5,540,930
`[11] Patent Number:
`[19]
`United States Patent
`
`Guy et a1.
`[45] Date of Patent:
`Jul. 30, 1996
`
`USOOSS40930A
`
`[54] SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`[75]
`
`Inventors: Yaacov J. Guy, Rehovot; Damn I.
`F . d
`C
`. Y f 1)
`th f1
`M mm" mm” 056 ’
`°
`0
`
`1
`“a"
`
`[73] Assignee: Pharmos Corporation, New York, NY.
`»
`
`21
`
`]
`[
`[22]
`
`A 1. N .2142743
`pp
`0
`’
`Filed:
`Oct. 25, 1993
`
`[51]
`
`[52] U.S. CI.
`
`Int. Cl.6 ............................ A61K 9/10; A61K 47/32;
`A61K 47/36
`.......................... 424/427; 424/437; 424/434;
`514/7722; 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
`
`2,861,920
`4,383,992
`
`................................ 167/65
`11/1958 Dale et a1.
`
`5/1983 Lipari ..........
`.
`.
`424/238
`
`4,409,205
`4,602,026
`4,710,495
`5,089,482
`
`5’149’693
`5,277,901
`5,424,078
`
`10/1933 Shively ................................... 514/912
`7/1986 Awata et al.
`.
`514/912
`
`12/1987 Bodor ..............
`514/174
`2/1992 Hermens et al. ......... 514/58
`
`
`514/912
`9/1992 C1919“ et 81'
`514/912
`.......
`1/1994 Vlgh et a1.
`.......................... 514/912
`6/1995 Dziabo et al.
`
`OTHER PUBLICATIONS
`CA117: 178175 Albertha et a1. 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-
`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 um
`which remain in such a state so as to allow for immediate
`suspension, when desired, even after extended periods of
`settling.
`
`17 Claims, No Drawings
`
`Page 1 of 7
`
`LUPIN EX 1071
`
`LUPIN EX 1071
`
`Page 1 of 7
`
`

`

`1
`SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`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 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. 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-
`trins. However, certain drugs, in their therapeutic concen-
`trations, are not sufiiciently 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-
`tions, including posterior subcapsular cataract formation,
`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-
`cation of corticosteroids. These complications include adre—
`nal insufliciency, 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.
`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 particle
`size of the suspended steroids. Furthermore, these compo—
`
`Page 2 of 7
`
`5,540,930
`
`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-
`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 efl°ects of preser-
`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-
`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
`17B-position is occupied with a metabolically-labile ester
`function. In biological systems, LE is hydrolysed to the
`inactive carboxylic acid metabolite (Pl-91) that does not
`bind to glucocorticoid receptors. LE also provides superior
`safety by reducing the risk of steroid induced cataracts and
`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-
`ing efficacy similar to its parent compound, namely, pred-
`nisolone acetate, with fewer deleterious
`systemic side
`effects. Soft steroids have the potential advantage of treating
`inflammation without inducing elevation of intraocular pres-
`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 LB for
`ocular applications and other uses, however, has been ham-
`pered by agglomeration of the steroid particles. Unexpect—
`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-
`ticosteroids such as LE which can be formulated without
`agglomeration. A further need exists for aqueous suspen-
`sions which have therapeutically eifective 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
`water-insoluble drugs of mean particle sizes of <15 pm
`which remain in such a state so as to allow for immediate
`
`suspension, when desired, even after extended periods of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 2 of 7
`
`

`

`3
`
`4
`
`5,540,930
`
`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 LB 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.
`The aqueous suspensions of the invention comprise com-
`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
`about l:0.01:0.05 to about l: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
`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 110.5
`to about 1:3. The surfactant of component (C) is present in
`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-
`servative(s) in an aqueous medium.
`In a preferred aspect, stable aqueous suspensions of LB
`are provided by preparing aqueous suspensions of LE in
`concentrations of about 05—10% 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%
`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-
`
`bacterial action, preferably about 0.01—0.025%, based on the
`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
`used sodium chloride.
`
`Stable aqueous suspensions of the invention can be pro-
`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.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Therapeutic suspensions of LE for ophthalmic or oto-
`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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Drugs of component (A), preferably soft steroids, most
`preferably LE, can be employed. Also other steroids such as
`beclomethasone,
`betamethasone,
`fluocinolone,
`fluo-
`rometholone, exednisolone, may be employed. The suspen-
`sions of component (A) of the invention have a particle size
`of about 0.1—30p, preferably about l—20u, most preferably
`about 2—10 microns 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, 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-
`tralization of the bacteriocidal effects on the accompanying
`preservatives, or by concentrations which may cause irrita-
`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 suflicient 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 80-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-
`glaucoma drugs include but are not limited to timolol-base,
`betaxalol, athenolol, levobanolol, epinenephrin, dipivalyl,
`oxonolol,
`acetazilumide-base
`and
`methazalornide.
`Examples of anti-inflammatory drugs include but are not
`limited to non-steroids such as piroxicarn, indomethacine,
`naproxen, phenylbutazone, ibuprofen and diclofenac. Addi-
`tional therapeutic materials which may be employed include
`but are not limited to tobrarnycin, 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 considered 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.
`(B) employed in the
`The preservatives of component
`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
`
`Page 3 of 7
`
`Page 3 of 7
`
`

`

`5,540,930
`
`5
`
`from microbiological contamination. In a preferred embodi-
`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,
`thimerosal, chlorbutanol and benzethonium chlorides. Pref-
`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-
`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-
`nent C), the tonicity agent(s) and the preservatives (Com-
`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
`one minute. The amounts of these components are shown in
`Table 1.
`
`10
`
`15
`
`SAMPLE COMPOSITION (% w/w)
`
`Example
`TWEEN
`
`Number
`LE
`80
`Tyloxapol
`POLOXAMER-l 88
`HPMCl
`PVA PVP
`Dextran Osmolarity Agent
`EDTA"
`BKA5
`
`—
`—
`— —
`0.6 —
`—
`—
`0.2
`——
`0.5
`1
`—
`—
`—
`10 mM PBS2
`—-
`0.
`—
`—
`-—-
`0.2
`0.5
`2
`—-
`—
`—- —
`— 0.4
`0.2
`—
`0.4
`—
`0.5
`3
`—
`—
`——
`10 mM PBS
`0.2
`——
`—
`—
`0.2
`—
`0.5
`4
`—
`—
`—
`100 mM PBS
`-—
`-——
`0.4
`—
`—
`0.6
`0.5
`5
`0.001
`—
`— 5 mM PBS
`1.4 —
`-—
`—-
`—
`0.4
`0.5
`6
`—
`—
`— —
`— 1
`—
`—
`0.2
`——
`1
`7
`—
`—
`— ——
`— 1.4
`——
`—
`0.6
`—
`1
`8
`—-
`——
`—— —
`— 1.4
`——
`—
`—
`0.6
`1
`9
`0.001
`—-
`—
`0.9% saline3
`l
`—
`—
`—
`0.4
`——
`0.5
`10
`0.001
`—
`—
`0.9% saline
`l
`—-
`——
`—
`—
`0.4
`0.5
`11
`0.01
`0.01
`—
`2.4% glycerol
`——
`2
`-—-
`—
`—
`0.6
`0.5
`12
`0.01
`0.01
`—
`24% glycerol
`— 1.5
`——
`——
`0.3
`—-
`0.5
`13
`0.015
`0.01
`0.5
`2.4% glycerol
`— 0.6
`—-
`—
`0.3
`—
`0.5
`14
`0.001
`—
`—
`2.4% glycerol
`1.4 —
`—
`—
`—
`0.4
`0.5
`15
`0.01
`—
`——-
`2.4% glycerol
`— 1
`—
`—
`0.2
`—
`1
`16
`0.01
`——
`—
`2.4% glycerol
`1.4 —
`—
`—
`0.6
`—
`0.5
`17
`0.004
`0.01
`—
`24% glycerol
`— 2
`—
`0.6
`——
`—
`0.5
`18
`0.004
`0.01
`16
`2.4% glycerol
`— —-
`—
`—
`-—
`0.4
`0.5
`19
`0.01
`0.01
`2.4
`2.4% glycerol
`— —
`—
`—
`0.4
`—
`0.5
`20
`0.01
`0.01
`—
`2.4% glycerol
`— l
`—
`——
`0.3
`—
`0.5
`21
`—
`——
`—
`2.4% glycerol
`1,4 —
`—
`——
`—
`0.6
`0.5
`22
`0.004
`—
`—
`2.4% glycerol
`1.4 —
`—
`——
`—
`0.6
`0.5
`23
`0.01
`0.01
`2
`2.4% glycerol
`— —
`—
`——
`——
`0.6
`0.5
`24
`0.01
`0.01
`—
`2.4% glycerol
`--
`0.6
`——
`—
`0.3
`—
`0.5
`25
`0.01
`0.01
`0.5
`2.4% glycerol
`— 0.6
`—
`——
`0.3
`—
`0.5
`26
`0.015
`0.01
`0.5
`2.4% glycerol
`— 0.6
`—
`-—-
`0.3
`—
`1
`27
`0.015
`0.01
`—
`2.4% glycerol
`— 0.6
`—
`~—
`0.3
`—
`1
`28
`0.01
`0.01
`—
`2.4% glycerol
`— 0.4
`—
`—
`0.1
`—
`l
`29
`0.01
`0.01
`—
`2.4% glycerol
`——
`0.6
`——
`—
`0.2
`—
`0.5
`30
`0.01
`0.01
`—
`2.4% glycerol
`— 0.6
`—
`—
`0.2
`—
`1
`31
`0.015
`0.01
`—
`2.4% glycerol
`~—
`0.8
`—
`—
`0.2
`—
`I
`32
`0.015
`0.01
`—
`2.4% glycerol
`~—
`1.5
`—
`—
`0.3
`—
`0.5
`33
`0.01
`0.01
`—
`2.4% glycerol
`— 0.4
`—
`—
`0.4
`—
`1
`34
`0.01
`0.01
`0.3
`2.4% glycerol
`— 0.6
`-—
`-——
`0.3
`—
`0.5
`35
`36
`0.5
`—
`0.1
`—
`—
`— 0.4
`0.3
`2.4% glycerol
`0.01
`0.01
`37
`0.5
`—
`0.3
`—
`—
`— 0.6
`—
`2.4% glycerol
`0.01
`0.015
`
`
`1hydroxypropylrnethyl cellulose
`thosphate buflered physiological saline
`fsodium chloride
`4ethylene diamine tetraacetic acid
`sbenzalkonium 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 srze for ophthalmic suspen
`s10ns 1s élS um. The results appear in Table 2.
`
`TABLE 2
`
`Page 4 of 7
`
`
`
`Particle Size(s) (pm) and
`Exam?“
`Ham” of T‘m lawman“
`
`Number
`Population A
`A %
`Population B
`B %
`
`1
`2
`3
`4
`
`3.906 +/_ 2.677
`112.7 +/_ 13.27
`3.526 +/— 1.706
`111.4 +/— 18.59
`
`86.62
`100
`100
`100
`
`53.67 +/_ 13.13
`_
`—
`_
`
`13.38
`_
`—
`_
`
`60
`
`65
`
`Page 4 of 7
`
`

`

`5,540,930
`
`8
`
`TABLE 3~continued
`
`RESUSPENSION OF LE SUSPENSIONS WHICH
`HAVE UNDERGONE ACCELERATED AND
`NATURALl SETTLING
`
`Accelerated
`
`Suspension of
`naturally settled material‘
`
`Example
`Stability
`Initial Value
`
`Number
`(time to resuspend)2
`(# inversions)
`Months Tested3
`25
`5
`27
`8
`26
`5
`22
`6(1)
`27
`5
`35
`6(1)
`28
`5
`35
`8(1)
`29
`—
`49
`7
`30
`5
`25
`7
`31
`5
`43
`7
`32
`—
`74
`7
`33
`—
`136
`3(1)
`34
`—
`40
`7
`35
`——
`18
`7
`36
`——
`48
`7
`
`—- 4637 8
`
`
`
`1Refers to settling, at room temperature, on an open shelf
`1Number of seconds of wrist shaking to suspend material that was settled by
`a plication of 5000 X G for 2 minutes.
`During the test period, samples were periodically examined to verify the
`retention of the initial values “1" indicates instability for the noted period, i.e.,
`agglomeration.
`
`The results shown in Table 3 show samples which do not
`form agglomerates during the longest period of observation.
`Acceptable samples require E 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
`each material are exposed to the indicated microbiological
`organisms for four weeks and evaluated for growth as
`described in the US. Pharrnacopeia. The results, shown in
`Table 4, indicate whether the preservative was effective (+)
`or ineffective (——) according to U.S.P. requirements.
`
`TABLE 4
`
`Challenge Microorganism
`
`Staph.
`aureus
`
`P. aemg.
`
`Candida
`albicans
`
`Asper. niger
`
`E. coli
`
`6N
`
`D
`ND
`ND
`
`++
`
`ND
`
`+++
`
`++++++++++
`
`+++++++l
`
`+++++r+|
`
`++++++++l
`
`Example
`23
`24
`25
`26
`27
`28
`29
`30
`3 1
`32
`
`ND: denotes not done; (+) denotes challenge withstood; (—) denotes unac-
`ceptable microbe growth
`The test was performed according to U.S.P. specifications.
`
`UNIDOSE SUSPENSIONS WIIHOUT
`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.
`
`7
`—
`—
`100
`23.52 +/— 20.58
`5
`51.26
`94.06 +/—— 40.57
`48.74
`32.83 +/— 2.563
`6
`7.57
`57.91 +/—- 18.14
`92.43
`4.596 +/— 2.698
`7
`6.86
`62.38 +/— 20.38
`93.14
`3.805 +/— 2.417
`8
`——
`—
`100
`6.591 +/— 3.566
`9
`82.48
`96.28 +/— 38.13
`17.52
`3.828 +/— 2.693
`10
`85.98
`110.1 +/— 58.02
`10.95
`3.888 +/— 2.69
`11
`94.38
`82.84 +/— 13.08
`5.62
`3.559 +I— 1.469
`12
`96.48
`100.1 +/— 24,56
`3.52
`2.932 +/— 2.32
`13
`—
`—
`100
`88.52 +I— 30.19
`14
`—
`—
`100
`3.652 +/— 2.692
`15
`—
`——
`100
`3.851 +/— 2.401
`16
`—
`—
`100
`3.969 +/— 2.572
`17
`7.71
`41.59 +/— 7.125
`92.29
`4.926 +/- 2.955
`18
`—
`-—
`100
`4.429 +/— 2,732
`19
`—
`—
`100
`3.980 +/— 2.566
`20
`~—
`—
`100
`3.633 +/— 2.457
`21
`—
`—
`100
`4.716 +/— 2.762
`22
`—
`—
`100
`4.789 +/— 2.823
`23
`——
`——
`100
`4.528 +/— 2.552
`24
`—
`—
`100
`5.261 +/— 2.990
`25
`—
`—
`100
`5.262 +l— 3.013
`26
`——
`—
`100
`5.204 +/— 2.985
`27
`—
`—
`100
`4.918 +/— 2.832
`28
`—
`——
`100
`4.126 +/— 2.390
`29
`—
`—
`100
`12.45 +/— 10.91
`30
`—
`——
`100
`3.976 +/— 2.245
`31
`~—
`—-
`100
`3.789 +/-— 1.609
`32
`53.23
`107.3 +/— 14.74
`46.77
`3.821 +/— 2.181
`33
`——
`—
`100
`3.813 +/— 2.305
`34
`21.56
`25.16 +/— 1.421
`78.44
`3.385 +/— 1.506
`35
`~—
`—
`100
`3.737 +/—- 2.044
`36
`
`
`
`
`——1003.965 +/— 2.22937 ~—
`
`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
`
`Samples containing particles with desirable size distribu—
`tions (average of 2—10 pm) 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 SOOOXG 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-
`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.
`
`TABLE 3
`
`RESUSPENSION OF LE SUSPENSIONS WHICH
`HAVE UNDERGONE ACCELERATED AND
`NATURAL1 SETTLING
`
`Accelerated
`
`Suspension of
`naturally settled material1
`
`Example
`Number
`
`Stability
`(time to resuspend)2
`
`Initial Value
`(# inversions)
`
`Months Tested3
`
`15
`16
`17
`1 8
`19
`20
`21
`22
`23
`24
`
`15
`5
`5
`5
`5
`—
`—-
`—
`—
`-—-
`
`——
`—
`—
`—-
`—
`67
`46
`83
`37
`—
`
`10(1)
`10(1)
`10(1)
`9
`9
`9
`9
`9
`9
`6(1)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 5 of 7
`
`Page 5 of 7
`
`

`

`5,540,930
`
`10
`
`TABLE 5
`COMPOSITIONS OF EXEMPLARY LE FORMULATIONS FOR UNIDOSE APPLICATION
`
`Ex. No.
`LE
`Tween 80
`Tyloxapol
`Poloxamer-l88
`PVA
`PVP
`dextran
`glycerol
`Purified Water
`
`1
`1
`0.6
`—
`—
`—
`1.4
`—
`2.4
`Remainder
`2
`0.5
`—
`—
`0.6
`—
`2
`—
`2.4
`Remainder
`3
`0.5
`0.4
`——
`—
`—-
`—
`1.6
`2.4
`Remainder
`4
`0.5
`—
`0.4
`—
`—
`—
`2.4
`2.4
`Remainder
`5
`0.5
`—
`0.3
`——
`—
`1
`—
`2.4
`Remainder
`6
`0.5
`——
`0.6
`—
`0.8
`—
`——
`2.4
`Remainder
`7
`0.5
`0.6
`——
`——
`1.4
`0.8
`—
`2.4
`Remainder
`8
`0.5
`0.6
`—
`—
`—
`—
`2
`2.4
`Remainder
`9
`0.5
`0.6
`—
`—
`—
`—
`2.4
`2.4
`Remainder
`10
`0.5
`—
`0.3
`—
`—
`0.6
`—-
`2.4
`Remainder
`11
`0.5
`—-
`0.3
`——
`—
`0.6
`0.5
`2.4
`Remainder
`12
`1
`—
`0.3
`—
`—
`0.6
`0.5
`2.4
`Remainder
`13
`1
`—
`0.3
`—
`—
`0.6
`—
`2.4
`Remainder
`14
`1
`-——
`0.1
`-—
`—
`0.4
`—
`2.4
`Remainder
`15
`0.5
`—
`0.2
`—-—
`—
`0.6
`—
`2.4
`Remainder
`16
`1
`—
`0.2
`—
`—
`0.6
`——
`2.4
`Remainder
`17
`1
`—
`0.4
`—
`—
`0.6
`——
`2.4
`Remainder
`18
`1
`—
`0.2
`——
`—
`0.8
`—
`2.4
`Remainder
`19
`1
`—
`0.4
`——
`—
`0.4
`—
`2.4
`Remainder
`20
`0.5
`—
`0.4
`—
`—
`0.4
`—
`2.4
`Remainder
`21
`0.5
`—
`0.3
`—
`-—
`0.6
`0.3
`2.4
`Remainder
`22
`0.5
`—
`0.1
`—
`—
`0.4
`0.3
`2.4
`Remainder
`
`25
`
`35
`
`teroid, wherein said additional therapeutic drug is selected
`We claim:
`from the group consisting of betaxalol, athenolol, livoban~
`1. A composition for ophthalmic or otolaryngological
`olol, epinenephrin, dipivalyl, oxonolol, acetazilumide-base,
`anti—inflammatory use comprising:
`(A) a corticosteroid having a particle size of 0.1 to 30 3o methazalomrde,
`tobramycm,
`gentamycrn,
`prroxrcam,
`microns in diameter in an amount of about 0.2 to 2% by
`Indomethacm; naproxen, phenylbutazone,
`ibuprofen, and
`weight;
`drclofenac-acrd.
`(B) a nonionic polymer in an aqueous medium;
`1.2. A composrtron for ophthalmic 0? otolaryngologrcal
`.
`fli
`C
`.
`.
`urf
`_
`,
`antr-rnflammatory use accordmg to claim 1 1n wh1ch the
`(
`) a “091mg: 3
`ace 3‘5““?dagem in an amountgu crent
`nonionic tonicity agent is glycerol in an amount 2 to 2.8%.
`to retain t .e COR-IC'OStCI'OI
`1? 3115931151011, an
`.
`13. A composition for ophthalmic or otolaryngological
`(D) 31101110910 1091911531 agent in an amount SUfliCle t0
`anti-inflammatory use comprising a nonionic polymer in an
`achieve 150191110105 wherein the molar 13th 0f
`aqueous medium, a nonionic tonicity agent in an amount
`(A)3(B)5(C)
`15 between about
`152011
`and about
`effective to product isotonicity, and a nonionic surface active
`.
`_
`1'0-01'0-5'
`,
`_
`_
`_
`agent in an amount sufficient to retain the polymer and
`, 2.1TheEgrmpositlon 0f claim-1 wherecm fire cortlgoiterold 40
`tonicity agent in the aqueous medium, and further compris-
`1s :eietate
`0?” egtroupcons1st1ng 0 so
`steror S avmg
`ing a corticosteroid having a particle size of 0.1 to 30
`an ' n amma 0173f ac 1v1ty.
`.
`.
`.
`.
`microns in diameter in an amount of about 0.2 to 2% by
`3. The composrtron of claim 1 wherein the cortrcosterord
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`weight, wherein the molar ratio of cortrcostermd to nomomc
`.
`1s loteprednol etabonate and IS present in an amount of about
`.
`.
`.
`.
`05 to 1% by weight.
`pozlgrrlrer t: ntpmorpcé) zulrfgcé;active agent is between about
`4. The composition of claim 3 wherein said corticosteroid 45
`'
`'
`an a out
`_' ,'
`'
`'
`',
`.
`_
`,
`_
`has a particle size less than about fifteen microns.
`14. The composrtron of claim 13 wherein said HOIIIOIIIC
`5_ The composition of claim 1 further including a preser—
`tomcrty agent is a nomonrc drol and is present in an amount
`vative for preventing microbial formation in said composi-
`0f about 2 t0 23%}?3’ weight.
`.
`.
`_
`tion and in an amount of about 0.01 to 0.025% by weight.
`15. The compos1t}on of clmm 13 wherem the nomomc
`6. The composition of claim 5 wherein said preservative 50 polymer is present in an amount of about 0.2 to 2% by
`is benzalkonium chloride.
`weight; the nonionic tonicity agent is present in an amount
`7. The composition of claim 6 further comprising diso-
`of about 2 to 2.8% by weight; and the nonionic surface
`dium edetate.
`active agent is present in an amount of about 0.05 to 1% by
`8. The composition of claim 1 wherein said nonionic
`weight.
`polymer is selected from the group consisting of polyvi- 55
`16. The composition of claim 13 further comprising a
`nylpyrrolidone, polyvinyl alcohol, or dextran and is present
`preservative of benzalkonium chloride, disodium edetate,
`in an amount of about 0.2 to 2% by weight and wherein the
`and mixtures thereof in an amount of about 0.01 to 0.025%
`nonionic surfactant is present in an amount of about 0.05 to
`by weight.
`1% by weight.
`17. The composition of claim 13 wherein the nonionic
`9. The composition of claim 1 wherein said nonionic 60 polymer is polyvinyl pyrrolidone and is present
`in an
`polymer is polyvinylpyrrolidone and is present in an amount
`amount of about 0.4 to 1% by weight, the nonionic tonicity
`of about 0.4 to 1% by weight.
`agent is mannitol or a diol and is present in an amount of
`10. The composition of claim 1 wherein said nonionic
`about 2 to 2.8% by weight, and the nonionic surface active
`surface active agent is tyloxapol and is present in an amount
`agent is tyloxapol and is present in an amount of about 0.1
`of about 0.1 to 0.6% by weight.
`to 0.6% by weight.
`11. The composition of claim 1 further comprising an
`additional therapeutic drug in admixture with said corticos-
`
`65
`
`Page 6 of 7
`
`Page 6 of 7
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`DATED
`
`INVENTORIS)
`
`:
`
`:
`
`:
`
`5,540,930
`
`July 30, 1996
`
`Guy et a!.
`
`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--.
`
`A[(0.315
`
`Signed and Sealed this
`
`Twenty-second Day of July, 1997
`
`60144 W
`
`BRUCE LEHMAN
`
`Arresting Officer
`
`Cmmnmvinnrr of Palm“ and ’I'rur/wmu‘h
`
`
`
`Page 7 of 7
`
`Page 7 of 7
`
`