United States Patent
`
`[191
`
`[11]
`
`Patent Number:
`
`5,747,061
`
`Amselem et al.
`
`[45] Date of Patent:
`
`*May 5, 1998
`
`USO05747061A
`
`[54] SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`[75]
`
`Inventors: Shimon Amselem. Rehovot; Doron
`Friedman. Carmei Yosef, both of Israel
`
`[73] Assignee: Pharmos Corporation. Machua. Fla.
`
`[*] Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat, No,
`5.540.930.
`
`[21] Appl. No‘: 688,157
`
`[22] Filed:
`
`Jul. 29, 1996
`
`Rehted U_S, Appfigafion D313
`
`[51]
`
`[63] Continuatiomin-part ofSer. No. 142,743, Oct 25, 1993, Pat
`N0’ 5’540’930'
`Int. Cl.“ ............................ A61K 9/10; A6lK 47/32;
`A61K 47/36
`[52] U.s. Cl. .......................... 424/427; 424/437; 424/434;
`514/772.2; 514fl72.3; 514/772.5; 514/778;
`514/914; 514/937
`[58] Field of Search ..................................... 424/427. 437.
`424/434. 489; S14/772.2—772.3. 772.5.
`778. 914. 937
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`................................ 167/65
`2,861,920 ll/1958 Dale et al.
`424/238
`4,383,992
`5/1983 Lipari
`..
`.... .. 424/78
`4,409,205
`10/1983 Shively ... ....
`514/369
`4,602,026
`7/1986 Awata et al.
`514/174
`4,710,495
`12/1987 Bodor ..........
`------ 514/58
`5,089,482
`2/199/2 Hemlens et 81.
`5,149,693
`9/1992 Cagle et al.
`.............................. 514/40
`5,192,535
`3/1993 Davis et al. .
`5,277,901
`1/1994 Vighet al.
`........................... 424/7804
`
`
`
`5,424,078
`
`6/1995 Dziabo et al.
`
`.......................... 424/661
`
`Primary E.xaminer—Edward J. Webman
`Attorney; Agent, or Firm—Pennie & Edrnonds
`
`ABSTRACT
`[57]
`The invention provides novel compositions of matter for
`delivering water-insoluble steroid drugs suitable for thera-
`peutic use. The invention also provides stable aqueous
`suspensions of water-insoluble steroid drugs of particle sizes
`Of §30 pm which remain in such a state so as to allow for
`immediate suspension. when desired. even after extended
`periods of settling-
`
`30 Claims, No Drawings
`
`Petitioner |nnoPharma EX 1090
`
`|PR2015—00902
`
`|PR2015—00903
`
`Page 1
`
`

`
`1
`SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation—in-part of application
`Ser. No. 08/142,743 filed Oct. 25. 1993. now U.S. Pat. No.
`5.540.930.
`
`FIELD OF INVENTION
`
`The invention relates to aqueous suspensions for treat-
`ment of ophthalmic and otolaryngological inflammations.
`
`BACKGROUND OF THE INVENTION
`
`Numerous drugs are prepared in the form of suspensions
`for ophthalmic. oral. otic. nasal respiratory is topical. and
`parenteral applications. Formulation of pharmaceutical dos-
`ages of water-insoluble drugs as suspensions is frequently
`hampered by the subsequent formation of cakes resulting
`from aggregation of the suspended material. Polymmic
`compounds (e.g. polyvinyl pyrrolidone (PVP). polyvinyl
`alcohol (PVA). dextran) are commonly used to stabilize such
`suspensions. An alternative approach to the preparation of
`such drugs is to enhance the solubility of the drugs within
`the formulation by vehicles including emulsions. liposomes.
`and cyclodextrins. However. certain drugs. in their thera-
`peutic concentrations. are not sufliciently stabilized or solu-
`bilized by these methods for the above-mentioned applica-
`tions.
`
`Topical steroids such as corticosteroids are commonly
`used for anti-inflammatory therapy of the eye. especially for
`treating inflammatory conditions of the palpebral or bulbar
`conjunctiva. cornea and anterior segment of the globe.
`Common therapeutic applications for steroids include aller-
`gic conjunctivitis. acne rosacea. superficial punctate keratitis
`and iritis cyclitis. Steroids also are used to ameliorate
`inflammation associated with corneal injury due to chemical
`or thermal burns, or penetration of foreign bodies. Such
`conditions may result from surgery. injury. allergl or infec-
`tion to the eye and can cause severe discomfort.
`Despite their therapeutic advantages. topical ocular use of
`corticosteroids is associated with a number of
`
`including posterior subcapsular cataract
`complications.
`formation. elevation of intraocular pressure. secondary ocu-
`lar infection. retardation of corneal wound healing. uveitis.
`mydriasis. transient ocular discomfort and ptosis. Numerous
`systemic complications also may arise from the topical
`ocular application of corticosteroids. These complications
`include adrenal insufticiency. Cushing's syndrome. peptic
`ulceration. osteoporosis. hypertension. muscle weakness or
`atrophy.
`inhibition of growth. diabetes. activation of
`infection. mood changes and delayed wound healing.
`Topical steroids for treating ocular inflarnmations can be
`based on soft drugs. Soft drugs. as is known in the art. are
`designed to provide maximal therapeutic effect and minimal
`side effects. By one approach. synthesis of a “soft drug” can
`be achieved by structurally modifying a known inactive
`metabolite of a known active drug to produce an active
`metabolite that undergoes a predictable one-step transfor-
`mation in-vivo back to the parent. (see. U.S. Pat. Nos.
`4.996.335 and 4.710.495 for soft steroids) inactive metabo-
`lite. “Soft drugs” therefore are biologically active chemical
`components characterized by predictable in vivo metabo-
`lism to non-toxic derivatives after they provide their thera-
`peutic effect.
`
`10
`
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`25
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`30
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`35
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`
`50
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`55
`
`65
`
`5,747.06]
`
`2
`
`Pharmaceutical compositions of water-insoluble drugs
`such as corticosteroids in aqueous suspensions for ocular
`and other uses must satisfy constraints imposed by physi-
`ological compatibilities such as pH. osmolality. and article
`size of the suspended steroids. Furthermore. these compo-
`sitions must meet requirements for reservative efliciency and
`ease of suspension over extended periods of time.
`Therapeutic suspensions of corticosteroids typically
`employ polymeric compounds such as polyvinyl pyrroli-
`done (“PVP”) and polyvinyl alcohol (“PVA”) as suspending
`agents in concentrations ranging from 0.1 to 10% (U.S. Pat.
`No. 2.861.920). Combinations of polymeric compounds
`such as PVP. PVA. sodium carboxymethylcellulose
`(“CMC”). and dextran. with surface-active agents such as
`Polysorbate 80. Polysorbate 20. and tyloxapol also have
`been used to stabilize corticosteroid suspensions intended
`for ophthalmic. nasal. and otic uses.
`The amounts of polymeric compounds and surface active
`agents must be determined to provide stability to suspen-
`sions of corticosteroids. Excessive amounts of polymeric
`compounds may hamper the antimicrobial effects of preser-
`vatives added to the suspension. Also. pharmaceutical ocular
`and nasal dosages of these suspensions either must be
`buifered or have an appropriate pH with no buifering capac-
`ity. These suspensions also should be isotonic.
`Loteprednol etabonate (“LE”) is a known soft corticos-
`teroid based on the known inactive metabolite prednisolone
`acetate of the active drug prednisolone. See U.S. Pat. Nos.
`4.996.335 and 4.710.495.
`LE is an analog of prednisolone that does not have a
`20-keto group attached to the 17B-position. Instead. the 17-[5
`position is occupied with a metabolically-labile ester func-
`tion. In biological systems. LE is hydrolysed to the inactive
`carboxylic acid metabolite (PI-91) that does not bind to
`glucocorticoid receptors. LE also provides superior safety
`by reducing the risk of steroid induced cataracts and eleva-
`tion of intra—ocular pressure. The lability of LE to enzymes
`located in the blood and/or liver also reduces the likelihood
`of systemic side efiects. LE therefore provides therapeutic
`advantages over other corticosteroids by providing eflicacy
`similar to its parent compound. namely. prednisolone
`acetate. with fewer deleterious systemic side effects. Soft
`steroids have the potential advantage of treating inflamma-
`tion without inducing elevation of intraocular pressure. In
`addition. soft steroids can provide the added benefit of a
`lower tendency to induce cataracts which may result from
`interaction of corticosteroids with the ocular lens proteins.
`Formulation of stable aqueous suspensions of LE for
`ocular applications and other uses. however. has been harn-
`pered by agglomeration of the steroid particles.
`Unexpectedly. common tonicity agents such as aqueous
`solutions containing 0.9% NaCl. 0.1% EDTA. or phosphate
`buffer. even in concentrations as low as 1 mM. can not be
`employed to provide stable aqueous suspensions of corti-
`costeroids such as LE.
`
`A need therefore exists for aqueous suspensions of cor-
`ticosteroids such as LE which can be formulated without
`agglomeration. A further need exists for aqueous suspen-
`sions which have therapeutically effective amounts of cor-
`ticosteroids such as LE but which avoid the problems
`associated with the steroid suspensions of the prior art.
`
`SUMMARY OF THE INVENTION
`
`The invention provides novel compositions of matter
`containing water-insoluble drugs suitable for therapeutic
`use. The invention provides stable aqueous suspensions of
`
`Page 2
`
`Page 2
`
`

`
`5.747.061
`
`3
`water-insoluble drugs of mean par1icle sizes of §15 pm
`which remain in such a state so as to allow for immediate
`suspension. when desired. even after extended periods of
`settling.
`More particularly. the invention is directed to aqueous
`suspensions of soft corticosteroids such as loteprednol eta-
`bonate suitable for therapeutic use in the eye. ear. or nose.
`The aqueous suspensions of LE are surprisingly stable and
`can remain in a state suitable for immediate suspension
`when desired. even after extended periods of settling. The
`suspensions of the invention. moreover. do not cause dis-
`comfort upon application.
`Alternatively. the present invention is directed to aqueous
`formulations (e.g.. suspensions or solutions) wherein the
`amount of corticosteroids is either minimized (e.g..
`suspensions) or altogether avoided (e.g.. solutions) for the
`therapeutic use in the eye. ear. nose or throat for the topical
`treatment of inflammatory conditions therein.
`The aqueous suspensions of the invention containing a
`steroid comprise component (A) of a therapeutic quantity of
`a “soft” steroid such as LE present as particles preferably
`having a mean diameter of less than about fifteen microns.
`component (B) of a suspending agent of a nonionic polymer
`in an aqueous medium. and component (C) of a nonionic
`surface active agent. Advantageous molar ratios of (A):(B)
`:(C) can vary from about 1:0.01:0.05 to 1:20:l.
`The steroid of component (A) preferably is loteprednol
`etabonate and is added to obtain a final concentration in the
`suspension of O to about 2% by weight. more preferably
`about 0.01—l% by weight and most preferably about
`0.05—0.5% by weight. The suspending agent may be any
`nonionic polymer which is soluble in an aqueous medium.
`and can be present in an amount of about 0.2 to 2% by
`weight. preferably about 0.3 to 1.75% by weight. more
`preferably about O.4—1.5% by weight. The molar ratio of
`component (A) to component (B) typically is in the range of
`about 1:0.01 to about 1:20. preferably about 1:0.05 to about
`1:10 and more preferably about 1:0.1 to 1:3.
`The nonionic surfactant of component (C) of the compo-
`sition may be any one of a wide variety of nonionic alkylene
`oxide condensates of an organic compounds which contain
`one or more hydroxyl groups. This component (C) is advan-
`tageously present in an amount of between about 0.05 and
`1% by weight of the composition. The molar ratio of
`component (A) to component (C) typically is in the range of
`about 1:0.05 to about 1:1.
`
`The compositions generally include component (D) of a
`nonionic tonicity agent for producing isotonicity. and. if
`necessary, component (B) of one or more preservatives.
`It is essential that these components (A)—(D) be nonionic
`insofar as possible since it has now been discovered that the
`presence of ions is the major cause of caking. Thus, the
`preferred tonicity agents would be nonionic diols such as
`glycerol or mannitol rather than the commonly used sodium
`chloride. The nonionic tonicity agent is preferably present in
`an amount of about 0.5 to 10% by weight. more preferably
`about 1 to 7%. and most preferably about 1.5 to 4%.
`Accepted preservatives such as benzalkonium chloride
`and disodium edetate (EDTA) may be included in the
`suspensions of the invention in concentrations suflicient for
`effective antibacterial action. preferably about 0.0001 to
`0.025%. based on the weight of the suspension.
`Having briefly summarized the invention. the invention
`will now be described in detail by reference to the following
`specification and non-lirniting examples. Unless otherwise
`specified. all percentages are by weight.
`
`4
`DETAILED DESCRIPTION OF THE
`INVEN'I'ION
`
`Therapeutic suspensions of LE for ophthalmic or oto-
`laryngological uses are made by aseptic preparation. Purity
`levels of all materials employed in the suspensions of the
`invention exceed 98%. The suspensions of the invention are
`prepared by thoroughly mixing the drug (component (A)).
`suspending agent (component (B)). and surface active agent
`(component (C)). Optionally. tonicity agents (component
`(D)) and preservatives (component (E)) may be included.
`Drugs of component (A). when used. are preferably soft
`steroids and most preferably LE. Also. other steroids such as
`beclomethasone. betamethasone.
`fluocinolone.
`fluorometholone. exednisolone. may be employed The sus-
`pensions of component (A) of the invention have a particle
`size of about 0.l—30 pm. preferably about 1-20 pm. most
`preferably about 2-10 um in mean diameter. LE in this size
`range is commercially available from suppliers such as the
`Sipsy Co. (Avrillé. France).
`The nonionic polymer of component (B) can be any
`nonionic water-soluble polymer. Typical compounds such as
`PVP. PVA. dextran or cyclodextrin can be used in a con-
`centration of about 0.2—2% by weight. and preferably about
`0.3—1.75% by weight.
`Component (C) is a surface-active agent that is acceptable
`for ophthalmic or otolaryngological uses. Preferably. this
`surfactant is non-ionic. Generally. the nonionic surfactant is
`a nonionic alkylene oxide condensate of an organic com-
`pound which contains one or more hydroxyl groups. For
`example. ethoxylated andlor propoxylated alcohol or ester
`compounds or mixtures thereof are commonly available and
`are well known to those skilled in the art. Useful surface
`active agents include but are not limited to POLYSORBATE
`30. tyloxapol. TWEEN 80 (e.g.. polyoxyethylene sorbitan
`mono-oleate ester;ICI America Inc.. Wilmington. De1.).
`PLURONIC F-68 (from BASF. Ludwigshafen. Germany)
`and the POLOXAMER (e.g., po1y(oxypropylene)-poly
`(oxyethylene) copolymer) surfactants can also be used. See.
`Remington’s Pharmaceutical Sciences. 16th Edition. Arthur
`osol. Editor. Mack Publishing Company. Easton. Pa. (1980).
`See also. The United States Pharmacopeia. 21st Revision.
`The National Formulary. 16th Edition. United States Phar-
`macopeial Convention. Inc., Rockville. Md.. (Jan. 1. 1985).
`The tyloxapol and TWEEN surfactants are preferred
`because they are FDA approved for human use. The con-
`centration in which the surface active agent may be used is
`only limited by neutralization of the bacteriocidal eifects on
`the accompanying preservatives. or by concentrations which
`may cause irritation. Advantageously. the concentration of
`component (C) is about 0.05 to 1% based on the weight of
`the suspension (or solution). and preferably about 0.1 to
`0.6%.
`
`The tonicity agents of component (D) can be nonionic
`diols including mannitol and preferably glycerol. in sulfi-
`cient amounts to achieve isotonicity. The nonionic tonicity
`agent is advantageously present in an amount of about 1 to
`7% by weight. and preferably about 1.5 to 4%.
`The nonionic polymeric compounds of component (B).
`and the surface active agents of component (C) have good
`solubility in water. have sufficient number of hydroxyl
`groups to interact with the steroid. and have mild effects on
`the viscosity of the suspension. Final viscosity should not
`exceed 80-centipoise.
`In a preferred aspect. stable aqueous suspensions of LE
`are provided by preparing aqueous suspensions of LE in
`concentrations of about 0.05-0.2% with about 0.3—1.5%
`PVP. about 2—3% glycerol. and about 0.05-1% tyloxapol.
`
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`Page 3
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`Page 3
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`

`
`5 ,747,061
`
`5
`
`The suspensions of the invention also may include addi-
`tional therapeutic drugs such as drugs for treating glaucoma.
`anti-inflammatory drugs. antibiotic drugs. anti-cancer drugs.
`anti-fungal drugs and anti-viral drugs. Examples of anti-
`glaucoma drugs include but are not limited to timolol-base.
`betaxolol. atenolol.
`levobunolol. epinephrin. dipivalyl.
`oxonolol. acetazolamide-base and methazolamide.
`Examples of anti-inflarnmatory drugs include but are not
`limited to non-steroids such as piroxicam. indomethacin.
`naproxen. phenylbutazone. ibuprofen and diclofenac. Addi-
`tional therapeutic materials which may be employed include
`but are not
`limited to tobramycin. gentamycin or other
`antibiotics.
`
`Health regulations in various countries generally require
`that ophthalmic preparations shall include a preservative.
`'Many well known preservatives that have been used in
`ophthalmic preparations of the prior art. however. cannot be
`used in the preparations of the invention. since those pre-
`servatives may no longer be considaed safe for ocular use.
`or may interact with the surfactant employed in the suspen-
`sion to form a complex that reduces the bacteriocidic
`activity of the preservative.
`The preservatives of component (B) employed in the
`suspensions of the invention therefore are chosen to not
`interact with the surface active agent to an extent that the
`preservatives are prevented from protecting the suspension
`from microbiological contamination. In a preferred embodi-
`ment benzalkonium chloride may be employed as a safe
`preservative. most preferably benzalkonium chloride with
`EDTA. Disodium edetate has also been found to be effective
`
`in reducing microbial growth in the present formulations.
`Other possible preservatives include but are not limited to
`bcnzyl alcohol, methyl parabens. propyl parabens.
`thimerosal. chlorbutanol and benzethonium chlorides.
`Preferably. a preservative (or combination of preservatives)
`that will impart standard antimicrobial activity to the sus-
`pension and protect against oxidation of components (A)-
`(D) is employed. These preservatives are generally used in
`an amount of about 0.0001 to 0.025% by weight and
`preferably 0.001 to 0.015%.
`Stable aqueous suspensions of the invention can be pro-
`duced over a broad range of pH values. A p}! of about
`4.5-7.4 especially is useful for preparing the stable LE
`suspensions of the invention.
`It has been surprisingly discovered that the carriers (i.e..
`components (B). (C). (D) and. optionally. (E)) for compo-
`nent (A) have anti-inflammatory properties of their own.
`Thus. a solution of components (B). (C). (D) and. optionally.
`(E). at least partially relieves inflammation when applied to
`inflamed ophthalmic or otolaryngological tissue. Thus. for
`example. when applied to the eye. in the absence of a
`
`10
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`
`30
`
`35
`
`40
`
`45
`
`SCI
`
`6
`corticosteroid. a solution of components (B). (C) and (D)
`surprisingly produces at
`least a partial reduction of the
`inflammation of the eye. The addition of component (B)
`does not detract from this result.
`
`Formulations in the form of a solution. when component
`(A) is absent. are prepared according to the procedures
`outlined for Examples l-37. infra. with the exception that
`the concentration of component (B) is changed to preferably
`between about 0.3-1.75% by weight and more preferably
`between about 04-15% by weight. Components (C). (D)
`and (E) can be used in the same amounts as stated above.
`For formulations in the form of a suspension. the afore-
`mentioned concentration(s) of component (B) (see preced-
`ing paragraph) can be used in combination with the con-
`centration of component (A) as indicated below. The
`concentration of component (A) is typically between about
`0.0l—2% by weight. preferably between about 0.03—l% by
`weight. more preferably between about 0.05-0.5% by
`weight and most preferably between about 0.05—0.2% by
`weight. Such suspensions are prepared according to the
`procedures outlined for Examples 1-37.
`infra. with the
`exception that the concentration of components (A) and (B)
`is changed as indicated herein. Components (C). (D) and (E)
`can be used in the same amounts as stated above.
`Without further elaboration. it is believed that one skilled
`in the art can. using the preceding description. utilize the
`present invention to its fullest extent. The following pre-
`ferred specific embodiments therefore are to be construed as
`merely illustrative. and not limitative of the remainder of the
`disclosure in any way whatsoever.
`In the following
`examples. all parts and percentages are by weight unless
`otherwise indicated.
`
`EXAMPLES 1-37
`
`Each of Examples 1-37 are prepared by dissolving the
`suspending agent (Component B)
`in water by gentle
`mechanical mixing. Subsequently.
`the surfactant
`(Component C). the tonicity agent(s) and the preservatives
`(Components (D) and (B). respectively) are added in that
`order. The solution is then sterilized by filtration or auto-
`claving. LE. presterilized by irradiation. is added aseptically
`to the solution. and the dispersion is then mixed at 12.000
`rpm for one minute. The amounts of these components are
`shown in Table 1.
`
`SIZE DETERMINATION
`
`The size distributions of the LE particles in the samples of
`Table 1 are measured with a Coulterk LS 130 instrument. An
`acceptable average particle size for ophthalmic suspensions
`is §15 pm. The results’ appear in Table 2.
`
`TABLE 1
`
`Example
`
`SAMPIE COLIPOSITION §% wlwl
`
`Number LE Tween 80 Tyloxapol Poloxamer-188 HPMC‘ PVA PVP dextran Osmolarity Agent
`l
`0.5
`—
`0.2
`——
`——
`0.6 —
`— -—
`2
`0.5
`0.2
`-—
`—
`—-
`0.2
`——
`10 mM PBS2
`3
`0.5
`0.4
`—
`0.2
`— 0.4
`— —
`4
`0.5
`0.2
`—
`—
`0.2 —
`— 10 mM PBS
`5
`0.5
`—
`——
`0.4
`— --
`— 100 mM PBS
`6
`0.5
`—
`—
`——
`1.4 —
`——
`5 mM PBS
`7
`1
`0.2
`—
`—
`—
`1
`— —
`8
`1
`0.6
`—
`—
`— 1.4
`— —
`9
`1
`—
`—
`—
`— 1.4
`— —
`
`—-
`0.6
`0.4
`—
`—
`0.6
`
`EDTA‘ BKA’
`——
`—
`—
`—
`—
`—
`-—
`-
`—
`—
`—
`0.001
`—
`—
`—
`—
`—
`—
`
`Page 4
`
`Page 4
`
`

`
`5,747,061
`
`TABLE 1—continued
`
`
`Example
`
`Number
`10
`11
`12
`13
`14
`15
`16
`17
`13
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`3-4
`35
`36
`37
`
`SAMPLE COMPOSITION §% W/W]
`
`LE Tween80 Tyloxapol Poloxarner-188 HPMC‘
`0.5
`—
`0.4
`——
`—
`0.5
`0.4
`—
`—
`—
`0.5
`0.6
`——
`—
`——
`0.5
`—
`0.3
`—
`—
`0.5
`—
`0.3
`—
`—
`0.5
`0.4
`-
`—
`—
`1
`—
`0.2
`~—
`——
`0.5
`——
`0.6
`—
`-—
`0.5
`—
`—
`0.6
`-
`0.5
`0.4
`—
`—
`—
`0.5
`~—
`0.4
`—
`—
`0.5
`-—
`0.3
`—
`——
`0.5
`0.6
`-—
`—-
`—
`0.5
`0.6
`—
`'—
`*
`0.5
`0.6
`—
`—-
`—-
`0.5
`—
`0.3
`—
`—
`0.5
`—
`0.3
`—
`—
`1
`—
`0.3
`—-
`—
`1
`_
`0.3
`—
`——
`1
`——
`0.1
`—
`—
`0.5
`——
`0.2
`—
`——
`1
`-—
`0.2
`——
`——
`1
`—
`0.2
`—
`-—
`0.5
`——
`0.3
`—-
`—
`1
`—
`0.4
`—
`—
`0.5
`——
`0.3
`——
`—
`0.5
`—
`0.1
`——
`—
`0.5
`——
`0.3
`—-
`—
`
`PVA PVP dextrarl Osmolarity Agent
`—
`— 0.9% saline’
`1
`—
`— 0.9% saline
`1
`2
`— 24% glycerol
`—-
`15
`—-
`2.4% glycerol
`-
`0.6
`0.5
`2.4% glycerol
`-—
`—
`— 2.4% glycerol
`1.4
`1
`— 2.4% glycerol
`—
`—
`—-
`2.4% glycerol
`1.4
`2
`— 2.4% glycerol
`—-
`-
`1.6
`2.4% glycerol
`—
`—
`2.4
`24% glycerol
`-
`1
`——
`2.4% glycerol
`-
`——
`-— 2.4% glycerol
`.4
`—
`— 2.4% glycerol
`1.4
`—
`2
`2.4% glycerol
`—
`0.6
`— 2.4% glycerol
`—
`0.6
`0.5
`2.4% glycerol
`-
`0.6
`0 5
`2.4% glycerol
`--
`0.6
`——
`2.4% glycerol
`—
`0.4
`— 2.4% glycerol
`—
`0.6
`——
`2.4% glycerol
`--
`0.6
`— 2.4% glycerol
`—
`0.3
`— 2.4% glycerol
`—-
`1.5
`— 2.4% glycerol
`—
`0.4
`— 24% glycerol
`——
`0.6
`0.3
`2.4% glycerol
`—
`0.4
`0 3
`2.4% glycerol
`—
`0.6
`— 2.4% glycerol
`-
`
`EDTA‘ BKA’
`—
`0.001
`—
`0.001
`0.01
`0.01
`0.01
`0.01
`0.01
`0.015
`—-
`0.001
`——
`0.01
`—
`0.01
`0.01
`0.004
`0.01
`0.004
`0.01
`0.01
`0.01
`0.01
`—
`—
`—
`0.004
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.015
`0.01
`0.015
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.015
`0.01
`0.015
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.015
`
`‘hydroxyprmpylmethyl cellulose
`’pbosphate buflered physiological saline
`’sodium chloride
`‘ethylene diamine tetraacetic acid
`sbeuzalkonium chloride
`
`TABLE 2-continued
`
`Example
`
`Particle sgs; gig} and Fraction of Total P_g_fllation
`
`35
`
`40
`
`45
`
`TABLE 2
`
`Example
`
`Particle Si1.e[s) {Q} andFraction of Tbtal Pofllntion
`
`Number
`l
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`
`Population A
`3.9061»/-2.677
`112.7+/-13.27
`3.526-O-/-1.706
`111.4-l-/-18.59
`23 .52+/-20.58
`32.83-I-I—2.563
`4.596-1-/-2.698
`3305+/-2.417
`6.591-1-I—3.566
`3.82.3-iv/-2.693
`3.888-l-I—2.69
`3.559-I-/-1.469
`2.932-I-/-2.32
`88.52-4-/—-30.19
`3.652+I—2.692
`3.8514-/-2.401
`3.969-1*-/-2.572
`4.926+I—2.955
`4.4-29+/-2,732
`3930+/-2.566
`3.63314-2.457
`4.7 l6+I—2.762
`4.789-l~/-2.823
`4.528-l-/-2.552
`5261+/-2.990
`5.262-i~/-3.013
`5.204-§~/-2.985
`4.913-l-/-2.332
`4.126-l-I‘-2.390
`12.45+l—-10.91
`3.976-I-/-2.245
`
`41%
`86.62
`100
`1(X)
`100
`100
`48 .74
`92.43
`93.14
`100
`17.52
`14.02
`5.62
`3.52
`100
`100
`100
`100
`92.29
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`
`Population B
`53.67-I-/-13.13
`——
`—
`—
`—
`94.06+I—40.57
`5791+/-13.14
`62.384-/-20.38
`—
`96.28-+/-38.13
`110.1-+-/-58.02
`82.84-H-13.08
`100.1+I—24,56
`—
`—-
`—
`——
`4l.59+4—7 .125
`—
`—
`—-
`—
`—-
`—
`——
`-—
`——
`—-
`——
`—-
`——
`
`11%
`13.38
`--
`—
`—
`—
`51.26
`7.57
`6.86
`——
`82.43
`85.93
`94.38
`96.48
`-
`—
`——
`—
`7.71
`—
`—-
`—
`—
`—
`-
`—
`—
`—
`-
`—
`—
`—-
`
`Number
`32
`33
`34
`35
`36
`37
`
`Population A
`3789+/—-1.609
`3.821-1-/-2.181
`3.8134-I—2.305
`3.385-+1-1.506
`3.737+/-2.044
`3.9654-[-2.229
`
`A%
`100
`46.77
`100
`78.44
`100
`100
`
`Population B
`—
`1073+/-14.74
`——
`25.16-1-I—l.42l
`—
`—
`
`B%
`—
`53.23
`—
`21.56
`—
`
`— 1
`
`. In the Coulter particle size analysis two distinct populations of particles
`were sometirnesdiscerned. In tliesecasesthe twopopulationsaredenotedas
`populations A and B. If only a single population was detected it is denoted
`50 population A.
`
`EVALUATION OF SUSPENDABIIIFY OVER
`TIME
`
`55
`
`Samples containing particles with desirable size distribu-
`tions (average of 2-10 urn) are tested for stability using
`accelerated stability tests as well as “real time” studies.
`Accelerated stability studies are performed by subjecting
`the samples to a centrifugal force of 5000XG for two
`minutes. The suspendability of the settled material is tested
`by measuring the number of seconds of wrist shaking
`required to eliminate visible residue attached to the con-
`tainer. Since existing marketed products require as much as
`sixty seconds of wrist shaking to suspend the entire amount
`of settled residue.
`ten seconds is determined to be an
`acceptable amount of time to suspend the residue. The
`results are shown in Table 3.
`
`Page 5
`
`Page 5
`
`

`
`5,747,061
`
`9
`
`TABLE 3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`RESUSPENSION OF LE SUSPENSIONS WHICH HAVE
`UNDERGONE ACCELERATED AND NATURAL‘ SETTLING
`
`Example
`Number
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`E
`30
`31
`32
`33
`34
`35
`36
`37
`
`Accelerated Stability
`(time to tesuspend)2
`15
`5
`5
`5
`5
`—
`—
`—
`—
`—
`5
`5
`5
`S
`—
`5
`5
`—
`—
`—
`—
`——
`—
`
`Suspension of naturally
`settled material‘
`
`Months
`Initial Value (# inversions) Tested’
`—
`10 (1)
`—
`10 (I)
`—
`10 (I)
`—
`9
`—-
`9
`67
`9
`46
`9
`83
`9
`37
`9
`—
`6 (I)
`27
`8
`22
`6 (I)
`35
`6 (I)
`35
`8 (I)
`49
`7
`25
`7
`43
`7
`74
`7
`136
`3 (I)
`40
`7
`18
`7
`48
`7
`46
`8
`
`‘Refers to settling, at room temperature, on an open shelf
`‘Number of seconds of wrist shaking to suspend material that was settled by
`application of 5000 X G for 2 minutes.
`3During the test period, samples were periodically examined to verify the
`retention of the initial valules “I" indicates instability for the noted period, i.e.,
`agglomeration.
`
`The results shown in Table 3 show samples which do not
`fonn agglomerates during the longest period of observation.
`Acceptable samples require § 100 gentle inversions follow-
`ing the indicated period of settling.
`The stability of suspensions intended for multiple doses is
`supported by the addition of preservatives which prevent
`potential microbiological growth. The indicated prepara-
`tions are prepared under aseptic conditions and aliquots of
`
`10
`each material are exposed to the indicated microbiological
`organisms for four weeks and evaluated for growth as
`described in the U.S. Pharmacopeia. The results. shown in
`Table 4. indicate whether the preservative was effective (+)
`or inefiective (-) according to U.S.P. requirements.
`
`UNIDOSE SUSPENSIONS VVITHOUT
`PRESERVATIVES
`
`Compositions with satisfactory particle sizes and stabili-
`ties for unidose suspensions without preservatives appear in
`Table 5. These compositions are satisfactory for ophthalmic
`or otolaryngological uses when prepared under aseptic con-
`ditions and packaged in containers for single doses.
`
`TABLE 4
`
`Challenge Microorganism
`
`Example
`
`Staph.
`auteur
`
`R aerug.
`
`Candida
`albicaru
`
`Aspen
`niger
`
`E mix’
`
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`
`—
`—
`—
`+
`+
`+
`+
`+
`+
`+
`
`—
`—
`—
`+
`—
`+
`+
`+
`+
`+
`
`—
`—
`+
`+
`+
`+
`+
`+
`+
`+
`
`ND
`ND
`ND
`ND
`+
`+
`ND
`+
`+
`+
`
`ND: denotes not done; (+) denotes challenge withstood; (-) denotes unac-
`ceptable microbe growth
`The test was performed according to U.S.P. specifications.
`
`TABLE 5
`
`COMPOSITIONS OF Y LE FORMULATIONS FOR UNIDOSE APPLICATION
`
`Ex. No. LE Tween 80 Iyloxapol Poloxarner-188
`—
`—
`1
`l
`0.6
`2
`05
`—
`—
`0.6
`3
`0.5
`0.4
`—
`—
`4
`0.5
`—
`0.4
`—
`S
`05
`——
`0.3
`—
`6
`0.5
`—
`0.6
`—
`7
`0.5
`0.6
`———
`—
`8
`0.5
`0.6
`—
`—
`—
`—
`9
`0.5
`0.6
`0.3
`—
`10
`0.5
`—
`11
`0.5
`—
`0.3
`—
`12
`1
`—
`0.3
`—
`13
`—
`0.3
`—
`14
`—
`0. l
`—
`15
`—-
`0.2
`——
`16
`—-
`0.2
`-—
`17
`—
`0.4
`—
`18
`—
`0.2
`—
`19
`—
`0.4
`—
`
`1
`0.5
`1
`l
`1
`1
`
`PVA PVP
`— l .4
`—
`2
`— —
`— —
`—
`l
`0.8 —
`1 4
`0.8
`——
`——
`——
`— 0.6
`— 0.6
`— 0.6
`— 0.6
`— 0.4
`—-
`0.6
`——
`0.6
`— 0.6
`— 0.8
`——
`0.4
`
`dextrin glycerol Purifiedwater
`—
`2.4
`Rcmnimler
`—
`2.4
`Remainder
`1.6
`2.4
`Remainder
`2.4
`2.4
`Remainder
`——
`2.4
`Remainder
`—
`2.4
`Remainder
`—
`2.4
`Remainder
`2
`2.4
`Remainder
`2.4
`2.4
`Remainder
`—
`2.4
`Remainder
`0.5
`2.4
`Remainder
`0.5
`2.4
`Remainder
`—
`2.4
`Remainder
`—
`2.4
`Remainder
`——
`2.4
`Remainder
`—
`2.4
`Remainder
`—
`2.4
`Remainder
`—
`2.4
`Remainder
`—
`2.4
`Remainder
`
`Page 6
`
`Page 6
`
`

`
`11
`
`5,747,061
`
`12
`
`TABLE S-continued
`
`COMPOSITIONS OF EX'EMPLARY IE FORMULATIONS FOR UNIDOSE APPLICATION
`
`
`Ex. No. LE 'I’ween30 Tyloxapol Poloxamer-188 PVA PVP dextrin glycerol Purifiedwater
`20
`0.5
`—-
`0.4
`—
`— 0.4
`—
`2.4
`Remainder
`21
`0.5
`—
`0.3
`—
`— 0.6
`0.3
`2.4
`Remainder
`
`— 0.1 — — 0.4 0.3 2.40.522 Remainder
`
`
`
`
`
`
`
`
`EXAMPLE 38
`
`15
`
`25
`
`30
`
`The soft steroid loteprednol etabonate was formulated as
`an aqueous ophthalmic suspension containing polyvinyl
`pyrrolidone (0.6%). glycerine (2.4%).
`tyloxapol (0.3%).
`'edetate disodium (0.01%) and benzalkonium chloride
`(0.01%). Loteprednol etabonate (0.5%) was incorporated
`into this vehicle for use in clinical studies. During these
`studies. the formulation was evaluated on a total of 446
`patients. 220 of which had giant papillary conjunctivitis 20
`(“ PC”). 145 of which had seasonal allergic conjunctivitis
`(“SAC”) and 81 had acute anterior uveitis.
`Loteprednol etabonate in this formulation was readily
`suspendable throughout extended periods of storage (i.e..
`greater than 18 months) as well as throughout the clinical
`treatment. The preparation was well tolerated in all patients
`and was significantly more effective than the vehicle itself.
`which was used as a placebo. with regard to the reduction of
`signs and symptoms of ocular inflammation.
`The vehicle was administered as a placebo to 219 GPC
`patients and 143 SAC patients. In SAC. treatment was
`initiated prophylactically. and therefore it was not possible
`to quantitate accurately the placebo eifect. The GPC patients
`were enrolled in the study after the appearance of signs or
`symptoms. A significant number of GPC patients experi-
`enced clinically meaningful relief of signs and symptoms
`with the application of the vehicle alone. While the use of a
`demulcent solution applied four times per day should have
`some benefit in the treatment of GPC. the extent to which
`this occurred was higher than expected. Specifically. the size
`of the papillae was reduced in 50% of the patients. itching
`was reduced in 78% of the patients. and contact lens comfort
`was increased in 71% of the patients. This shows that the
`vehicle itself is useful for such treatments.
`
`35
`
`45
`
`is about
`
`(A) a corticosteroid in an amount of about 0.01% to about
`2% by weight. said corticosteroid having a particle size
`of about 0.1 to 30 microns diameter to substantially
`prevent discomfort upon use of the composition for
`said ophthalmic or otolaryngological anti-
`inflammato
`a
`ficafiony
`,
`.1-y pp
`_
`’
`_
`(B) 3 nomomc polymcr 1" an aqueous medium;
`(C) a nonionic tonicity agent in an amount suflicient to
`,
`_
`_
`.
`achleve ‘s°t°m°1ty3 and
`(D) a nonionic surface active agent in an amount suflicient
`to retain the corticosteroid. the nonionic tonicity agent
`and the nonionic polymer in suspension.
`wherein the molar ratio of (A):(B):(D)
`l:0.0l:0.05 to about 1:20:1.
`3. The composition of claim 2 wherein the corticosteroid
`is selected from the group consisting of soft steroids having
`anti-inflammatory activity and is present in an amount of
`between about 0.01 and 1% by weight.
`4. The composition of claim 2 wherein the corticosteroid
`is loteprednol etabonate and is present in an amount of
`between about 0.05 and about 0.5% by