`
`0)
`
`Europaisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`
`
`
`
`(4) Publication number: 0 605 203 A2
`
`(©)
`
`EUROPEAN PATENT APPLICATION
`
`@1) Application number : 93310464.8
`
`1) Int. cl.®: A61K 31/495, A61K 9/08
`
`(2) Date offiling : 23.12.93
`
`Priority : 25.12.92 JP 346031/92
`
`Date of publication of application :
`06.07.94 Bulletin 94/27
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GRIE IT LI LU MC
`NL PT SE
`
`(1) Applicant : Senju Pharmaceutical Co., Ltd.
`5-8, Hiranomachi 2-chome,
`Chuo-Ku
`Osaka-shi, Osaka 541 (JP)
`
`Inventor: Ikejiri, Yoshifumi
`18-2, Ai 2-chome
`Ibaraki-shi, Osaka (JP)
`
`
`
`Inventor : Ogawa, Takahiro
`8-23, Atogoyama
`Nishinomiya-shi, Hyogo (JP)
`Inventor : Tokumochi, Fuminori
`366-1-402, Minamibefu 4-chome,
`Nishi-ku
`Kobe-shi, Hyogo (JP)
`Inventor : Sameshima, Shogo
`366-1-104, Minamibefu 4-chome,
`Nishi-ku
`Kobe-shi, Hyogo (JP)
`Inventor : Kimura, Motoko
`7-43, Kawamo 4-chome
`Takarazuka-shi, Hyogo (JP)
`
`Representative : Lewin, John Harvey
`Elkington and Fife
`Prospect House
`8 Pembroke Road
`Sevenoaks, Kent TN13 1XR (GB)
`
`Antiallergic composition for ophthalmic or nasal use.
`
`There is disclosed an antiallergic composition for ophthalmic or nasal use, comprising cetirizine or a
`salt
`thereof as an active ingredient. The antiallergic composition may further contain a cyclodextrin
`compound, as well as a surfactant and/or a water soluble polymer.
`
`EP0605203A2
`
`Jouve, 18, rue Saint-Denis, 75001 PARIS
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 001
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 001
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`
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`EP 0 605 203 A2
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`FIELD OF THE INVENTION
`
`The present invention relates to an antiallergic composition for ophthalmic or nasal use, and more partic-
`ularly,it relates to a cetirizine-containing antiallergic composi tion which is useful for the treatmentof allergic
`diseasesin the fields of ophthalmology and otorhinology.
`
`BACKGROUND OF THE INVENTION
`
`Cetirizine is an antiallergic compound of the formula:
`
`Cl
`
`3
`CH—-N
`C
`
`N- CH,CH,OCH,COOH
`
`the chemical nameof which is [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid.
`Cetirizine is well known to have an antiallergic effect, for example, by oral administration, andit is partic-
`ularly useful as an antiallergic agent with significant specificity to histamine (see, e.g., JP-B 63-11353).
`In the ophthalmic or nasalallergic diseases, taking the former as an example, systemic symptomsare fre-
`quently associated with ophthalmic symptoms, in which case the oral administration of an antiallergic agent
`is effective for their treatment. There are, however, some cases where no systemic abnormality can be de-
`tected even if marked changesare found in the eyes, and in particular, lesions found only in the eyes are not
`always accompanied by systemic abnormality. In such cases, topical therapy is preferred to systemic therapy
`becauseofits safety and effectiveness. This relationship between the systemic and topical symptoms holds
`true even in the field of otorhinology.
`As an ophthalmic solution containing cetirizine, there is disclosed an anti allergic and antihistaminic com-
`position (see, e.g., JP-A4-9339). This composition comprises an antiallergic agent and an antihistaminic agent
`capable of exhibiting effective antihistaminic action when used in combination with the antiallergic agent. Ce-
`tirizine is exemplified as such an antihistaminic agent that is one of the essential ingredients of the composi-
`tion.
`
`However, no report has hitherto been made of an effect attained by the ophthalmic application of an an-
`tiallergic composition containing cetirizine as only one active ingredient.
`Cetiridine has, although it is readily soluble in water, a disadvantage that a solution of cetirizine at low
`concentrations (below 1 w/v%) may cause the deposition of insoluble matter with the lapse of time, thereby
`decreasing the stability as an aqueoussolution. This seems becausecetirizine is one of the diphenylmethane
`derivatives capable of forming molecular aggregates (see, e.g., Masayuki Nakagaki (ed.), "Bussei-Butsuri (Ma-
`terial Science)," Nankodo, Tokyo, 1986, pp. 238-239). On the other hand, a solution ofcetirizine at high con-
`centrations where no insoluble matter will be deposited has strongirritating properties when applied in oph-
`thalmic or nasal use, and it cannot be used as an ophthalmic or nasal solution. For this reason, there have
`not yet been developed an antiallergic composition for practical use containing cetirizine as the main active
`ingredi ent, which can be applied as an ophthalmic or nasal solution.
`In general, it is difficult in most cases to prepare an ophthalmic or nasal solution with satisfactory safety
`and stability from a drug having irritating properties or capable of forming molecular aggregates, although it
`depends on the kind of the drug used.
`Cyclodextrin compounds are well known to have a property of taking various drugs into their central por-
`tion to form clathrate compounds of these drugs becausetheyare cyclic sugars. Therefore, cyclodextrin com-
`pounds havehitherto been used for the purpose of making a solution of various slightly-soluble drugs or im-
`proving the stability of drugs. However, when a cyclodextrin compoundis blended with a certain drug, it be-
`comesdifficult in most cases to exhibit the efficacy of the drug, and this problem is particularly serious for
`external preparations.
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`EP 0 605 203 A2
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`SUMMARYOF THE INVENTION
`
`Underthese circumstances, the present inventors have intensively studied to develop a cetirizine-con-
`taining ophthalmic or nasal solution with satisfactory safety and stability, which can overcome the above-
`described disadvantagesof cetirizine and which hasno irritating properties to eyes and nasal mucosae. As
`the result, they have found that the addition of a cyclodextrin compound to an aqueoussolution of cetirizine
`can reduce the deposition of insoluble matter even at low concentrations where molecular aggregates of ce-
`tirizine will be found in conventional cases. They have also found that an aqueoussolution of cetirizine blended
`with a cyclodextrin compound can suppresstheirritation of cetirizine to eyes or nasal mucosae even at high
`concentrations where suchan irritation will be found in conventional cases, and that such an aqueoussolution
`can maintain a sufficient inhibitory effect on allergic diseases of ocular or nasal portions. Further, they have
`found that the addition of a surfactant and/or a water-soluble polymerto an aqueoussolutionofcetirizine blend-
`ed with a cyclodextrin compound can prevent the association of cetirizine in the aqueous solution for a long
`period of time. Thus, they have completed the present invention.
`Thatis, the present invention provides an antiallergic composition for oph thalmic or nasal use, charac-
`terized in that it comprises cetirizine or a salt thereof as an active ingredient. It may further contain a cyclo-
`dextrin compound, as well as a surfactant and/or a water-soluble polymer.
`The antiallergic composition of the present invention has almostnoirritation to eyes and nasal mucosae,
`andit can be effectively used as a prophylactic and therapeutic agentfor allergic diseasesin the fields of oph-
`thalmology and otorhinology, such as allergic conjunctivitis (e.g., conjunctival pollinosis), vernal conjunctivitis,
`uveitis and allergic rhinitis.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The antiallergic composition of the present invention contains cetirizine or a salt thereof as an active in-
`gredient. Examplesof the salt of cetirizine are inorganic acid salts such as hydrochloride, sulfate, nitrate and
`phosphate; and organic acid salts such as acetate,citrate, tartrate and maleate.
`The antiallergic composition of the present invention may further contain a cyclodextrin compound, as
`well as a surfactant and/or a water-soluble polymer.
`Typical examplesof the cyclodextrin compound are a-cyclodextrin, B-cycledextrin, y-cyclodextrin, hydrox-
`ypropyl B-cyclodextrin, dimethyl B-cyclodextrin, maltosyl B-cyclodextrin and B-cyclodextrin sulfate. Particular-
`ly preferred are a-cyclodextrin, B-cyclodextrin and y-cyclodextrin. These cyclodextrin compounds may be used
`alone orin combination.
`
`The amount of cyclodextrin compound to be used mayvary with its solubility and the concentration of
`cetirizine. It is, however, desirable that the amount of cycle dextrin compoundis 0.5 to 3.0 times, preferably
`1.0 to 2.0 times, as much as the mole ofcetirizine.
`The surfactants are preferably of the non-ionic type. Typical examples of the non-ionic surfactant are poly-
`sorbate 80, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60.
`These surfactants may be used alone orin combination.
`The water-soluble polymerincludes cellulose derivatives, vinyl polymers and polyols. Examplesof the cel-
`lulose derivative are alkylcelluloses such as methylcellulose and carboxymethylcellulose; and hydroxyalkyl-
`celluloses such as hydroxypropylcellulose and hydroxyethylcellulose. Typical examples of the vinyl polymer
`are polyvinyl pyrrolidone and polyvinyl alcohol. Typical examples of the polyol are a series of macrogol 200 to
`6000. These water-soluble polymers may be used aloneor in combination.
`The amountof surfactant or water-soluble polymerto be used mayvary with its kind and the concentration
`of cetirizine. It is, however, desirable that the amount of surfactant is 0.01 to 1.0 time, preferably 0.05 to 0.5
`times, as muchas the weight ofcetirizine, and the amountof water-soluble polymeris 0.01 to 10.0 times, pre-
`ferably 0.02 to 5.0 times, as much as the weightofcetirizine.
`The antiallergic composition of the present invention can be used within the pH range adoptedfor ordinary
`ophthalmic or nasal solutions, and it is usually adjusted to pH 4.0 to 9.0, preferably pH 5.0 to 8.0.
`The antiallergic composition of the present invention may further contain any conventional additives in
`suitable amounts, which are used in ordinary ophthalmic or nasal solutions, e.g., preservatives such as p-hy-
`droxybenzoates, benzalkonium chloride and chlorobutanol; chelating agents such as disodium edetate and so-
`dium citrate; agents for making isotonic solutions, such as sodium chloride, sorbitol and glycerin; buffer agents
`such as phosphates, boric acid and citrates; and pH controlling agents such as hydrochloric acid, acetic acid
`and sodium hydroxide. The amount of additive to be used can be determined by those skilled in the art within
`the same range as adopted for ordinary ophthalmic or nasal solutions.
`The antiallergic composition of the present invention may further contain any therapeutic ingredients
`
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`EP 0 605 203 A2
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`other than cetirizine in suitable amounts, so long as the excellent advantagesattained by the present invention
`are not deteriorated.
`
`The antiallergic composition of the present invention may have various dosage forms which are pharma-
`ceutically acceptable in the field of ophthalmology or otorhinology, such as solutions, suspensions, emulsions,
`gels and ointments. It may also be prepared, for example, in aqueous solution form and then lyophilized in
`powderform, which is reconstructed into an aqueous solution with distilled water at the time of use.
`The concentration of cetirizine in the antiallergic composition of the present invention may vary with the
`administration route and allergic symptoms. It is, however, usually in the range of about 0.01 to 4.0 w/v%, pre-
`ferably about 0.05 to 2.0 w/v%. For example, when used as an ophthalmic solution for adult patients, the an-
`tiallergic composi tion of the present invention is preferably administrated about 3 to 6 times a day in a dose
`of one to several drops at each time. When usedas a nasalsolution, the antiallergic corn position of the present
`invention is preferably atomized and inhaled about3 to 6 times a day in a dose of 1 to 2 sprays at each time
`into the nasal cavity with an atomizer.
`The present invention will be furtherillustrated by way of the following test examples and working exam-
`ples, which are not to be construedto limit thereof.
`
`Test Example 1: Eyeirritation test in rabbits
`
`(Method)
`
`Using male Japanese white rabbits without any abnormality in the anterior parts of their eyes (4 groups
`of 3 rabbits), Composition C, D, E or F prepared in solution form according to the formulation shownin Table
`1 wasinstilled into the right eyes of the rabbits in the corresponding group and only the vehicle into their left
`eyes 8 times a dayat 1-hour intervals in a dose of one drop at each time for 5 days. For evaluation, a macro
`scopic examination of the anterior parts of the eyes and a corneal fluorescein staining assay were performed
`beforethefirst instillation on day 1, 30 minutes after the lastinstillation on each of days 1, 3 and 5 of treatment,
`and on day 6.
`
`TABLE1
`
`Ingredient (w/v%)
`
`Compositions
`
`B Cc D E F G H JA K
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Active ingredient
`
`Cetirizine hydro-
`chloride
`
`Additional ingredients
`
`a-Cyclodextrin
`
`B-Cyclodextrin
`
`0.25
`
`0.4
`
`0.5
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`2.0
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`2.1
`
`-
`
`9.45
`
`-
`
`-
`
`-
`
`2.81
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`4.9
`
`-
`
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`y-Cyclodextrin
`
`Polyvinyl pyrroli-
`
`done
`
`Chlorobutanol
`
`-
`
`-
`
`Vehicle
`
`Con. glycerin
`
`Boric acid
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`pH
`
`7.0
`
`7.0
`
`7.0
`
`7.0
`
`7.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`
`
`
`
`
`
`
`
`
`
`0.3
`
`-
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`
`
`7.0
`
`7.0
`
`7.0
`
`7.0
`
`7.0
`
`
`55
`
`Sodium hydroxide|q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
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`(Results)
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`In the groups of rabbits topically dosed with Solution C or D, redness was observed onthe palpebral con-
`junctiva andnictitating membrane afterthe lastinstillation on day 1. Particularly, in the group of rabbits given
`Solution D, their symptoms were so severe thatindividual blood vessels to be clearly observed on the normal
`palpebral conjunctiva were notdefinitely discernible. In addition, bulbar conjunctival vasodilation and palpe-
`bral conjunctival edema were observed. The redness as mentioned above wasstill observed even 16 hours
`after the last administration on day 1 and up to the beginning ofinstillation on day 2. The observation on day
`3 of treatment also found redness of the conjunctiva as in the observation after the last instillation on day 1
`but with an increased severity in both groups, indicating that cetirizine has a strongirritating effect on the con-
`junctiva. In the corneal fluorescein stain assay performed at the completionofinstillation treatment, dye spots
`were observed overthe entire corneal area in both groups, indicating that cetirizine alsoirritates the corneal
`epithelium. Judging that the rabbit eyes could not tolerate further instillation, the treatment with Solution C
`or D was discontinued on day3.
`In the group of rabbits given Solution E containing a cyclodextrin compound, slight redness was observed
`on the palpebral and bulbar conjunctivae after the last instillation on day 1, while very small amounts of dis-
`charge were found in somerabbits of the group dosed with Solution F. However, neither the redness nor the
`eye discharge as found on day 1 was no longer observed on and after day 3. Even in the corneal fluorescein
`staining assay doneat the end of treatment, no change wasfound from the condition before the treatment
`and all the findings were invariably within the normal range, clearly indicating that a reduction in ocular irri-
`tation can be attained by the addition of a cyclodextrin compound to a composition ofcetirizine hydrochloride.
`The eyestreated with the vehicle showednosign ofirritation caused by the vehicle.
`
`Test Example 2: Toxicity test by instillation into rabbit eyes
`
`(Method)
`
`Using male Japanese white rabbits in good health without any abnormality in the ophthalmological ex-
`amination (2 groups of 5 rabbits), ophthalmic composition F or K prepared in solution form according to the
`formulation shownin Table 1 wasinstilled into both eyes of the rabbits in the corresponding group 8 times a
`dayin a doseofone drop at each time for 28 days. The rabbits were examined for the general condition, food
`con sumption, body weight and ophthalmological items (macroscopic observation of the anterior part of eyes,
`observation of the corneal stained spots and fundusoculi, measurement of the intraocular tension) with the
`lapse of time for 28 days, after which they were subjected to urinalysis, hematological examination, blood
`chemical examination, autopsy, organ weight measurement, histopathological examination of the eyeball and
`electron microscopic examination of the cornea.
`
`(Results)
`
`With respectto the instillation of Solution F or K, no abnormality was found in the ophthalmological ex-
`amination, general condition and other examinations.
`
`Test Example 3: Effect on rat histamine-induced conjunctivitis
`
`(Method)
`
`Male Wistar rats of about 100 g in weight were injected subconjunctivally each with 50 ul of 0.1 w/v% his-
`tamine at the upper eyelid. Each of the following test ophthalmic compositions in solution form wasinstilled
`into both eyesof the rats in the corresponding group at a dose of 3 ul for each eye 40 and 20 minutes before
`the histamine injection. The rats were sacrificed one hour after the histamine injection. The palpebral con-
`junctival edema weight was measured, and the edemainhibition rate was calculated using the edema weight
`of the physiological saline group as the maximal response. As the test ophthalmic solutions, a solution pre-
`pared by dissolving cetirizine hydrochloride in the vehicle (2.0 wiv% conc. glycerin, 0.4 w/v% aqueousboric
`acid and sodium hydroxide (q.s.); pH 7.0) to have a specified final concentration (hereinafter referred to as
`CE ophthalmic solution), a solution prepared by dissolving equimolar amounts ofcetirizine hydrochloride and
`either a- or B-cyclodextrin in the vehicle at a specified final concentration (hereinafter referred to as CE + a-
`CD ophthalmic solution and CE + B-CD ophthalmic solution, respectively) and a solution prepared by dissolv-
`ing diphenhydramine hydrochloride in the vehicle (hereinafter referred to as DPH ophthalmic solution) were
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`used.
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`(Results)
`
`In the rat model of histamine-induced conjunctivitis, cetirizine hydrochloride exhibited an inhibition rate of
`about 88.8% at the concentration of 0.5 w/v%, indicating that cetirizine hydrochloride has a sufficient antihis-
`taminic effect even when topically used in the field of ophthalmology.
`To compare the efficacy against histamine-induced conjunctivitis of cetirizine hydrochloride when formu-
`lated with a- or B-cyclodextrin, the cetirizine hydrochloride concentration (mM) of each ophthalmic solution
`which exhibited a 50% inhibition of the edema (IC5,) was determined using the edemarate of the physiological
`saline-instilled rat group as a control. The ICs values obtained for the test ophthalmic solutions are shown in
`Table 2.
`
`TABLE 2
`
`Inhibitory Effect of Cetirizine on Histamine-induced Conjunctivitis
`eee
`Test ophthalmic solution
`ICso*
`eee
`CE
`2.05 mM
`CE + a-CD
`1.97
`CE + B-CD
`2.76
`DPH
`120.0
`eee
`*: The concentration ofcetirizine hydrochloride
`which gives 50% inhibition of histamine-
`induced rat conjunctivitis.
`
`As shownin Table 2, the ICg9 value of CE ophthalmic solution was 2.05 mM (about 0.1 w/v%), indicating
`that cetirizine hydrochloride has an antihistaminic effect to a certain extent even belowirritating concentra-
`tions. The groupsof rats treated with CE or CE + a-CD ophthalmic solution gave substantially equal ICgo val-
`ues, indicating that, in this experimental system, a-cyclodextrin does not substantially affect the efficacy of
`cetirizine hydrochloride. The ICs, value in the group of rats treated with CE + B-CD ophthalmic solution was
`somewhathigher than that found in the group of rats treated with CE ophthalmic solution (containing cetirizine
`hydrochloride alone). This fact suggests that the addition of B-cyclodextrin to a composition of cetirizine hy-
`drochloride causesa slight decreasein the efficacy of cetirizine hydrochloride in this experimental system but
`the degree of decrease is so small that the efficacy of cetirizine hydrochloride can be well maintained.
`
`Test Example 4: Eyeirritation test in humans
`
`(Method)
`
`There is some differencein irritation response between the human and animal eyes when an ophthalmic
`solution is instilled thereinto. In addition, some subjective factors such as a feeling after the use should be
`considered in case of human eyes. It is, therefore, be concluded that ophthalmic solutions without anyirritation
`to human eyes are more preferred, and any strongly irritative composition cannot be put to practical use. In
`this regard, Compositions A, B, D, E, F, G, H, J and K in solution form as shownin Table 1 were evaluated for
`the feeling after their use when instilled into the eyes of human subjects(I, Il, IIl and IV). The results are shown
`in Table 3.
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`TABLE3
`Irritation to Human Eves
`
`Human subjects
`Ophthalmic
`composition §=—
`I
`0
`Ill
`IV
`
`10
`++
`++
`+
`+
`
`ttt tt+0FH $4
`|
`
`15
`
`tit044 ttt0$44
`ttt
`tt Ot
`
`ATAwpS
`
`-: No irritation or discomfort
`+: Slightirritation
`++: Moderate irritation (pain)
`+++: Strong irritation
`
`(Results)
`
`Among the cyclodextrin-free ophthalmic compositions, i.e., Compositions A, B and D in solution form, Sol-
`ution Acontaining 0.25 w/v% cetirizine hydrochloride gaveslightirritation only to two of four subjects, indicating
`that the irritation of cetirizine hydrochloride to human eyesis significantly reduced at relatively low concen-
`trations. In contrast, Solutions B and D both having a cetirizine hydrochloride concentration of 0.4 w/v% or
`more gaveirritation to all the subjects, and in particular, Solution D was so much irritative that it has no prac-
`tical use.
`
`On the other hand, Solutions E, F, G and K each containing a-, B- or y-cyclodextrin caused no ocularirri-
`tation, although their cetirizine hydrochloride concentrations were as high as 1 w/v%. It was, therefore, clear
`that the addition of a cyclodextrin compound to a composition of cetirizine hydrochloride can reducetheirri-
`tation responseof eyesto cetirizine hydrochloride and the resulting composition in solution form can be used
`safely as an ophthalmic solution.
`Solution H containing polyvinyl pyrrolidone which caused no ocularirritation but has the property of form-
`ing complexes with manydifferent substances, and Solution J containing chlorobutanol which has local anes-
`thetic action and is usually used for reducing the local pain caused by an injection, gave strong ocularirritation,
`indicating that neither polyvinyl pyrrolidone nor chlorobutanolis suitable as an additional ingredientfor the ob-
`ject of the present invention, that is, for suppressing ocularirritation caused bycetirizine or salts thereof.
`
`Test Example 5: Human Nasal MucosalIrritation Test
`
`(Method)
`
`It can also be said that nasal solutions without anyirritation to human noses are morepreferred asis true
`of ophthalmic solutions, and anystrongly irritative composi tion cannot be put to practical use. In this regard,
`Solutions C, D and F were evaluatedfor the feeling after their use when sprayed into the noses of human sub-
`jects (I, Il and III). The results are shownin Table 4.
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 007
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 007
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`
`
`EP 0 605 203 A2
`
`TABLE 4
`
`Imtation to Human Noses
`ee
`Ophthalmic
`Humansubjects
` composition
`I
`0
`I
`ae
`Cc
`-
`4
`_
`
`D +++0+44++
`
`10
`F
`-
`-
`+
`
`—: No uritation or discomfort
`+: Slight irritation
`++: Moderate irritation (pain)
`+++: Strong irritation
`
`(Results)
`
`When Solution C was sprayedinto the nose, one of three subjects felt it irritative. When Solution D was
`applied, all the subjects felt strong irritation which persisted for a fairly long time, indicating that a composition
`containing only cetirizine hydrochloride in the vehicle is alsoirritative to nasal mucosae.
`On the other hand, Solution F containing B-cyclodextrin gaveslight irritation only to one of three subjects,
`although thecetiridine hydrochloride concentration thereof was the same as that of Solution D giving strong
`irritation. Moreover, the irritation from Solution F disappeared in a brief time. It is, therefore, clear that the
`addition of a cycle dextrin compoundto a composition of cetirizine or a salt thereof can suppresstheirritation
`to nasal mucosae and such a composition in solution form can be used as a nasalsolution.
`
`Test Example 6: Stability Test
`
`(Method)
`
`Compositions A and K shownin Table 5, and Compositions L to N and P to R shownin Table 5 were pre-
`pared in solution form. Each of the solutions wasfiltered through a membranefilter of 0.45 um mesh, followed
`byfilling into a glass ampoule. These ampoules were stored at room temperature for 6 months, during which
`they were subjected to macroscopic observation for the presence of insoluble matter with the lapse of time.
`
`15
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`8
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`Apotex,Inc. (IPR2019-00400), Ex. 1004, p. 008
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 008
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`
`
`EP 0 605 203 A2
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`
`TABLE 5
`
`Ingredient (w/v%)
`
`
`Compositions
`
` L M N P Q R
`
`
`
`
`
`
`
`
`
`
`
`
`
`Active ingredient
`
`Cetirizine hydrochloride
`
`0.25
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`Additional ingredients
`
`B-Cyclodextrin
`
`0.61
`
`Hydroxypropylmethylcellulose
`
`Polyvinyl alcohol
`
`Polysorbate 80
`
`Polyvinyl pyrrolidone
`
`-
`
`-
`
`-
`
`-
`
`4.9
`
`0.2
`
`-
`
`-
`
`-
`
`4.9
`
`4.9
`
`4.9
`
`4.9
`
`-
`
`0.2
`
`-
`
`-
`
`-
`
`-
`
`0.2
`
`-
`
`-
`
`-
`
`-
`
`2.0
`
`-
`
`-
`
`-
`
`-
`
`-
`
`1.0
`
`10
`
`15
`
`20
`
`
`
`
`
`
`
`Sodium hydroxide
`q.s.
`q.s.
`q.s.
`q.s.
`qs.
`q.-s.
`
`pH
`
`7.0
`
`7.0
`
`7.0
`
`7.0
`
`
`
`Macrogol 4000
`
`-
`
`-
`
`Vehicle
`
`Conc. glycerin
`
`Boric acid
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`
`
`
`
`
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`7.0
`
`7.0
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`(Results)
`
`The deposition of insoluble matter was observed in the ampoule of Solution A after one day from the be-
`ginning of the storage at room temperature. The ampoules of Solution K and L exhibited a slight deposition of
`insoluble matter after six months. In contrast, no deposition of insoluble matter was found in the ampoules of
`Solution M, N and P to R even after six months.
`It was, therefore, found that the addition of a cyclodextrin compound to a composition of cetirizine hydro-
`chloride can reduce the association of cetirizine and the addition of a surfactant or a water-soluble polymer
`to a composition of cetirizine hydrochloride and a cyclodextrin compound can prevent the association of ce-
`tirizine, thereby makingit possible to obtain an antiallergic composition in stable solution form. It was also found
`that a combinationof cetiridine hydrochloride only with a surfactant or a water-soluble polymer cannotprevent
`the deposition of insoluble matter.
`
`45
`
`Example 1
`
`An ophthalmic composition was prepared in lyophilized powder form according to the following formula-
`tion:
`
`Ingredient
`
`Amount
`
`
`
`
`
`
`
`Cetirizine hydrochloride
`
`Boric acid
`
`Sodium hydroxide
`
`0.59
`
`5.09
`
`q.s.
`
`Distilled water
`
`ad 100 ml
`
`9
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 009
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 009
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`
`
`EP 0 605 203 A2
`
`Cetirizine hydrochloride and boric acid are dissolved in about 80 ml of distilled water, and the solution is
`adjusted to pH 7.0 by the addition of aqueous sodium hydroxide, to which distilled water is further added to
`have a total volume of 100 ml. The solution thus obtainedis sterilized by filtration, and dispensed in 2 ml por-
`tions, which are then lyophilized, resulting in an ophthalmic composition. At the time of use, the ophthal mic
`composition is dissolved in 5 ml ofdistilled water for injection.
`
`Example 2
`
`An ophthalmic composition was prepared in solution form according to the following formulation:
`
`
`
`Ingredient
`
`Amount
`
`Cetirizine hydrochloride
`
`a-cyclodextrin
`
`Boric acid
`
`Sodium hydroxide
`
`1.09
`
`2.19
`
`2.09
`
`q.s.
`
`
`
`Distilled water ad 100 ml
`
`
`
`
`
`Cetirizine hydrochloride, a-cyclodextrin and boric acid are dissolved in about 80 mlof distilled water, and
`the solution is adjusted to pH 7.0 by the addition of aqueous sodium hydroxide, to which distilled water is fur-
`ther added to have a total volume of 100 ml, resulting in an ophthalmic composition.
`
`Example 3
`
`An ophthalmic composition was prepared in solution form according to the following formulation:
`
`
`
`
`
` Ingredient Amount
`
`Cetirizine hydrochloride
`
`a-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Sodium hydroxide
`
`Distilled water
`
`1.0g
`
`2.19
`
`0.19
`
`2.0g
`
`q.s.
`
`ad 100 ml
`
`
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`About 80 ml ofdistilled water is heated to about 90°C,in which hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersionis stirred in an ice-water bath so that the hydroxypropylmethylcellulose is dissolved.
`After warming to room temperature, cetirizine hydrochloride, «-cyclodextrin and boric acid are dissolvedin the
`solution. The solution thus obtained is adjusted to pH 7.0 by the addition of aqueous sodium hydroxide, to which
`distilled water is further added to have a total volume of 100 ml, resulting in an ophthalmic composition.
`
`Example 4
`
`50
`
`A nasal composition was prepared in solution form according to the following formulation:
`
`55
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`10
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 010
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 010
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`
`
`EP 0 605 203 A2
`
`
`Ingredient
`
`Cetirizine hydrochloride
`
`B-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Disodium edetate
`
`Sodium hydroxide
`
`Distilled water
`
`Amount
`
`2.0g
`
`4.93 g
`
`0.29
`
`2.59
`
`0.02 g
`
`q.s.
`
`ad 100 ml
`
`About 80 ml ofdistilled water is heated to about 90°C,in which hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersionis stirred in an ice-water bath so that the hydroxypropylmethylcellulose is dissolved.
`After warming to room temperature, cetirizine hydrochloride, B-cyclodextrin, boric acid and disodium edetate
`are dissolved in the solution. The solution thus obtained is adjusted to pH 7.0 by the addition of aqueous sodium
`hydroxide, to whichdistilled water is further added to have a total volume of 100 ml, resulting in a nasal com-
`position.
`
`
`
`
`
`
`
`
`Example 5
`
`An ophthalmic composition was prepared in solution form according to the following formulation:
`
`Ingredient
`
`Amount
`
`Cetirizine hydrochloride
`
`a-cyclodextrin
`
`Polyvinyl alcohol
`
`Sodium acetate
`
`Propylene glycol
`
`Methylparaben
`
`Propylparaben
`
`Sodium hydroxide
`
`0.39
`
`0.89
`
`0.29
`
`0.19
`
`2.09
`
`0.29
`
`0.19
`
`q.s.
`
`Distilled water
`
`ad 100 ml
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`About 80 ml of distilled water is heated to about 90°C, in which polyvinyl alcohol, methylparaben and pro-
`pylparaben are dissolved. After cooling to room temperature, cetirizine hydrochloride, a-cyclodextrin, sodium
`acetate and propylene glycol are dissolved in the solution. The solution thus obtained is adjusted to pH 7.0 by
`the addition of aqueous sodium hydroxide, to which distilled water is further added to have a total volume of
`100 ml, resulting in an ophthalmic composition.
`
`50
`
`Example 6
`
`A nasal composition was prepared in solution form according to the following formulation:
`
`55
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`11
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 011
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`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 011
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`
`
`EP 0 605 203 A2
`
`
`Ingredient
`
`Amount
`
`Cetirizine hydrochloride
`
`B-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Disodium edetate
`
`Sodium hydroxide
`
`1.0g
`
`2.479
`
`0.19
`
`1.25 g
`
`0.01 g
`
`q.s.
`
`
`
`Distilled water ad 100 ml
`
`About 80 ml ofdistilled water is heated to about 90°C,in which hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersionis stirred in an ice-water bath so that the hydroxypropylmethylcellulose is dissolved.
`After warming to room temperature, cetirizine hydrochloride, B-cyclodextrin, boric acid and disodium edetate
`are dissolved in the solution. The solution thus obtained is adjusted to pH 7.0 by the addition of aqueous sodium
`hydroxide, to whichdistilled water is further added to have a total volume of 100 ml, resulting in a