`
`a,
`
`Europaisches Patentamt
`European Patent Office
`Office européen des brevets
`
`Hllm
`
`
`
`
`
`@ Publication number: 0 605 203 A2
`
`@
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 933104648
`
`@ Int. CI.5: A61K 31/495, A61 K 9/08
`
`@ Date of filing: 23.12.93
`
`Priority: 25.12.92 JP 346031l92
`
`Date of publication of application :
`06.07.94 Bulletin 94I27
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU MC
`NL PT SE
`
`@ 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
`lbaraki-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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`

`

`EP 0 605 203 A2
`
`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 forthe treatment of allergic
`diseases in the fields of ophthalmology and otorhinology.
`
`BACKGROUND OF THE INVENTION
`
`Cetirizine is an antiallergic compound of the formula:
`
`Cl
`
`/_\
`CH—N
`
`N-CH2CH20CH2COOH ,
`
`the chemical name of 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, and it is partic-
`ularly useful as an antiallergic agent with significant specificity to histamine (see, e.g., JP-B 63-11353).
`In the ophthalmic or nasal allergic diseases, taking the former as an example, systemic symptoms are 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 changes are 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
`because of its 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 aqueous solution. This seems because cetirizine 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 of cetirizine at high con-
`centrations where no insoluble matter will be deposited has strong irritating 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
`ingredient, 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 because they are cyclic sugars. Therefore, cyclodextrin com-
`pounds have hitherto 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 compound is blended with a certain drug, it be-
`comes difficult 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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`SUMMARY OF THE INVENTION
`
`Under these 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 disadvantages of cetirizine and which has no irritating properties to eyes and nasal mucosae. As
`the result, they have found that the addition of a cyclodextrin compound to an aqueous solution 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 aqueous solution ofcetirizine blended
`with a cyclodextrin compound can suppress the irritation of cetirizine to eyes or nasal mucosae even at high
`concentrations where such an irritation will be found in conventional cases, and that such an aqueous solution
`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/ora water-soluble polymer to an aqueous solution of cetirizine 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.
`That is, 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 ant iallergic composition of the present invention has almost no irritation to eyes and nasal mucosae,
`and it can be effectively used as a prophylactic and therapeutic agentfor allergic diseases in 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. Examples of 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 examples of the cyclodextrin compound are a—cyclodextrin, ji—cycledextrin, y-cyclodextrin, hydrox-
`ypropyl [S-cyclodextrin, dimethyl [i-cyclodextrin, maltosyl fi-cyclodextrin and ji-cyclodextrin sulfate. Particular-
`ly preferred are a—cyclodextrin, B-cyclodextrin and y-cyclodextrin. These cyclodextrin compounds may be used
`alone or in combination.
`
`The amount of cyclodextrin compound to be used may vary with its solubility and the concentration of
`cetirizine. It is, however, desirable that the amount of cycle dextrin compound is 0.5 to 3.0 times, preferably
`1.0 to 2.0 times, as much as the mole of cetirizine.
`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 or in combination.
`The water-soluble polymer includes cellulose derivatives, vinyl polymers and polyols. Examples of 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 alone or in combination.
`The amount of surfactant or water-soluble polymerto be used may vary 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 much as the weight of cetirizine, and the amount of water-soluble polymer is 0.01 to 10.0 times, pre-
`ferably 0.02 to 5.0 times, as much as the weight of cetirizine.
`The ant iallergic composition of the present invention can be used within the pH range adopted for 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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`otherthan cetirizine in suitable amounts, so long as the excellentadvantages attained 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
`powder form, 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 used as a nasal solution, the antiallergic corn position of the present
`invention is preferably atomized and inhaled about 3 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 further illustrated by way of the following test examples and working exam-
`ples, which are not to be construed to limit thereof.
`
`Test Example 1: Eye irritation 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 shown in Table
`1 was instilled into the right eyes of the rabbits in the corresponding group and only the vehicle into their left
`eyes 8 times a day at 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
`before the first instillation on day 1, 30 minutes afterthe last instillation on each ofdays 1, 3 and 5 oftreatment,
`and on day 6.
`
`
`TABLE 1
`
`Ingredient (w/v%)
`
`Compositions
`
`
`
`
`
`
`
`
`
`C D E F G H JBA K
`
`
`
`
`
`
`
`
`
`
`
`Active ingredient
`
`Cetirizine hydro-
`chloride
`
`Additional ingredients
`
`0.25
`
`0.4
`
`0.5
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`2.0
`
`a—Cyclodextrin
`
`[i-Cyclodextrin
`
`—
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`2.81
`
`2.1
`
`-
`
`2_45
`
`-
`
`-
`
`-
`
`_
`
`-
`
`-
`
`_
`
`-
`
`_
`
`4.9
`
`_
`
`10
`
`15
`
`20
`
`25
`
`30
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`35
`
`40
`
`
`
`y-Cyclodextrin
`
`Polyvinyl pyrroli-
`
`Chlorobutanol
`
`done
`
`—
`
`'
`
`—
`
`—
`
`'
`
`—
`
`'
`
`-
`
`'
`
`-
`
`'
`
`-
`
`'
`
`-
`
`'
`
`-
`
`2'05
`
`-
`
`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
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`2.0
`
`0.4
`
`'
`
`0.3
`
`2.0
`
`0.4
`
`'
`
`_
`
`2.0
`
`0.4
`
`
`
`
`
`
`
`
`
`
`
`
`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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`EP 0 605 203 A2
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`(Results)
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`In the groups of rabbits topically dosed with Solution C or D, redness was observed on the palpebral con-
`junctiva and nictitating membrane afterthe last instillation on day 1. Particularly, in the group of rabbits given
`Solution D, their symptoms were so severe that individual blood vessels to be clearly observed on the normal
`palpebral conjunctiva were not definitely discernible. In addition, bulbar conjunctival vasodilation and palpe-
`bral conjunctival edema were observed. The redness as mentioned above was still observed even 16 hours
`after the last administration on day 1 and up to the beginning of instillation 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 thatcetirizine has a strong irritating effect on the con-
`junctiva. In the corneal fluorescein stain assay performed at the completion of instillation treatment, dye spots
`were observed overthe entire corneal area in both groups, indicating that cetirizine also irritates the corneal
`epithelium. Judging that the rabbit eyes could not tolerate further instillation, the treatment with Solution C
`or D was discontinued on day 3.
`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 some rabbits 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 done at the end of treatment, no change was found 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 of cetirizine hydrochloride.
`The eyes treated with the vehicle showed no sign of irritation 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 shown in Table 1 was instilled into both eyes ofthe rabbits in the corresponding group 8 times a
`day in a dose of one 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 fundus oculi, 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 respect to 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 su bconju nctivally each with 50 pl of 0.1 w/v% his-
`tamine at the upper eyelid. Each of the following test ophthalmic compositions in solution form was instilled
`into both eyes of the rats in the corresponding group at a dose of 3 pl 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 edema inhibition 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 w/v% conc. glycerin, 0.4 w/v% aqueous boric
`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 of cetirizine hydrochloride and
`either (1- or [S-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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`EP 0 605 203 A2
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`used.
`
`(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 ot- or B-cyclodextrin, the cetirizine hydrochloride concentration (mM) of each ophthalmic solution
`which exhibited a 50% inhibition of the edema (IC50) was determined using the edema rate of the physiological
`saline-instilled rat group as a control. The IC50 values obtained for the test ophthalmic solutions are shown in
`Table 2.
`
`TABLE ;
`Inhibitog Effect of Cetirizine on Histamine-induced Conjunctivitis“a
`Test ophthalmic solution
`1C50*
`
`M C
`
`E
`
`205 mM
`
`CE + a-CD
`
`1.97
`
`CE + B-CD
`DPH
`
`2.76
`120.0
`
`H *
`
`z The concentration of cetirizine hydrochloride
`which gives 30% inhibition of histamine-
`1nduced rat conjunctivitis.
`
`As shown in Table 2, the IC5o 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 below irritating concentra-
`tions. The groups of rats treated with CE or CE + a—CD ophthalmic solution gave substantially equal IC5o val-
`ues, indicating that, in this experimental system, a—cyclodextrin does not substantially affect the efficacy of
`cetirizine hydrochloride. The IC50 value in the group of rats treated with CE + ji-CD ophthalmic solution was
`somewhat higher 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 causes a slight decrease in 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: Eye irritation test in humans
`
`(Method)
`
`There is some difference in 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 any irritation
`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 shown in Table 1 were evaluated for
`the feeling after their use when instilled into the eyes of human subjects (I, II, III and IV). The results are shown
`in Table 3.
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`EP 0 605 203 A2
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`TABLE 3
`.
`Irritation to Human Eves
`N
`Ophthalmic
`Human subjects
`composition H
`I
`II
`III
`IV
`
`l A
`
`B
`D
`E
`1:
`G
`H
`J
`K
`
`—
`+
`+++
`_
`_
`_
`+++
`+++
`_
`
`+
`+
`+++
`_
`_
`_
`++
`+++
`_
`
`—
`++
`+++
`_
`_
`_
`+++
`+++
`_
`
`+
`++
`+++
`_
`_
`_
`+++
`+++
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`_M —
`
`: No imitation or discomfort
`+: Slight irritation
`++: 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 gave slight irritation only to two of four subjects, indicating
`that the irritation of cetirizine hydrochloride to human eyes is 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 gave irritation 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 (1-, [3- or y—cyclodextrin caused no ocular irri-
`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 reduce the irri-
`tation response of eyes to 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 ocular irritation but has the property of form-
`ing complexes with many different 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 ocular irritation,
`indicating that neither polyvinyl pyrrolidone nor chlorobutanol is suitable as an additional ingredient for the ob-
`ject of the present invention, that is, for suppressing ocular irritation caused by cetirizine or salts thereof.
`
`Test Example 5: Human Nasal Mucosal Irritation Test
`
`45
`
`(Method)
`
`It can also be said that nasal solutions without any irritation to human noses are more preferred as is true
`of ophthalmic solutions, and any strongly irritative composi tion cannot be put to practical use. In this regard,
`Solutions C, D and F were evaluated for the feeling after their use when sprayed into the noses of human sub-
`jects (I,
`II and Ill). The results are shown in Table 4.
`
`50
`
`55
`
`7
`
`Apotex, Inc. (IPR2019-00400), EX. 1004, p. 007
`
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 007
`
`

`

`EP 0 605 203 A2
`
`TABLE 4_1
`Imitation to Human Noses
`
`M O
`
`phthalmic
`composition
`
`Human subjects
`
`I
`
`_
`++
`-
`
`II
`
`III
`
`+
`+++
`—
`
`_
`+++
`+
`
`M C
`
`D
`F
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`—: No irritation or discomfort
`+: Slight irritation
`++: Moderate imitation (pain)
`+++: Strong irritation
`
`(Results)
`
`When Solution C was sprayed into 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 ti me, indicating that a composition
`containing only cetirizine hydrochloride in the vehicle is also irritative to nasal mucosae.
`On the other hand, Solution F containing [i-cyclodextrin gave slight irritation only to one of three subjects,
`although the cetiridine 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 compound to a composition of cetirizine or a salt thereof can suppress the irritation
`to nasal mucosae and such a composition in solution form can be used as a nasal solution.
`
`B Example 6: Stability E
`
`(Method)
`
`Compositions Aand K shown in Table 5, and Compositions L to N and P to R shown in Table 5 were pre-
`pared in solution form. Each of the solutions was filtered through a membrane filter of 0.45 gm mesh, followed
`by filling 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.
`
`8
`
`Apotex, Inc. (IPR2019-00400), EX. 1004, p. 008
`
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 008
`
`

`

`EP 0 605 203 A2
`
`
`% é
`
`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
`
`fi-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
`
`_
`
`_
`
`_
`
`_
`
`10
`
`15
`
`20
`
`
`
`
`
`
`
`
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`
`
`
`
`-
`
`2.0
`
`0.4
`
`1.0
`
`2.0
`
`0.4
`
`
`
`
`
`Macrogol 4000
`
`Vehicle
`
`Conc. glycerin
`
`Boric acid
`
`-
`
`2.0
`
`0.4
`
`-
`
`2.0
`
`0.4
`
`
`Sodium hydroxide
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`
`
`PH
`7.0
`7.0
`7.0
`7.0
`7.0
`7.0
`
`(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 making it possible to obtain an antiallergic composition in stable solution form. ltwas also found
`that a combination of cetiridine hydrochloride only with a surfactant or a water-soluble polymer cannot prevent
`the deposition of insoluble matter.
`
`45
`
`Example 1
`
`An ophthalmic composition was prepared in lyophilized powder form according to the following formula-
`tion:
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`Ingredient
`
`Amount
`
`
`
`Cetirizine hydrochloride
`
`Boric acid
`
`Sodium hydroxide
`
`Distilled water
`
`0.5 g
`
`5.0 g
`
`q.s.
`
`ad 100 ml
`
`
`
`
`
`9
`
`Apotex, Inc. (IPR2019-00400), EX. 1004, p. 009
`
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 009
`
`

`

`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 obtained is 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 of distilled water for injection.
`
`Example 2
`
`An ophthalmic composition was prepared in solution form according to the following formulation:
`
`
`Ingredient
`Amount
`
`
`
`
`
`1.0 g
`
`2.1 g
`
`2.0 g
`
`q.s.
`
`ad 100 ml
`
`
`
`Cetirizine hydrochloride
`
`a—cyclodextrin
`
`Boric acid
`
`Sodium hydroxide
`
`Distilled water
`
`Cetirizine hydrochloride, a—cyclodextrin 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 fur-
`ther added to have a total volume of 100 ml, resulting in an ophthalmic composition.
`
`Example g
`
`An ophthalmic composition was prepared in solution form according to the following formulation:
`
`
`
` Ingredient Amount
`
`
`
`
`
`Cetirizine hydrochloride
`
`oc-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Sodium hydroxide
`
`Distilled water
`
`1.0 g
`
`2.1 g
`
`0.1 g
`
`2.0 g
`
`q.s.
`
`ad 100 ml
`
`
`
`About 80 ml of distilled water is heated to about 90°C, in which hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersion is stirred in an ice-water bath so that the hydroxypropylmethylcellulose is dissolved.
`After warming to room temperature, cetirizine hydrochloride, a—cyclodextrin and boric acid are dissolved in the
`solution. The solution thus obtained is adjusted to pH 7.0 bythe 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 5
`
`A nasal composition was prepared in solution form according to the following formulation:
`
`10
`
`Apotex, Inc. (IPR2019-00400), EX. 1004, p. 010
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 010
`
`

`

`EP 0 605 203 A2
`
`
`
`Ingredient
`Amount
`
`Cetirizine hydrochloride
`
`B-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Disodium edetate
`
`Sodium hydroxide
`
`Distilled water
`
`
`
`
`
`
`
`2.0 g
`
`4.93 g
`
`0.2 g
`
`2.5 g
`
`0.02 g
`
`q.s.
`
`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 hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersion is 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 which distilled water is further added to have a total volume of 100 ml, resulting in a nasal com-
`position.
`
`Example §
`
`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
`
`Methyl paraben
`
`Propylparaben
`
`Sodium hydroxide
`
`Distilled water
`
`
`
`
`
`0.3 g
`
`0.8 g
`
`0.2 g
`
`0.1 g
`
`2.0 g
`
`0.2 g
`
`0.1 g
`
`q.s.
`
`ad 100 ml
`
`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 §
`
`A nasal composition was prepared in solution form according to the following formulation:
`
`55
`
`11
`
`Apotex, Inc. (IPR2019-00400), EX. 1004, p. 011
`
`Apotex, Inc. (IPR2019-00400), Ex. 1004, p. 011
`
`

`

`EP 0 605 203 A2
`
`
`
`Ingredient
`Amount
`
`
`
`
`
`
`
`1.0 g
`
`2.47 g
`
`0.1 g
`
`1.25 g
`
`0.01 g
`
`q.s.
`
`ad 100 ml
`
`Cetirizine hydrochloride
`
`B-cyclodextrin
`
`Hydroxypropylmethylcellulose
`
`Boric acid
`
`Disodium edetate
`
`Sodium hydroxide
`
`Distilled water
`
`About 80 ml of distilled water is heated to about 90°C, in which hydroxy-propylmethylcellulose is uniformly
`dispersed. The dispersion is 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