
`
`25
`
`40
`
`45
`
`EXAMPLE 1
`
`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
`
`55
`
`60
`
`65
`
`8
`EXAMPLE 2
`
`Formulation of diclofenac potassium eye drops
`(0.05%)
`
`diclofenac potassium
`benzalkonium chloride
`disodium edetate
`tyloxapol
`y-cyclodextrin
`tromethamine
`hydrochloric acid 10%
`sorbitol
`deion. water ad.
`
`0.50 mg/ml
`0.05 mg/ml
`1.0 mg/ml
`1.0 mg/ml
`20.0 mg/ml
`1.0 mg/ml
`1.3 mg/ml
`46.0 mg/ml
`1.00 ml
`
`EXAMPLE 3
`
`Formulation of non-preserved uni-dose diclofenac
`potassium eye drops (0.1 %)
`
`diclofenac potassium
`disodium edetate
`tyloxapol
`dimethyl-1)-cyclodextrin
`tromethamine
`hydrochloric acid 10%
`sorbitol
`deion. water ad.
`
`1.00 mg/ml
`1.0 mg/ml
`0.1 mg/ml
`40.0 mg/ml
`1.0 mg/ml
`1.3 mg/ml
`41.0 mg/ml
`1.00 ml
`
`EXAMPLE 4
`
`Formulation of oily eye drops
`
`diclofenac potassium
`benzalkonium chloride
`cremophor RH 40 ®, (polyoxyl 40 hydrogenated castor
`oil)
`castor oil ad.
`
`0.50 mg!ml
`0.1 mg!ml
`20.0 mg!ml
`
`1.00 ml
`
`EXAMPLE 5
`
`Formulation of an eye gel
`
`diclofenac potassium
`thiomersal
`boric acid
`cremophor EL ® (polyoxyl 35 castor oil)
`tromethamine
`carbomer 980
`deion. water ad.
`
`0.50 mg!g
`0.04 mg!g
`1.8 mg!g
`4.0 mg!g
`13.0 mg!g
`4.0 mg!g
`1.00 g
`
`EXAMPLE 6
`
`Formulation of an eye gel
`
`diclofenac potassium
`benzalkonium chloride
`tyloxapol
`
`1.00 mg/g
`0.1 mg/g
`1.0 mg/g
`
`LUPIN EX1009, Page 5
`
`

`
`9
`
`-continued
`
`6,107,343
`
`10
`
`-continued
`
`mannitol
`hydrochloric acid 10%
`disodium edetate
`chitosan
`deion. water ad.
`
`30.0 mg!g
`1.0 mg!g
`0.5 mg!g
`10.0 mg!g
`1.00 g
`
`sorbitol
`benzalkonium chloride
`5 hydrochloric acid 1N
`water for injections ad
`pH:
`osmolality (mOsmol):
`
`49.0 mg!ml
`0.15 mg!ml
`5.0 mg!ml
`1.0 ml
`7.53
`301
`
`EXAMPLE 7
`
`Formulation of an eye ointment
`
`diclofenac potassium
`phenylethyl alcohol
`tyloxapol
`disodium edetate
`y-cyclodextrin
`deion. water
`cetylstearyl alcohol
`liquid paraffin
`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 11
`
`Formulation of diclofenac potassium eye drops
`(0.1 %)
`
`10
`
`15
`
`diclofenac potassium
`cremophor RH ® (polyoxyl 40 hydrogenated castor oil)
`tromethamine
`disodium edetate
`20 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!ml
`0.15 mg!ml
`5.7 mg!ml
`1.0 ml
`7.35
`314
`
`EXAMPLE 8
`
`25
`
`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/ml
`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
`
`0.6 mg/ml
`1.0 mg/ml
`0.5 mg/ml
`
`EXAMPLE 12
`
`35
`
`Changes in aqueous flares (expressed as the area under the
`30 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 ,ul 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 ,ul 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
`40 solution, freshly prepared b