United States Patent [19]
`Guy et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005540930A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,540,930
`Jul. 30, 1996
`
`[54] SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`[75]
`
`Inventors: Yaacov J, Guy, Rehovot; Doron I.
`Friedman, Carmei Yosef, both of Israel
`
`4,409,205
`4,602,026
`4,710,495
`5,089,482
`5,149,693
`5,27'l,901
`5,424,078
`
`1011983 Shively ................................... 514/912
`711986 Awata et al ............................. 514/912
`12/1987 Bodor ...................................... 5141174
`2/1992 Hermens et al .......................... 514/58
`9/1992 Cagle et al ............................. 514/912
`1/1994 Vigh et al ............................... 514/912
`6/1995 Dziabo et al ........................... 514/912
`
`[73] Assignee: Pharmos Corporation, New York, N.Y.
`
`OTHER PUBLICATIONS
`
`[21] Appl. No.: 142,743
`
`[22] Filed:
`
`Oct. 25, 1993
`
`[51]
`
`Int. Cl.6
`
`............................ A61K 9/10; A61K 47/32;
`A61K 47/36
`[52] U.S. Cl . .......................... 424/427; 424/437; 424/434;
`514/772.2; 514/772.5; 514/778; 514/914;
`514/772.3; 514/937
`[58] Field of Search .............................. 514/772.3, 772.2,
`514/772.5, 778, 914; 424/489, 427, 428,
`437
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`CA117: 178175, Albertha et al., 1991.
`Remington's Pharmaceutical Sciences, 18th Edition, p.
`1587-1592, 1990.
`
`Primary Examiner-Edward J. Webman
`Attorney, Agent, or Firm-Pennie & Edmonds
`
`[57]
`
`ABSTRACT
`
`The invention provides novel compositions of matter con(cid:173)
`taining water-insoluble steroid drugs suitable for therapeutic
`use. The invention provides stable aqueous suspensions of
`water-insoluble steroid drugs of particle sizes of ~ 15 llffi
`which remain in such a state so as to allow for immediate
`suspension, when desired, even after extended periods of
`settling.
`
`2,861,920 1111958 Dale et al ................................. 167/65
`4,383,992
`511983 Lipari ...................................... 424/238
`
`17 Claims, No Drawings
`
`Metrics EX1036, Page 1
`
`

`
`5,540,930
`
`1
`SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`FIELD OF INVENTION
`
`The invention relates to aqueous suspensions for treat(cid:173)
`ment of ophthalmic and otolaryngological inflammations.
`
`BACKGROUND OF THE INVENTION
`
`20
`
`2
`sitions must meet requirements for preservative efficiency
`and ease of suspension over extended periods of time.
`Therapeutic suspensions of corticosteroids
`typically
`employ polymeric compounds such as polyvinyl pyrroli-
`5 done ("PYP") and polyvinyl alcohol ("PYA") as suspending
`agents in concentrations ranging from 0.1 to 10% (U.S. Pat.
`No. 2,861,920). Combinations of polymeric compounds
`such as PYP, PYA,
`sodium carboxymethylcellulose
`("CMC"), and dextran, with surface-active agents such as
`10 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-
`15 sions of corticosteroids. Excessive amounts of polymeric
`compounds may hamper the antimicrobial effects of preser(cid:173)
`vatives added to the suspension. Also, pharmaceutical ocular
`and nasal dosages of these suspensions either must be
`buffered or have an appropriate pH with no buffering capac-
`ity. These suspensions also should be isotonic.
`Loteprednol etabonate ("LE") is a known soft corticos(cid:173)
`teroid based on the known inactive metabolite prednisolone
`acetate of the active drug prednisolone. See U.S. Pat. Nos.
`25 4,996,335 and 4,710,495.
`LE is an analog of prednisolone that does not have a
`20-keto group attached to the 17~-position. Instead, the
`17~-position is occupied with a metabolically-labile ester
`function. In biological systems, LE is hydrolysed to the
`inactive carboxylic acid metabolite (PJ-91) that does not
`bind to glucocorticoid receptors. LE also provides superior
`safety by reducing the risk of steroid induced cataracts a11d
`elevation of intra-ocular pressure. The lability of LE to
`enzymes located in the blood and/or liver also reduces the
`likelihood of systemic side effects. LE therefore provides
`therapeutic advantages over other corticosteroids by provid(cid:173)
`ing efficacy similar to its parent compound, namely, pred(cid:173)
`nisolone acetate, with fewer deleterious systemic side
`effects. Soft steroids have the potential advantage of treating
`inflammation without inducing elevation of intraocular pres(cid:173)
`sure. 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 ham(cid:173)
`pered by agglomeration of the steroid particles. Unexpect(cid:173)
`edly, 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 corticosteroids
`such as LE.
`A need therefore exists for aqueous suspensions of cor(cid:173)
`ticosteroids such as LE which can be formulated without
`agglomeration. A further need exists for aqueous suspen(cid:173)
`sions which have therapeutically effective amounts of cor(cid:173)
`ticosteroids such as LE but which avoid the problems
`associated with the steroid suspensions of the prior art.
`
`30
`
`35
`
`Numerous drugs are prepared in the form of suspensions
`for ophthalmic, oral, otic, nasal respiratory topical, and
`parenteral applications. Formulation of pharmaceutical dos(cid:173)
`ages of water-insoluble drugs as suspensions is frequently
`hampered by the subsequent formation of cakes resulting
`from aggregation of the suspended material. Polymeric
`compounds (e.g. polyvinyl pyrrolidone, polyvinyl alcohol,
`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 cyclodex(cid:173)
`trins. However, certain drugs, in their therapeutic concen(cid:173)
`trations, are not sufficiently stabilized or solubilized by these
`methods for the above-mentioned applications.
`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, ache rosacea, superficial punctate kerati-
`tis 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, allergy 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 complica(cid:173)
`tions, including posterior subcapsular cataract formation, 40
`elevation of intraocular pressure, secondary ocular infection,
`retardation of corneal wound healing, uveitis, mydriasis,
`transient ocular discomfort and ptosis. Numerous systemic
`complications also may arise from the topical ocular appli(cid:173)
`cation of corticosteroids. These complications include adre- 45
`nal insufficiency, 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 inflammations can be so
`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 55
`metabolite that undergoes a predictable one-step transfor(cid:173)
`mation in-vivo back to the parent, (see, U.S. Pat. Nos.
`4,996,335 and 4,710,495 for soft steroids) inactive metabo(cid:173)
`lite. "Soft drugs" therefore are biologically active chemical
`components characterized by predictable in vivo metabo- 60
`lism to non-toxic derivatives after they provide their thera(cid:173)
`peutic effect.
`Pharmaceutical compositions of water-insoluble drugs
`such as corticosteroids in aqueous suspensions for ocular
`and other uses must satisfy constraints imposed by physi- 65
`ological compatibilities such as pH, osmolality, and particle
`size of the suspended steroids. Furthermore, these compo-
`
`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
`water-insoluble drugs of mean particle sizes of <15 J.llll
`which remain in such a state so as to allow for immediate
`suspension, when desired, even after extended periods of
`
`Metrics EX1036, Page 2
`
`

`
`settling.
`More particularly, the invention is directed to aqueous
`suspensions of soft corticosteroids such as loteprednol eta(cid:173)
`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(cid:173)
`comfort upon application.
`The aqueous suspensions of the invention comprise com- 10
`ponent (A) of a therapeutic quantity of a "soft" steroid such
`as LE present as particles less than fifteen microns mean
`diameter, component (B) of a nonionic polymer in an
`aqueous medium, and component (C) of a nonionic surface
`active agent. The molar ratio of (A):(B):(C) can vary from 15
`about 1:0.01:0.05 to about 1:20:1. The steroid of component
`(A) preferably is loteprednol etabonate added to obtain a
`final concentration in the suspension of about 0.2-2.0%,
`preferably about 0.5-1.0% (w/w). The nonionic polymer of
`component (B) is present in an amount of between about 0.2 20
`to 2% by weight, and preferably between about 0.4 to 1.5%,
`and more preferably between about 0.4 to 1%. 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 1:0.5
`to about 1:3. The surfactant of component (C) is present in 25
`an amount of about 0.05 to 1% by weight. The compositions
`also may, if necessary, include component (D) of a tonicity
`agent for producing isotonicity, and component (E) of pre(cid:173)
`servative(s) in an aqueous medium.
`In a preferred aspect, stable aqueous suspensions of LE
`are provided by preparing aqueous suspensions of LE in
`concentrations of about 0.5-1.0% with about 0.6% PVP,
`about 2-2.8% glycerol, preferably about 2.2-2.6% glycerol,
`most preferably about 2.4% glycerol, and about 0.05 to 0.1% 35
`tyloxapol, preferably about 0.1 to 0.6% tyloxapol. Accepted
`preservatives such as benzalkonium chloride and disodium
`edentate ("EDTA") may be included in the suspensions of
`the invention in concentrations sufficient for effective anti(cid:173)
`bacterial action, preferably about 0.01-0.025%, based on the 40
`weight of the suspension. However, 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, a preferred tonicity agent
`would be mannitol or glycerol rather than the commonly 45
`used sodium chloride.
`Stable aqueous suspensions of the invention can be pro(cid:173)
`duced over a broad range of pH values. A pH of about
`4.5-7.4 especially is useful for preparing the stable LE
`suspensions of the invention.
`Having briefly summarized the invention, the invention
`will now be described in detail by reference to the following
`specification and non-limiting examples. Unless otherwise
`specified, all percentages are by weight and all temperatures
`are in degrees Celsius.
`
`30
`
`50
`
`55
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Therapeutic suspensions of LE for ophthalmic or oto(cid:173)
`laryngological uses are made by asceptic 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.
`
`3
`
`5,540,930
`
`5
`
`4
`Drugs of component (A), preferably soft steroids, most
`preferably LE, can be employed. Also other steroids such as
`beclomethasone,
`betamethasone,
`fluocinolone,
`fluo(cid:173)
`rometholone, exednisolone, may be employed. The suspen-
`sions of component (A) of the invention have a particle size
`of about 0.1-30fl, preferably about 1-20fl, most preferably
`about 2-10 microns in mean diameter. LE in this size range
`is commercially available from suppliers such as the Sipsy
`Co., (Avrille, France) The nonionic polymer of component
`(B) can be any nonionic water-soluble polymer. Typical
`compounds such as PVP, PVA, HPMC or dextran can be
`used at a concentration of about 0.2-2%, and preferably
`between about 0.4 to 1.5%, and more preferably between 0.4
`to 1%.
`Component (C) is a surface-active agent that is acceptable
`for ophthalmic or otolaryngological uses. Preferably, this
`surfactant is non-ionic. Useful surface active agents include
`but are not limited to polysorbate 80, tyloxapol, TWEEN 80
`(ICI America Inc., Wilmington, Del.), PLURONIC F-68
`(from BASF, Ludwigshafen, Germany) and the poloxamer
`surfactants can also be used. These surfactants are nonionic
`alkaline oxide condensates of an organic compound which
`contains hydroxyl groups. The concentration in which the
`surface active agent may be used is only limited by neu(cid:173)
`tralization of the bacteriocidal effects on the accompanying
`preservatives, or by concentrations which may cause irrita(cid:173)
`tion. Preferably, the concentration of component (C) is about
`0.05 to 1%, and more preferably 0.1 to 0.6% by weight
`based on the weight of the suspension.
`The tonicity agents of component (D) can be nonionic
`diols, preferably glycerol, in sufficient amounts to achieve
`isotonicity. The nonionic tonicity agents can be present in an
`amount of about 2 to 2.8% by weight, and preferably about
`2.2 to 2.6%.
`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 SO-centipoise.
`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(cid:173)
`glaucoma drugs include but are not limited to timolol-base,
`betaxalol, athenolol, levobanolol, epinenephrin, dipivalyl,
`oxonolol,
`acetazilumide-base
`and methazalomide.
`Examples of anti-inflammatory drugs include but are not
`limited to non-steroids such as piroxicam, indomethacine,
`naproxen, phenylbutazone, ibuprofen and diclofenac. Addi(cid:173)
`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-
`60 servatives may no longer be considered safe for ocular use,
`or may interact with the surfactant employed in the suspen(cid:173)
`sion to form a complex that reduces the bacteriocidic
`activity of the preservative.
`The preservatives of component (E) employed in the
`65 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
`
`Metrics EX1036, Page 3
`
`

`
`5,540,930
`
`5
`from microbiological contamination. In a preferred embodi(cid:173)
`ment benzalkonium chloride may be employed as a safe
`preservative, most preferably benzalkonium chloride with
`EDTA. Other possible preservatives include but are not
`limited to benzyl alcohol, methyl parabens, propyl parabens, 5
`thimerosal, chlorbutanol and benzethonium chlorides. Pref(cid:173)
`erably, a preservative (or combination of preservatives) that
`will impart standard antimicrobial activity to the suspension
`and protect against oxidation of components (A)-(D) is
`employed.
`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(cid:173)
`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
`
`6
`examples, all temperatures are set forth in degrees Celsius;
`unless otherwise indicated, all parts and percentages are by
`weight.
`
`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 (Compo-
`10 nent C), the tonicity agent(s) and the preservatives (Com(cid:173)
`ponents (D) and (E), respectively) are added in that order.
`The solution is then sterilized by filtration or autoclaving.
`LE, presterilized by irradiation, is added aseptically to the
`solution, and the disperson is then mixed at 12,000 rpm for
`15 one minute. The amounts of these components are shown in
`Table 1.
`
`Example
`Number
`
`1
`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
`32
`33
`34
`35
`36
`37
`
`LE
`
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`1
`1
`1
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`1
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`1
`1
`1
`0.5
`1
`1
`0.5
`1
`0.5
`0.5
`0.5
`
`TWEEN
`80
`
`Tyloxapol
`
`POLOXAMER-188
`
`HPMC 1
`
`PVA PVP Dextran Osmolarity Agent
`
`EDTA4
`
`BKA5
`
`SAMPLE COMPOSITION (% w/w)
`
`0.2
`
`0.6
`0.4
`
`0.6
`
`0.4
`0.6
`
`0.4
`
`0.4
`
`0.6
`0.6
`0.6
`
`0.2
`
`0.4
`0.2
`
`0.2
`0.6
`
`0.4
`
`0.3
`0.3
`
`0.2
`0.6
`
`0.4
`0.3
`
`0.3
`0.3
`0.3
`0.3
`0.1
`0.2
`0.2
`0.2
`0.3
`0.4
`0.3
`0.1
`0.3
`
`0.2
`
`0.4
`
`0.6
`
`o.ii
`
`0.2
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`1.4
`
`0.2
`0.4
`
`1
`1.4
`1.4
`
`2
`1.5
`0.6
`
`2
`
`0.6
`0.6
`0.6
`0.6
`0.4
`0.6
`0.6
`0.8
`1.5
`0.4
`0.6
`0.4
`0.6
`
`10 mM PBS2
`
`lOmM PBS
`IOOmMPBS
`5 mMPBS
`
`0.9% saline3
`0.9% saline
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`2.4% glycerol
`
`0.5
`
`1.6
`2.4
`
`2
`
`0.5
`0.5
`
`0.3
`0.3
`
`0.001
`
`0.001
`0.001
`0.01
`0.01
`0.015
`0.001
`0.01
`0.01
`0.004
`0.004
`0.01
`0.01
`
`0.004
`0.01
`0.01
`0.01
`O.D15
`0.015
`0.01
`0.01
`0.01
`0.015
`0.015
`0.01
`0.01
`0.01
`0.015
`
`0.01
`0.01
`0.01
`
`0.01
`0.01
`0.01
`0.01
`
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`
`1hydroxypropylmetbyl cellulose
`'phosphate buffered physiological saline
`3sodium chloride
`4etbylene diamine tetraacetic acid
`5benzalkonium chloride
`
`SIZE DETERMINATION
`
`The size distributions of the LE particles in the samples of
`Table 1 are measured with a Coulter® LS 130 instrument.
`An acceptable average particle size for ophthalmic suspen-
`sions is ~ 15 J.illl. The results appear in Table 2.
`
`TABLE 2
`
`60
`
`65
`
`Example
`
`Particle Size(s) (lffil) and
`Fraction of Total Population
`
`Number
`
`Population A
`
`A%
`
`Population B
`
`B%
`
`1
`2
`3
`4
`
`3.906 +1- 2.677
`112.7 +1- 13.27
`3.526 +1- 1. 706
`111.4 +/- 18.59
`
`86.62
`100
`100
`100
`
`53.67 +1- 13.13
`
`13.38
`
`Metrics EX1036, Page 4
`
`

`
`23.52 +1- 20.58
`32.83 +/- 2.563
`4.596 +1- 2.698
`3.805 +1- 2.417
`6.591 +1- 3.566
`3.828 +/- 2.693
`3.888 +/- 2.69
`3.559 +1- 1.469
`2.932 +/- 2.32
`88.52 +/- 30.19
`3.652 +1- 2.692
`3.851 +1- 2.401
`3.969 +1- 2.572
`4.926 +1- 2.955
`4.429 +1- 2, 732
`3.980 +1- 2.566
`3.633 +1- 2.457
`4.716 +1- 2.762
`4.789 +/- 2.823
`4.528 +/- 2.552
`5.261 +1- 2.990
`5.262 +1- 3.013
`5.204 +1- 2.985
`4.918 +/- 2.832
`4.126 +/- 2.390
`12.45 +1- 10.91
`3.976 +1- 2.245
`3.789 +/- 1.609
`3.821 +/- 2.181
`3.813 +/- 2.305
`3.385 +/- 1.506
`3.737 +1- 2.044
`3.965 +1- 2.229
`
`7
`100
`48.74
`92.43
`93.14
`100
`17.52
`10.95
`5.62
`3.52
`100
`100
`100
`100
`92.29
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`100
`46.77
`100
`78.44
`100
`100
`
`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
`32
`33
`34
`35
`36
`37
`
`5,540,930
`
`94.06 +1- 40.57
`57.91 +1- 18.14
`62.38 +1- 20.38
`
`96.28 +/- 38.13
`110.1 +/- 58.02
`82.84 +1- 13.08
`100.1 +1- 24,56
`
`51.26
`7.57
`6.86
`
`82.48
`85.98
`94.38
`96.48
`
`41.59 +1- 7.125
`
`7.71
`
`8
`
`TABLE 3-continued
`
`RESUSPENSION OF LE SUSPENSIONS WHICH
`HAVE UNDERGONE ACCELERATED AND
`NATURAL 1 SETTLING
`
`Accelerated
`
`Suspension of
`naturally settled material 1
`
`Example
`Number
`
`Stability
`(time to resuspend)2
`
`Initial Value
`(#inversions)
`
`Months Tested3
`
`5
`5
`5
`5
`
`5
`5
`
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`
`27
`22
`35
`35
`49
`25
`43
`74
`136
`40
`18
`48
`46
`
`8
`6(I)
`6(I)
`8(I)
`7
`7
`7
`7
`3(I)
`7
`7
`7
`8
`
`5
`
`10
`
`15
`
`20
`
`107.3 +/- 14.74
`
`53.23
`
`25.16 +1- 1.421
`
`21.56 25
`
`1 Refers to settling, at room temperature, on an open shelf
`2Number of seconds of wrist shaking to suspend material that was settled by
`"¥,>Plication of 5000 x G for 2 minutes.
`During the test period, samples were periodically examined to verify the
`retention of the initial values "I'' indicates instability for the noted period, i.e.,
`agglomeration.
`
`1. In the Coulter particle size analysis two distinct populations of particles
`were sometimes discerned. In these cases the two populations are denoted as
`populations A and B. If only a single population was detected it is denoted
`population A.
`
`EVALUATION OF SUSPENDIBILITY OVER
`TIME
`
`The results shown in Table 3 show samples which do not
`form agglomerates during the longest period of observation.
`30 Acceptable samples require ~ 100 gentle inversions follow(cid:173)
`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
`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(+)
`40 or ineffective (-) according to U.S.P. requirements.
`
`35
`
`Samples containing particles with desirable size distribu(cid:173)
`tions (average of 2-10 j.llil) 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 suspendibility of the settled material is tested
`by measuring the number of seconds of wrist shaking
`required to eliminate visible residue attached to the con(cid:173)
`tainer. Since existing marketed products require as much as
`sixty seconds of wrist shaking to suspend the entire amount 45
`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.
`
`TABLE 3
`
`RESUSPENSION OF LE SUSPENSIONS WinCH
`HAVE UNDERGONE ACCELERATED AND
`NATURAL 1 SETTLING
`
`Accelerated
`
`Suspension of
`naturally settled material1
`
`Example
`Number
`
`Stability
`(time to resuspendf
`
`Initial Value
`(# inversions)
`
`Months Tested3
`
`15
`5
`5
`5
`5
`
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`10(I)
`10(!)
`10(!)
`9
`9
`9
`9
`9
`9
`6(1)
`
`67
`46
`83
`37
`
`TABLE 4
`
`Challenge Microorganism
`
`Example
`
`Staph.
`aureus
`
`P. aerng.
`
`Candida
`albicans
`
`Asper. niger
`
`E. coli
`
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`
`+
`+
`+
`+
`+
`+
`+
`
`+
`
`+
`+
`+
`+
`+
`
`ND
`ND
`ND
`ND
`+
`+
`ND
`+
`+
`+
`
`+
`+
`+
`+
`+
`+
`+
`+
`
`ND: denotes not done; (+) denotes challenge withstood; (-) denotes unac(cid:173)
`ceptable microbe growth
`The test was performed according to U.S.P. specifications.
`
`UNIDOSE SUSPENSIONS WITHOUT
`PRESERVATIVES
`
`50
`
`55
`
`60
`
`Compositions with satisfactory particle sizes and stabili(cid:173)
`ties for unidose suspensions without preservatives appear in
`65 Table 5. These compositions are satisfactory for ophthalmic
`or otolaryngological uses when prepared under aseptic con(cid:173)
`ditions and packaged in containers for single doses.
`
`Metrics EX1036, Page 5
`
`

`
`9
`
`5,540,930
`
`TABLE 5
`
`10
`
`COMPOSITIONS OF EXEMPLARY LE FORMULATIONS FOR UNIDOSE APPLICATION
`
`Ex. No.
`
`LE
`
`Tween 80
`
`Tyloxapol
`
`Poloxarner-188
`
`PYA
`
`PVP
`
`dextran
`
`glycerol
`
`Purified Water
`
`0.6
`
`0.4
`
`0.6
`0.6
`0.6
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`1
`1
`1
`0.5
`1
`1
`1
`1
`0.5
`0.5
`0.5
`
`0.4
`0.3
`0.6
`
`0.3
`0.3
`0.3
`0.3
`0.1
`0.2
`0.2
`0.4
`0.2
`0.4
`0.4
`0.3
`0.1
`
`1.4
`2
`
`0.8
`
`0.6
`0.6
`0.6
`0.6
`0.4
`0.6
`0.6
`0.6
`0.8
`0.4
`0.4
`0.6
`0.4
`
`1.6
`2.4
`
`2
`2.4
`
`0.5
`0.5
`
`0.3
`0.3
`
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`2.4
`
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`Remainder
`
`0.6
`
`0.8
`1.4
`
`25
`
`30
`
`35
`
`teroid, wherein said additional therapeutic drug is selected
`from the group consisting of betaxalol, athenolol, livoban(cid:173)
`olol, epinenephrin, dipivalyl, oxonolol, acetazilumide-base,
`methazalomide,
`tobramycin,
`gentamycin,
`piroxicam,
`indomethacin, naproxen, phenylbutazone, ibuprofen, and
`diclofenac-acid.
`12. A composition for ophthalmic or otolaryngological
`anti-inflammatory use according to claim 1 in which the
`nonionic tonicity agent is glycerol in an amount 2 to 2.8%.
`13. A composition for ophthalmic or otolaryngological
`anti-inflammatory use comprising a nonionic polymer in an
`aqueous medium, a nonionic tonicity agent in an amount
`effective to product isotonicity, and a nonionic surface active
`agent in an amount sufficient to retain the polymer and
`tonicity agent in the aqueous medium, and further compris(cid:173)
`ing a corticosteroid having a particle size of 0.1 to 30
`microns in diameter in an amount of about 0.2 to 2% by
`weight, wherein the molar ratio of corticosteroid to nonionic
`polymer to nonionic surface active agent is between about
`45 1:20:1 and about 1:0.01:0.05.
`14. The composition of claim 13 wherein said nonionic
`tonicity agent is a nonionic diol and is present in an amount
`of about 2 to 2.8% by weight.
`15. The composition of claim 13 wherein the nonionic
`polymer is present in an amount of about 0.2 to 2% by
`weight; the nonionic tonicity agent is present in an amount
`of about 2 to 2.8% by weight; and the nonionic surface
`active agent is present in an amount of about 0.05 to I% by
`weight.
`16. The composition of claim 13 further comprising a
`preservative of benzalkonium chloride, disodium edetate,
`and mixtures thereof in an amount of about 0.01 to 0.025%
`by weight.
`17. The composition of claim 13 wherein the nonionic
`polymer is polyvinyl pyrrolidone and is present in an
`amount of about 0.4 to 1% by weight, the nonionic tonicity
`agent is mannitol or a diol and is present in an amount of
`about 2 to 2.8% by weight, and the nonionic surface active
`agent is tyloxapol and is present in an amount of about 0.1
`to 0.6% by weight.
`
`We claim:
`1. A composition for ophthalmic or otolaryngological
`anti-inflammatory use comprising:
`(A) a corticosteroid having a particle size of 0.1 to 30
`microns in diameter in an amount of about 0.2 to 2% by
`weight;
`(B) a nonionic polymer in an aqueous medium;
`(C) a nonionic surface active agent in an amount sufficient
`to retain the corticosteroid in suspension; and
`(D) a nonionic tonicity agent in an amount sufficient to
`achieve
`isotonicity, wherein
`the molar ratio of
`(A):(B):(C)
`is between about 1:20:1 and about
`1:0.01:0.5.
`2. The composition of claim 1 wherein the corticosteroid
`is selected from the group consisting of soft steroids having
`anti-inflammatory activity.
`3. The composition of claim 1 wherein the corticosteroid
`is loteprednol etabonate and is present in an amount of about
`0.5 to 1% by weight.
`4. The composition of claim 3 wherein said corticosteroid
`has a particle size less than about fifteen microns.
`5. The composition of claim 1 further including a preser(cid:173)
`vative for preventing microbial formation in said composi(cid:173)
`tion and in an amount of about 0.01 to 0.025% by weight.
`6. The composition of claim 5 wherein said preservative 50
`is benzalkonium chloride.
`7. The composition of claim 6 further comprising diso(cid:173)
`dium edetate.
`8. The composition of claim 1 wherein said nonionic
`polymer is selected from the group consisting of polyvi- 55
`nylpyrrolidone, polyvinyl alcohol, or dextran and is present
`in an amount of about 0.2 to 2% by weight and wherein the
`nonionic surfactant is present in an amount of about 0.05 to
`1% by weight.
`9. The composition of claim 1 wherein said nonionic 60
`polymer is polyvinylpyrrolidone and is present in an amount
`of about 0.4 to 1% by weight.
`10. The composition of claim 1 wherein said nonionic
`surface active agent is tyloxapol and is present in an amount
`of about 0.1 to 0.6% by weight.
`11. The composition of claim 1 further comprising an
`additional therapeutic drug in admixture with said corticos-
`
`40
`
`65
`
`* * * * *
`
`Metrics EX1036, Page 6
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`5,540,930
`
`DATED
`
`July 30, 1996
`
`INVENTOR(S)
`
`Guy et al.
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Claim 1, line 39: "0.5" should read --0.05·-.
`
`Signed and Sealed this
`
`Twenty-second Day of July, 1997
`
`VL.a~
`
`BRlJCE LEHMAN
`
`Attest:
`
`Attesting Officer
`
`Metrics EX1036, Page 7