United States Patent
`[19]
`[11] Patent Number:
`5,916,550
`
`Inada et al.
`[45] Date of Patent:
`Jun. 29, 1999
`
`USOOS916550A
`
`[54] AQUEOUS SUSPENSION 0F LOTEPREDNOL
`ETABONATE
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`[75]
`
`Inventors: Katsuhiro Inada, Kobe; HideO
`Terayama, Itami, bOth 0f Japan
`
`[73] Assignee: Senju Pharmaceutical C0., Ltd.,
`Osaka, Japan
`
`[21] APPL N05 09/0353094
`[22]
`Filed:
`Mar. 5, 1998
`
`[30]
`
`Foreign Application Priority Data
`
`Mar. 14, 1997
`[JP]
`Japan .................................... 9—082207
`[51]
`Int. C16 ..................................................... A61K 31/74
`[52] US. Cl.
`........................ 424/7s.04; 424/434; 424/435
`[58] F' ld f S
`h
`424/78 04 434
`1e
`0
`earc
`.................................
`.
`,
`,
`424/435
`
`kL.L.
`onac ’
`
`............................... 424/427
`7/1996 Guy et a1.
`5,540,930
`Primary Examiner—Carlos A. Azpuru
`Art
`A
`t
`F' —W d
`th L'd&P
`omey, gen, 0r
`zrm
`en ero ’
`1n
`[57]
`ABSTRACT
`ote re no eta-
`e conventlona a ueous sus ens1on o
`p d
`l
`f l
`Th
`p
`'
`'
`l
`q
`bonate is not easily amenable to production pH control and
`entails a pH depression on long-term storage, thus irritating
`e e e or
`e nasa mucosa on ms 1 a 1on.
`th
`y
`th
`1
`t 11 t
`.
`.
`.
`.
`.
`When a C2—7 a11phat1c ammo ac1d 1s added to an aqueous
`suspension of loteprednol etabonate for topical ophthalmic
`“sci the Sgsfiensm ‘19:: 31‘” ““djtrgtfi 3H deiprisgilon eve“ 0“
`Pro 99g?“
`.Sorage’ W1
`6 ms“
`a “0 H“ a
`e ”Spouse
`1s el1c1ted 1n the eye or nasal mucosa.
`14 Claims, N0 Drawings
`
`Page 1 of4
`
`LUPIN EX 1069
`
`LUPIN EX 1069
`
`Page 1 of 4
`
`

`

`5,916,550
`
`1
`AQUEOUS SUSPENSION OF LOTEPREDNOL
`ETABONATE
`
`FIELD OF THE INVENTION
`
`The present invention relates to an aqueous suspension of
`loteprednol etabonate and more particularly to a stable and
`safe aqueous suspension of loteprednol etabonate which
`does not undergo change in pH on prolonged storage and is
`not irritating to the ocular and nasal mucosa.
`
`BACKGROUND OF THE INVENTION
`
`Many steroid compounds have been used as topical
`therapeutic agents for eye inflammations. While those ste-
`roid compounds show a potent antiinflammatory action, they
`tend to cause secondary (iatrogenic) disorders of the eye,
`such as cataract and glaucoma.
`Therefore, research has been done to develop steroid
`compounds which do not cause adverse reactions even when
`administered topically to the eye and recently loteprednol
`etabonate (hereinafter sometimes referred to briefly as LE)
`having very satisfactory antiinflammatory activity and only
`a low risk for side effects has been developed by modifica-
`tion of prednisolone acetate (US. Pat. Nos. 4,716,495 and
`4,996,335).
`LE is devoid of the 20-keto group in the 17B-position of
`prednisolone and instead has in this 17B-position an ester
`residue which is hydrolyzed in vivo to give an inert car-
`boxylic acid metabolite which does not bind to the gluco-
`corticoid receptor. Therefore, unlike many other steroidal
`agents, LE has a low incidence of side effects such as onset
`of cataract and elevation of intraocular pressure, thus being
`a very useful compound for the treatment of ocular inflam-
`mations.
`
`Since LE is a substantially water-insoluble crystalline
`substance, its dosage form has to be an aqueous suspension
`in order that it may be used as eye drops or nasal drops.
`However, when LE is formulated with an isotonizing agent
`such as sodium chloride and a buffer such as phosphoric
`acid, both of which are conventionally added in the prepa-
`ration of an aqueous suspension, particles of LE begin to
`aggregate within 3 months and, in certain cases, within a
`month.
`
`To overcome this disadvantage, there was proposed an
`aqueous suspension of LE formulated with a nonionic
`suspending agent such as polyvinylpyrrolidone (PVP), poly-
`vinyl alcohol (PVA), etc., a nonionic surfactant such as
`tyloxapol, polysorbate 80, etc., and further an isotonizing
`agent of polyhydric alcohols such as glycerin and mannitol
`(PCT/US94-12059) with fairly successful results. However,
`this formulation makes it difficult
`to control pH in the
`preparation of the aqueous suspension and, moreover, when
`the suspension is stored for a long time, there occurs a pH
`depression despite little change in appearance so that
`it
`elicits an irritable response in the eye or nasal mucosa.
`
`SUMMARY OF THE INVENTION
`
`The inventors of the present invention studied a broad
`spectrum of compounds for the purpose of improving the
`above formulation and providing a more stable and safe
`aqueous suspension which can be easily prepared and even
`after prolonged storage does not irritate the ocular and nasal
`mucosa and found surprisingly that certain kinds of amino
`acids are effective in meeting the above purpose. The finding
`was followed by further research which has brought the
`present invention into being.
`
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`2
`The present invention, therefore, is directed to:
`(1) an aqueous suspension of loteprednol etabonate which
`comprises loteprednol etabonate and an aliphatic amino
`acid containing 2—7 carbon atoms,
`(2) the aqueous suspension (1) wherein said amino acid is
`one having 1 or 2 amino groups and 1 or 2 carboxyl
`groups,
`
`(3) the aqueous suspension (2) wherein said amino acid is
`a neutral or acidic amino acid,
`
`(4) the aqueous suspension (3) wherein said amino acid is
`e-aminocaproic acid,
`(5) the aqueous suspension (1) which contains 0.01—3 w/v
`% of loteprednol etabonate and 0.002—2 w/v % of said
`amino acid in aqueous medium,
`(6) the aqueous suspension (1) further containing a sus-
`pending agent, a nonionic surfactant, and an isotonizing
`agent,
`
`9 which contains
`
`(7) the aqueous suspension (6) which contains 0.2—2 w/v
`% of the suspending agent, 0.05—1 w/v % of the
`nonionic surfactant, and 1—6 w/v % of the isotonizing
`agent in the aqueous medium,
`(8) the aqueous suspension (6) wherein said suspending
`agent is a water-soluble nonionic polymer, said non-
`ionic surfactant is a polyoxyalkylene monool or polyol,
`and said isotonizing agent is a polyhydric alcohol,
`(9)
`the aqueous suspension (6)
`further containing a
`preservative,
`10
`the a ueous sus ension
`q
`P
`0.0001—0.5 w/v % of said preservative,
`(11) the aqueous suspension (6) which contains 0.1—5
`moles of said amino acid, 0.01—20 moles of said
`suspending agent, and 0.05—1 mole of said nonionic
`surfactant per mole of loteprednol etabonate,
`(12)
`the aqueous suspension (1) wherein loteprednol
`etabonate occurs in finely divided form with particle
`diameters within the range of 0.1—30 um,
`(13) the aqueous suspension (1),
`the pH of which is
`4.5—7.0, and
`(14) the aqueous suspension (1), (6), or (9) which is an
`antiinflammatory agent for ophthalmic or otorhino-
`laryngological use.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The particle size of LE suited for preparation of the
`aqueous suspension of the present invention is generally
`0.1—30 um, preferably 1—20 pm, and more preferably 2—10
`pm. It is also preferable that the LE should be produced by
`a sterile procedure and has a purity of not less than 98 weight
`%. The concentration of LE in the aqueous suspension need
`only be therapeutically effective in the treatment of inflam-
`mations and is generally 0.01—3 w/v %, preferably 0.05—2
`w/v %, and more preferably 0.2—1 w/v %.
`The aqueous suspension of the present invention contains
`an aliphatic amino acid of 2 to 7 carbon atoms, preferably
`3—5 carbon atoms, not reckoning the carboxyl group carbon,
`as a buffer. The number of amino groups in this amino acid
`is preferably 1 or 2 and more preferably 1. The preferred
`number of carboxyl groups is 1 or 2. Such amino acid
`includes neutral amino acids such as alanine,
`B-aminopropionic acid, y-aminobutyric acid,
`e-aminocaproic acid, etc. and acidic amino acids such as
`aspartic acid, glutamic acid, etc. Particularly preferred are
`e-aminocaproic acid and glutamic acid.
`
`Page 2 of 4
`
`Page 2 of 4
`
`

`

`5,916,550
`
`4
`The molar ratio of LE and the above-defined amino acid,
`suspending agent and nonionic surfactant in the aqueous
`suspension of the present
`invention is generally
`1:0.1:0.01:0.05 through 12522021.
`The viscosity of the aqueous suspension of the present
`invention is preferably not over 100 cps. Moreover, the pH
`of the suspension is preferably within the range of 4.5—7.0
`and more preferably within the range of 5 .0—6.5 .
`The aqueous suspension of the present invention can be
`prepared by the per se known production technology for
`aqueous suspensions in general. A typical procedure com-
`prises dissolving the suspending agent in water, adding the
`surfactant, buffer, isotonizing agent, preservative, and other
`additives sequentially, sterilizing the mixture by filtration or
`autoclaving, adding pre-sterilized LE, and agitating the
`whole mixture with a stirrer to provide an aqueous suspen-
`sion of LE.
`
`The aqueous suspension of LE thus prepared can be used
`as an ophthalmological or otorhinolaryngological aqueous
`LE suspension in the prevention and treatment of various
`inflammations of the eye, ear, nose, or throat.
`Taking an ophthalmic aqueous suspension containing 0.5
`w/v % of LE according to the present
`invention as an
`example, various ocular inflammatory diseases such as aller-
`gic conjunctivitis and trachoma can be treated by instilling
`0.05—0.1 ml of the suspension in the eye 3 to 10 times daily
`for one day to one week.
`EXAMPLES
`
`The following working and experimental examples are
`intended to describe the present invention in further detail
`and should by no means be construed as defining the scope
`of the invention.
`
`Example 1
`Using the routine production procedure for eye drops, eye
`dropsAof the following formulation (Table 1) was prepared.
`
`10
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`3
`The above amino acid in an aqueous suspension of LE
`serves to prevent a pH depression of the suspension, and it
`is likely that this is why the irritation of the ocular and nasal
`mucosa is alleviated.
`
`The concentration of said amino acid in the aqueous
`suspension is generally 0.002—2.0 w/v %, preferably
`0.01—0.5 w/v %, and more preferably 0.04—0.2 w/v %.
`To provide a stable aqueous suspension in accordance
`with the present invention, a suspending agent, a nonionic
`surfactant, an isotonizing agent, and, where necessary, a
`preservative and other additives are incorporated.
`The suspending agent need only be a water-soluble poly-
`mer and is otherwise not critical in kind. Thus, for example,
`polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), car-
`boxymethylcellulose sodium (CMC. Na), dextrin,
`cyclodextrin, etc. can be mentioned. Among them, nonionic
`polymers such as PVP are preferred. The formulating
`amount of said suspending agent in the aqueous suspension
`is generally 0.2—2 w/v % and preferably 0.4—1 w/v %.
`The nonionic surfactant as well as said suspending agent
`serves to maintain the active ingredient loteprednol eta-
`bonate in evenly suspended state for a long time. The
`nonionic surfactant that can be used includes polyoxyalky-
`lene monools or polyols which are obtainable by addition-
`polymerizing 1 or 2 different alkylene oxides, e.g. ethylene
`oxide and propylene oxide, to an organic compound con-
`taining 1 or a plurality of hydroxyl groups per molecule,
`their esters, and mixtures thereof.
`The useful nonionic surfactant includes but is not limited
`
`to polysorbate 80, tyloxapol and poloxamers. Among them,
`tyloxapol and polysorbate 80 are preferred. The formulating
`amount of the nonionic surfactant is generally 0.05—1 w/v %
`and preferably 0.1—0.6 w/v %
`The isotonizing agent is preferably an aliphatic polyhy-
`dric alcohol, particularly an aliphatic polyol containing 2—6
`carbon atoms, such as glycerol and mannitol.
`The formulating amount of the isotonizing agent in the
`aqueous suspension is generally 1—6 w/v % and preferably
`1.5—4 w/v %. Where necessary, a preservative may be
`incorporated. The preservative that can be used includes
`benzalkonium chloride and/or sodium edetate, among oth-
`ers. The formulating amount of the preservative in the
`aqueous suspension is generally 0.0001—0.5 w/v % and
`preferably 0.001—0.2 w/v %.
`The aqueous suspension of the present invention may
`further contain therapeutically effective amounts of other
`drugs such as an antiglaucoma drug, a steroidal or nonste-
`roidal antiinflammatory agent, an antiallergic agent, an
`antibacterial agent, and a vasoconstrictor.
`The antiglaucoma drug includes but is not limited to
`betaxolol, atenolol,
`levobunolol, epinephrine, dipivefrin
`hydrochloride, pilocarpine hydrochloride, physostigmine
`salicylate, distigmine bromide, ecothiopate iodide, carteolol
`hydrochloride, and methazolamide.
`includes
`The steroidal antiinflammatory agent
`beclomethasone, dexamethasone, betamethasone,
`fluocinolone, fluorometholone, etc. and the nonsteroidal
`antiinflammatory agent includes piroxicam, indomethacin,
`naproxen, phenylbutazone,
`ibuprofen, and diclofenac
`sodium, among others.
`limited to
`is not
`includes but
`The antiallergic agent
`sodium cromoglycate, tranilast, ketotifen fumarate, diphen-
`hydramine hydrochloride, etc. and the antibacterial agent
`includes but is not limited to idoxuridine, erythromycin,
`sulfisoxazole,
`tobramycin, and gentamicin. The vasocon-
`strictor includes naphazoline hydrochloride, among others.
`
`Page 3 of 4
`
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`
`TABLE 1
`
`40
`
`Formula
`
`Loteprednol etabonate
`Concentrated glycerin
`e-Aminocaproic acid
`Tyloxapol
`Polyvinylpyrrolidone (K* — 30)
`Sodiuin edetate
`Benzalkonium chloride (10 w/v %)
`Hydrochloric acid
`Sterilized pure water
`pH
`
`*K stands for intrinsic viscosity.
`
`Eye drops A
`
`0.5 g
`2.6 g
`0.1 g
`0.3 g
`0.6 g
`0.01 g
`0.05 ml
`q.s.
`to make 100 ml
`5.53
`
`Stability Test
`Eye drops A according to Example 1 and Eye drops B of
`the composition available on elimination of e-aminocaproic
`acid from the composition used in Example 1 were respec-
`tively dispensed into colorless polypropylene bottles and
`stored at 40° C. and 75% RH for 6 months. Then,
`the
`description and pH of each preparation and the mean particle
`diameter of loteprednol etabonate were evaluated and deter-
`mined. The results are presented in Table 2. Eye Irritation
`Study
`
`Method
`
`In this eye irritation test, 0.05—0.1 ml each of Eye drops
`A and Eye drops B after 6 months of storage at 40° C. and
`75% RH were respectively instilled into the eyes of volun-
`teers.
`
`Page 3 of 4
`
`

`

`5
`Results
`
`5,916,550
`
`We claim:
`
`6
`
`The results of the test are shown in Table 2.
`
`TABLE 2
`
`Eye drops A
`
`Eye drops B
`
`—
`—
`—
`—
`—
`5.53
`
`5.11
`
`—
`+
`+
`+
`+
`5.51
`
`3.85
`
`3.052
`
`3.783
`
`Substantially
`unchanged from
`the particle
`diameter re-
`corded immedi—
`ately after
`preparation
`
`Substantially
`unchanged trom
`the particle
`diameter re-
`corded immedi-
`ately after
`preparation
`
`Subject
`
`pH
`
`Mean
`particle
`diameter
`(,um)
`
`a
`b
`c
`d
`e
`Immediately
`after pre-
`paration
`After 6
`months of
`storage
`(40° C.,
`75% RH)
`Immediately
`after pre-
`paration
`After 6
`months of
`storage
`(40° C.,
`75% RH)
`
`#: pain
`+: foreign sensation
`—: no irritation
`
`It was found that the eye drops containing e-aminocaproic
`acid does not cause an irritable response in the eye and can
`be used safely even after 6 month s of storage at 40° C. and
`75% RH.
`
`EFFECT OF THE INVENTION
`
`The aqueous suspension of loteprednol etabonate contain-
`ing a C2—7 aliphatic amino acid according to the present
`invention has the advantage that it is amenable to production
`pH control and remains stable without pH depression even
`on long-term (i.e. 6-month or longer) storage. Therefore, it
`does not irritate the ocular or nasal mucosa on instillation
`
`and hence can be safely administered as eye drops or nasal
`drops.
`
`1. An aqueous suspension of loteprednol etabonate which
`comprises loteprednol etabonate and an aliphatic amino acid
`containing 2—7 carbon atoms.
`2. The aqueous suspension according to claim 1 wherein
`said amino acid is one having 1 or 2 amino groups and 1 or
`2 carboxyl groups.
`3. The aqueous suspension according to claim 2 wherein
`said amino acid is a neutral or acidic amino acid.
`
`4. The aqueous suspension according to claim 3 wherein
`said amino acid is e-aminocaproic acid.
`5. The aqueous suspension according to claim 1 which
`contains 0.01—3 w/v % of loteprednol etabonate and 0.002—2
`w/v % of said amino acid in aqueous medium.
`6. The aqueous suspension according to claim 1 further
`containing a suspending agent, a nonionic surfactant, and an
`isotonizing agent.
`7. The aqueous suspension according to claim 6 which
`contains 0.2—2 w/v % of the suspending agent, 0.05—1 w/v
`% of the nonionic surfactant, and 1—6 w/v % of the isoton-
`izing agent in the aqueous medium.
`8. The aqueous suspension according to claim 6 wherein
`said suspending agent is a water-soluble nonionic polymer,
`said nonionic surfactant is a polyoxyalkylene monool or
`polyol, and said isotonizing agent is a polyhydric alcohol.
`9. The aqueous suspension according to claim 6 further
`containing a preservative.
`10. The aqueous suspension according to claim 9 which
`contains 0.0001—0.5 w/v % of said preservative.
`11. The aqueous suspension according to claim 6 which
`contains 0.1—5 moles of said amino acid, 0.01—20 moles of
`said suspending agent, and 0.05—1 mole of said nonionic
`surfactant per mole of loteprednol etabonate.
`12. The aqueous suspension according to claim 1 wherein
`loteprednol etabonate occurs in finely divided form with
`particle diameters within the range of 0.1—30 um.
`13. The aqueous suspension according to claim 1, the pH
`of which is 4.5—7.0.
`
`14. A method for treating inflammation of the eye, ear,
`nose or throat of a patient, which comprises administering an
`antiinflammatory amount of the aqueous suspension accord-
`ing to claim 1 to the eye, ear, nose or throat of a patient in
`need thereof.
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`Page 4 of 4
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