I Umted States Patent [19]
`Amselem et al.
`
`US005747061A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,747,061
`*May 5, 1998
`
`[54] SUSPENSION OF LOTEPREDNOL
`ETABONATE FOR EAR, EYE, OR NOSE
`TREATMENT
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`[75] Inventors: Shimon Amselem,Rehovot; Doron
`Friedman. Carmei Yosef, both of Israel
`
`2,861,920 11/1958 Dale et a1. .............................. .. 167/65
`4,383,992
`5/1983 Lipan
`424/238
`
`[73] Assignee: Pharmos Corporation. Machua. Fla.
`
`[*1 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
`
`Related Us. Applimtion Dam
`
`[63] Continuation-in-partofSer.No.142,743,0cL25,1993,PaL
`N0‘ 5’540’930'
`[51] Int. C16 .......................... .. A61K 9/10; A61K 47/32;
`A6lK 47/36
`[52] us. (:1. ........................ ..424/427;4241437;424/434;
`514/7722; 514/7723; 514/772.5; 514/778;
`514/914; 514/937
`[581 Field of Search ................................... .. 4241421437.
`424/434. 489; 514/772.2—772.3. 772.5,
`778. 914. 937
`
`4,409,205 10/1983 Shively . . . . . .
`
`. . . . .. 424/78
`
`514/369
`7/1986 Awata et a1.
`4,602,026
`514/174
`4,710,495 12/1987 Bodor ....... ..
`---- -- 514/58
`5,089,482 2/19% Hemmns e121-
`5,149,693
`9/1992 Cagle et a]. ............................ .. 514/40
`5,192,535
`3/1993 Davis et a1. .
`5,277,901
`1/1994 Vlgh et a1. ......................... .. 424/7804
`5,424,078
`6/1995 Dziabo et a], ........................ .. 424/661
`
`Primary Examiner—Edward I. Webman
`Attorney; Agent, or F irm--Pennie & Edmonds
`
`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“water-insolublesteroid drugsofpal?cl?sizes
`of 530 pm which remain in such a state so as to allow for
`immediate suspension. when desired. even after extended
`Periods 0f Settling
`
`30 Claims, No Drawings
`
`LUPIN EX 1065
`
`Page 1 of 8
`
`

`

`5.747.061
`
`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 e?iciency 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% (US. 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
`buffered 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 US. 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 e?ects. LE therefore provides therapeutic
`advantages over other corticosteroids by providing e?icacy
`similar to its parent compound. namely. prednisolone
`acetate. with fewer deleterious systemic side effects. Soft
`steroids have the potential advantage of treating in?amma
`tion without inducing elevation of intraocular pressure. In
`addition, soft steroids can provide the added bene?t 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.
`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.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`50
`
`55
`
`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/l42.743 ?led Oct. 25. 1993. now US. Pat. No.
`5.540.930.
`
`FIELD OF INVENTION
`The invention relates to aqueous suspensions for treat
`ment of ophthalmic and otolaryngological in?ammations.
`
`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. Polymeric
`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 su?iciently stabilized or solu
`bilized by these methods for the above-mentioned applica
`tions.
`Topical steroids such as corticosteroids are commonly
`used for anti-in?ammatory therapy of the eye. especially for
`treating in?ammatory 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. super?cial punctate keratitis
`and iritis cyclitis. Steroids also are used to ameliorate
`in?ammation associated with corneal injury due to chemical
`or thermal burns. or penetration of foreign bodies. Such
`conditions may result from surgery. injury. allerg' 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
`complications. including posterior subcapsular cataract
`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 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 in?armnations 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. US. 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 e?‘ect.
`
`65
`
`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 of 8
`
`

`

`5.747.061
`
`20
`
`25
`
`35
`
`3
`water-insoluble drugs of mean particle sizes of §l5 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 in?ammatory 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 ?fteen 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 1:20zl.
`The steroid of component (A) preferably is loteprednol
`etabonate and is added to obtain a ?nal concentration in the
`suspension of O to about 2% by weight. more preferably
`about 0.01-1% 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 0.4-1.5% 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 1:01 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 isotonieity. 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 su?icient for
`effective antibacterial action. preferably about 0.0001 to
`0.025%. based on the weight of the suspension.
`Having brie?y summarized the invention. the invention
`will now be described in detail by reference to the following
`speci?cation and non-limiting examples. Unless otherwise
`speci?ed. all percentages are by weight.
`
`4
`DETAILED DESCRIPTION OF THE
`INVENTION
`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. ?uocinolone.
`?uorometholone. exednisolone. may be employed The sus
`pensions of component (A) of the invention have a particle
`size of about 01-30 pm. preferably about l-20 um. most
`preferably about 2-10 tun 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 cyclodextn'n 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 ophthahnic 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 and/or 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
`80. tyloxapol. TWEEN 80 (e.g.. polyoxyethylene sorbitan
`mono-oleate ester;ICI America Inc.. Wilmington. Del.).
`PLURONIC F-68 (from BASF. Ludwigshafen. Germany)
`and the POLOXAMER (e.g., poly(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. (1 an. 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 effects 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 su?i
`cient amounts to achieve isotonieity. 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 SO-centipoise.
`In a preferred aspect. stable aqueous suspensions of LE
`are provided by preparing aqueous suspensions of LB 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.
`
`45
`
`50
`
`55
`
`Page 3 of 8
`
`

`

`5 ,747,061
`
`5
`The suspensions of the invention also may include addi
`tional therapeutic drugs such as drugs for treating glaucoma.
`anti-in?ammatory 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-in?ammatory 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 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 considm'ed 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
`benzyl 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 pH 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-in?ammatory properties of their own.
`Thus. a solution of components (B). (C). (D) and. optionally.
`(E). at least partially relieves in?ammation when applied to
`in?amed ophthalmic or otolaryngological tissue. Thus. for
`example. when applied to the eye. in the absence of a
`
`6
`corticosteroid. a solution of components (B). (C) and (D)
`surprisingly produces at least a partial reduction of the
`in?ammation 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 1-37. 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 0.4-1.5% 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 0.034% by
`weight. more preferably between about ODS-0.5% by
`weight and most preferably between about ODS-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 speci?c 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.
`
`EXANIPLES l-37
`
`10
`
`20
`
`25
`
`30
`
`35
`
`Each of Examples l-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 ?ltration 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 CoulterR LS 130 instrument. An
`acceptable average particle size for ophthalmic suspensions
`is §15 pm. The results appear in Table 2.
`
`TABLE 1
`
`45
`
`50
`
`Example
`
`SAMPLE COLIPOSITION (7o wlw)
`
`Number LE Tween 80 Tylcxapol Poloxamcr-l88 HP’MCl PVA PVP dexu-an Osmolarity Agent EDTA‘ BKAs
`
`0.5 —
`
`0.2
`
`0.5
`
`0.5
`
`0.5 —
`
`0.5
`
`0.5
`
`0.
`
`0.4
`
`0.2
`
`-—
`
`0.4
`
`0.2
`
`—
`
`—
`
`_
`
`0.2
`
`_
`
`0.6
`
`l
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`a
`
`9
`
`l
`
`l
`
`l
`
`—
`
`—-
`
`0.6 — — ——
`
`——
`
`—
`
`—
`
`—
`
`——
`
`—
`
`-
`
`-
`
`—~
`
`— 0.2
`
`—— 10 mM P‘BS2
`
`— —
`
`0.2
`
`—-
`
`0.4
`
`— —
`
`— —
`
`— 0.2
`
`—— — 10 mM PBS
`
`-—
`
`—
`
`0.4 — —- — 100 mM PBS
`
`— —
`
`—-
`
`1.4 — -— 5 mM PBS
`
`— 0.001
`
`_ - 1
`
`_ _
`
`_ -
`
`_ — 1.4
`
`-
`
`_
`
`0.6
`
`—
`
`—
`
`— — 1.4 — —
`
`_ _
`
`Page 4 of 8
`
`

`

`7
`
`5,747,061
`
`TABLE l-continued
`
`8
`
`Example
`
`SAMPLE COMPOSITION (% w/wl
`
`Number LE Tween 80 Tyloxapol Po1oxamer-188 HPMC‘ PVA PVP dermal-l Osmolarity Agent ED'IIA4 BKA’
`
`10
`
`11
`
`12
`
`13
`14
`15
`
`16
`
`17
`
`18
`19
`
`20
`21
`
`22
`
`0.5
`
`0.5
`
`0.5
`
`_
`
`0.4
`
`0.6
`
`0.5 -
`0.5 —
`0.5
`0.4
`
`1
`
`—
`
`0.5 _
`
`05 _
`0.5
`0.4
`
`0.5 —
`0.5 -
`
`0.5
`
`0.5
`
`0.6
`
`0.6
`
`0.4
`
`_
`
`--
`
`0.3
`0.3
`-
`
`0.2
`
`0.6
`
`-
`-
`
`0.4
`0.3
`
`_
`
`-
`
`-
`
`-
`
`—
`
`—
`—
`—
`
`-—
`
`_
`
`0.6
`—
`
`—
`
`-
`
`_
`
`- 1
`
`- 0.9% saline’
`
`— 1
`
`- — 0.9% saline
`
`- 0.001
`
`— 0.001
`
`-— — 2
`
`-— 2.4% glycerol
`
`0.01
`
`0.01
`
`— - l5 — 2.4% glycerol
`— --
`0.6
`0.5
`2.4% glycerol
`_ 1.4 - - 2.4% glycerol
`
`0.01
`0.01
`0.015
`0.01
`- 0.001
`
`——
`
`— l
`
`— 2.4% glycerol
`
`--
`
`0.01
`
`- 1.4 _ _- 2.4% glycerol
`
`_ 0.01
`
`- 2.4% glycerol
`_ _ 2
`_ - - 1.6
`2.4% glycerol
`
`_ - _ 2.4 24% glycerol
`— - 1
`_ 24% glycerol
`
`0.01
`0.01
`
`0.01
`0.01
`
`0.004
`0.004
`
`0.01
`0.01
`
`- 1.4 _ - 2.4% glycerol
`
`— _
`
`_ 1.4 — _ 2.4% glycerol
`
`- 0.004
`
`23
`
`24
`25
`26
`27
`28
`
`29
`
`30
`31
`
`32
`
`33
`34
`35
`36
`37
`
`0.6
`0.5
`0.5 —
`0.5 —
`1
`-
`l
`-—
`
`1
`
`-
`
`0.5 -
`1
`-
`
`1
`
`—
`
`0.5 -
`1
`_
`0.5 -
`0.5 —
`0.5 -
`
`_
`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
`
`‘hydmxypmpylmethyl cellulose
`2phosphate bu?ered physiological saline
`3sodium chloride
`‘ethylene diamine ten'aaeetic acid
`5beuzalltonium chloride
`
`-
`—
`—
`—
`—
`
`-
`
`-
`-
`
`-
`
`—
`-
`-
`-
`-
`
`2.4% glycerol
`_ - _ 2
`_ - 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
`
`_ - 0.8 _ 2.4% glycerol
`
`_ - 15 — 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
`
`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
`0.015
`0.015
`
`0.01
`
`0.01
`0.01
`
`0.015
`
`0.015
`0.01
`0.01
`0.01
`0.015
`
`TABLE 2
`
`TABLE 2-continued
`
`35
`
`Example
`
`Particle Sizels) lg] andFraction of 'Ibtal Po?lation
`
`Example
`
`Particle S‘gs] "g1 and Fraction of Total Mlation
`
`Number
`
`Population A
`
`A96
`
`Population B
`
`13%
`
`40
`
`Number
`
`Population A
`
`A% Population B
`
`8%
`
`390644-2677
`112.7+/-13.27
`352644-1706
`111.444-1859
`23.52+1-20.58
`328344-2563
`459614-2698
`380541-2417
`659144-3566
`382844-1693
`388844-269
`355944-L469
`293244-232
`88.S2+/-—30.19
`3.652+1-2.692
`385141-2401
`
`86.62 53.6744-13.13
`100 -
`100 —
`100 -
`100 —
`48.74 94.06+1-40.57
`92.43 57.91+1-18.14
`93.14 623844-2038
`100 —
`17.52 96.28+l—38.13
`14.02 110144-5802
`5.62 828441-1308
`3.52 100.1+I-24,56
`100 -
`100 -
`100 -
`
`13.38
`-
`—
`_
`- 45
`51.26
`7.57
`6.86
`—
`82.48
`85.98
`94.38
`96.48
`-
`-
`-
`
`50
`
`32
`33
`34
`35
`36
`37
`
`3.789+l-l.609
`3.821+/—2.181
`3.B13+I—2.305
`338544-1506
`373741-2044
`396544-2229
`
`100 -
`46.77 107344-1474
`100 _
`78.44 25.164-1-L421
`100 _
`100 —
`
`_
`53.23
`-
`21.56
`_
`_
`
`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 SUSPENDABHII'Y OVER
`TIME
`
`l
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`
`2
`
`i;
`19
`20
`2;
`23
`24
`25
`26
`;
`29
`30
`31
`
`3.6
`
`- .457
`
`33%:252:
`“29,44,732
`398044-2566
`4 713i 762
`4_789+/_2‘823
`4.528+/-2.5s2
`5.261+1-2.990
`“GM-3913
`291844322;
`4:126+,_2:390
`11.15.1140 .91
`397641-2245
`
`1
`
`_
`
`-
`
`55 ‘ Samples containing particles with desirable size-distribu
`13229 159M415 7-71
`tions (average of 2-10 um) are tested for stability using
`100 _
`_
`accelerated stability tests as well as “real time” studies.
`100 -
`-
`Accelerated stability studles are performed by SllbJCCtlllg
`1% _
`_
`{116 samples to a
`force Of
`for two
`10o _
`__
`100 _
`_ 60 minutes. The suspendability of the settled material is tested
`100 —
`—
`by measuring the number of seconds of wrist shaking
`100 -
`_
`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
`100
`100 _
`_ 65 of settled residue. ten seconds is determined to be an
`100 -
`—
`acceptable amount of time to suspend the residue. The
`results are shown in Table 3.
`
`. .
`
`.
`
`.
`
`.
`
`Page 5 of 8
`
`

`

`9
`
`TABLE 3
`
`RESUSPENSION OF LE SUSPENSIONS WHICH HAVE
`UNDERGONE ACCEIERA'IED AND NATURAL1 SE'I'I'LING
`
`Suspension of naturally
`settled material1
`
`Example Accelerated Stability
`Number
`(time to tesuspend)2
`
`Months
`Initial Value (it inversions) Tested’
`
`15
`16
`17
`18
`l9
`20
`21
`22
`23
`2A
`25
`26
`27
`28
`E
`30
`31
`32
`33
`34
`35
`36
`37
`
`15
`5
`5
`5
`5
`—
`—
`—
`—
`—
`5
`5
`5
`5
`—
`5
`5
`-—
`—
`—
`—
`——
`—
`
`-
`_
`—
`—
`—-
`67
`46
`83
`37
`—
`27
`22
`35
`35
`49
`25
`43
`74
`136
`40
`l8
`48
`46
`
`10 (I)
`10 (I)
`10 (I)
`9
`9
`9
`9
`9
`9
`6 (I)
`8
`6 (I)
`6 (I)
`8 (I)
`7
`7
`7
`7
`3 (I)
`7
`7
`7
`8
`
`1Refers to settling, at room temperature, on an open shelf
`2Number 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 "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 5100 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
`
`5,747,061
`
`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 etfective (+)
`or ine?ective (—) according to U.S.P. requirements.
`
`UNIDOSE SUSPENSIONS WH'HOUT
`PRESERVATIVES
`
`15
`
`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
`
`25
`
`30
`
`35
`
`Example
`
`Staph.
`auteur
`
`R aerug.
`
`Candida
`albicaru
`
`Aspen
`niger
`
`E 0011'
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`—
`
`—
`
`—
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`—
`
`—
`
`-
`
`+
`
`—
`
`+
`
`+
`
`+
`
`+
`
`+
`
`—
`
`—
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`ND
`
`ND
`
`ND
`
`ND
`
`+
`
`+
`
`ND
`
`+
`
`+
`
`+
`
`40
`
`ND: denotes not done; (+) denotes challenge withstood; (—) denotes unac
`eeptable microbe growth
`The test was performed according to U.S.P. speci?cations.
`
`TABLE 5
`
`COMPOSITIONS OF EXEMPLARY LE FORMULATIONS FOR UNIDOSE APPLICATION
`
`Ex.No. LE Tween 80 'Iyloxapol Poloxama-l88 PVA PVP dext'rin glycerol Puli?edWater
`
`—
`
`—
`
`— l .4 — 2 .4
`
`Remainder
`
`0.6
`
`0.4
`
`0.6
`0.6
`0.6
`
`l
`05
`0.5
`0.5
`05
`0.5
`0.5
`0.5
`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
`
`0.6
`
`— 2
`
`— 2.4
`
`Remainder
`
`—
`
`—
`
`—
`
`—
`
`—
`
`-—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`——
`
`——
`
`—
`
`—
`
`-
`
`—
`
`1.6
`
`— — 2.4
`
`— 1
`
`——
`
`2.4
`
`2.4
`
`2.4
`
`Remainder
`
`Remainder
`
`Remainder
`
`— — 2.4
`
`Remainder
`
`4
`
`0.8 — 2.4
`
`Remainder
`
`——
`
`2
`
`——
`
`-—
`
`2.4
`
`2.4
`
`2.4
`
`Remainder
`
`Remainder
`
`— 0.6 — 2.4
`
`Remainder
`
`— 0.6
`
`— 0.6
`
`0.5
`
`0.5
`
`2.4
`
`2.4
`
`Remainder
`
`Remainder
`
`— 0.6 — 2.4
`
`Remainder
`
`— 0.4 — 2.4
`
`Remainder
`
`——
`
`——
`
`0.6
`
`—~—
`
`2.4
`
`Remainder
`
`0.6 — 2.4
`
`Remainder
`
`— 0.6 — 2.4
`
`Remainder
`
`— 0.8 — 2.4
`
`Remainder
`
`- 0.4 — 2.4
`
`Remainder
`
`Page 6 of 8
`
`

`

`5,747,061
`
`12
`
`11
`
`TABLE S-continued
`
`COMPOSITIONS OF EXEMPLARY IE FORMULATIONS FOR UNIDOSE APPLICATION
`
`Ex. No. LE Tween 80 Tyloxapol Poloxamer-188 PVA PVP dextrin glycerol Puri?ed Water
`
`20
`21
`22
`
`0.5
`0.5
`0.5
`
`——
`
`0.4
`0.3
`0.1
`
`-—
`—
`
`— 0.4
`-—
`0.6
`0.4
`
`——
`0.3
`0.3
`
`2.4
`2.4
`2.4
`
`Remainder
`Remainder
`Remainder
`
`EXAMPLE 38
`
`25
`
`35
`
`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
`(“ 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 signi?cantly more etfective than the vehicle itself.
`which was used as a placebo. with regard to the reduction of
`signs and symptoms of ocular in?ammation.
`30
`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 e?’ect. The GPC patients
`were enrolled in the study after the appearance of signs or
`symptoms. A signi?cant 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 bene?t 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. Thi