United States Patent
`(12)
`(10) Patent N0.:
`US 6,770,675 B2
`
`Reed et al.
`(45) Date of Patent:
`Aug. 3, 2004
`
`USOO6770675B2
`
`(54) COMPOSITIONS AND METHODS FOR
`REDUCING OCULAR HYPERTENSION
`
`(75)
`
`Inventors: Kenneth Warren Reed, Lawrenceville,
`GA (US); Shau Fong Yen, Atlanta, GA
`,
`,
`(US); Mary Sou, Alpharetta, GA (US);
`Regma ann Pea°0°k>A1Pharena> GA
`(US)
`
`_
`.
`(73) Assignee: Novar‘tls AG, Bern (CH)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 252 days.
`
`5,057,621 A * 10/1991 Cooper et al.
`................ 560/53
`
`5,106,869 A
`4/1992 Ueno et al.
`.....
`.. 514/530
`.....
`.. 514/530
`5,151,444 A
`9/1992 Ueno et al.
`
`11/1992 Ueno 6t a1~ ~~~~~
`-- 514/573
`
`5/1993 Ueno ............
`514/530
`.....
`.. 514/530
`5/1993 Ueno et al.
`
`.....
`.. 560/121
`/1993 Ueno et al.
`6
`
`........
`.. 514/530
`8/1993 Ueno et al.
`
`......... 514/573
`8/1993 Woodward et al.
`3/1994 Stjernschantz et al.
`..... 514/530
`6/1995 Stjernschantz et al.
`..... 514/530
`
`.....
`.. 514/530
`8/1995 Chan et al.
`9/1996 Desai et al.
`................ 424/427
`11/1996 Stjernschantz et al.
`..... 514/365
`
`571669178 A
`5,208,256 A
`5,212,200 A
`,
`,
`5 221 763 A
`5,236,907 A
`5,238,961 A
`5,296,504 A
`5,422,368 A
`5,446,041 A
`5,558,876 A
`5,578,618 A
`
`FOREIGN PATENT DOCUMENTS
`
`(21) April. No: 09/812,162
`.
`.
`(22) Filed.
`(65)
`
`Mar. 19, 2001
`Prior Publication Data
`
`EP
`JP
`W0
`W0
`
`0 458 587 A1
`07316060
`W0 9213836
`W0 9530420
`
`5/1991
`2/1996
`2/1992
`5/1995
`
`US 2002/0002185 A1 Jan. 3, 2002
`
`* cited by examiner
`
`(63)
`(60)
`
`Related US. Application Data
`Continuation—in—part of application No. 09/042,817, filed on
`Mar. 17, 1998, now abandoned.
`Provisional application No. 60/093,065, filed on Mar. 17,
`1997'
`Int. Cl.7 .............................................. A61K 31/215
`(51)
`(52) US. Cl.
`....................... 514/530; 514/573; 514/912;
`514/913
`(58) Field of Search ................................. 514/530, 575,
`514/912, 913
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`Primary Examiner—Zohreh Fay
`(74) Attorney, Agent, or Flrm—DaVid E’ Wildman
`(57)
`ABSTRACT
`including
`An improved ophthalmic composition,
`docosanoid active agents, which is especially useful
`in
`lowering intraoeular pressure associated with glaucoma
`Improvements in IOP reduction efficacy, preservative effi-
`cacy and reduced additive concentrations are achieved by
`utilizing the disclosed compositions which include a
`docosanoid active agent (e.g., isopropyl unoprostone),
`in
`conjunction With selected non-ionic surfactants,
`preservatives, and non-ionic tonicity adjusting agents.
`
`5,001,153 A
`
`3/1991 Ueno et al.
`
`................. 514/530
`
`9 Claims, 1 Drawing Sheet
`
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`

`

`US. Patent
`
`Aug. 3, 2004
`
`US 6,770,675 B2
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`

`

`US 6,770,675 B2
`
`1
`COMPOSITIONS AND METHODS FOR
`REDUCING OCULAR HYPERTENSION
`
`This application is a continuation-in-part of US. patent
`application Ser. No. 09/042,817,
`filed Mar. 17, 1998,
`abandoned, which claimed priority under 35 U.S.C. §119(e)
`from US. Provisional Patent application Serial No. 60/093,
`065, abandoned, which was converted from US. patent
`application Ser. No. 08/819,221, filed Mar. 17, 1997, aban-
`doned.
`
`FIELD OF THE INVENTION
`
`The invention relates broadly to ophthalmic technology.
`More specifically, this invention relates to the therapeutic
`treatment of the eye to reduce elevated intraocular pressure,
`for example,
`the elevated intraocular pressure which is
`associated with glaucoma.
`BACKGROUND OF THE INVENTION
`
`US. Pat. No. 5,208,256 teaches a method of treating
`ocular hyertension by ocularly administering a combination
`of a docosanoid compound, e.g., [1R-[1a(Z),2[3,3(x,5(x]]—7-
`[3,5-Dihydroxy-2-(3-oxodecyl)cyclopentenyl]-5-heptenoic
`acid or a salt or ester thereof and a polyoxyethylenesorbitan
`unsaturated higher aliphatic acid monoester. Preferred
`examples of the latter includes myristoleic acid, palmitoleic
`acid, oleic acid, gadoleic acid and linoleic acid. Polyoxy-
`ethylene (20) sorbitan monooleate is also known as Polysor-
`bate 80 and sold, inter alia, under the names SORLATE,
`CRILLET, TWEEN 80, MONITAN and OLOTHORB.
`CREMOPHOR has been used as a surfactant in eye drops
`(See Japanese Patent 07316060, filed on Dec. 16, 1994).
`CREMOPHOR is an ethoxylated, hydrogenated castor oil,
`which is also referred to as a polyoxyethylene hardened
`castor oil. However,
`the use of CREMOPHOR with
`docosanoids in an ophthamic delivery system has not been
`disclosed or suggested.
`While docosanoids are useful for reducing intraocular
`pressure, there is a need to improve the efficacy of medica-
`ments containing them. In addition,
`there is a need for
`improvement in the preservative effectiveness of ophthalmic
`docosanoid compositions which include surfactants, while
`maintaining good efficacy and good ocular tolerance.
`Furthermore, improvements in the shelf life of ophthalmic
`docosanoid compositions are desirable. Also, it is always
`desirable to reduce manufacturing difficulties. Thus, there is
`a need for a docosanoid-containing ophthalmic composition
`that can be manufactured with a minimum of complexity
`and which exhibits a balance of efficacy, preservative
`effectiveness, ocular tolerance, and a long shelf life.
`SUMMARY OF THE INVENTION
`
`An object of the invention is to improve the efficacy of
`docosanoid-containing ophthalmic compositions.
`Another object of the invention is to improve the preser-
`vative effectiveness of docosanoid-containing ophthalmic
`compositions.
`Still another object of the invention is to improve shelf life
`of docosanoid-containing ophthalmic compositions.
`Yet another object of the invention is to reduce the
`complexity of manufacturing a docosanoid-containing oph-
`thalmic composition.
`A further object of the invention is to produce a
`docosanoid-containing ophthalmic composition with a
`desirable balance of efficacy, preservative effectiveness,
`ocular tolerance, and shelf life.
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`These and other objects and advantages of the invention
`are achieved with the various embodiments of the present
`docosanoid-containing ophthalmic compositions, methods
`of use and methods of manufacture. One embodiment of the
`
`invention is an ophthalmic composition which includes a
`docosanoid, a non-ionic surfactant (e.g. a CREMOPHOR)
`and a preservative (e.g. benzalkonium chloride). Another
`embodiment is an ophthalmic composition which includes a
`docosanoid, a surfactant, a non-ionic tonicity adjusting agent
`(e.g. mannitol) and a preservative. Still another embodiment
`is an ophthalmic composition which includes a docosanoid,
`one or more surfactants, a strong preservative (e.g. BAK)
`and a preservative enhancer (e.g., EDTA). Yet another
`embodiment of the invention relates to adding a buffer to
`improve product shelf life and reduce production complex-
`1ty.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 is a graph showing the time-course changes in the
`intraocular pressure of a rabbit eye, which received instil-
`lation of a 0.12%, 0.18% or 0.24% isaprapyl unaprostone
`ophthalmic formulation.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The various embodiments of the invention offer a number
`
`of improvements in docosanoid compositions which are
`useful,
`inter alia, for reducing intraocular pressure. The
`compositions are especially useful
`in treating elevated
`intraocular pressure associated with glaucoma. Accordingly,
`all of the components of the compositions are preferably
`ophthalmically acceptable, at the concentrations of use and
`under the conditions in which they are applied. An “oph-
`thalmically acceptable” component, as used herein, refers to
`a component which will not cause any significant ocular
`damage or ocular discomfort at the intended concentration
`and over the time of intended use.
`
`The invention embraces several embodiments, some of
`which are outlined below to improve the reader’s under-
`standing. One group of embodiments of the invention are
`ophthalmic compositions which are useful
`in reducing
`intraocular pressure, especially intraocular pressure which is
`associated with glaucoma. The ophthalmic compositions
`include an amount of a docosanoid active agent selected
`from the group of docosanoids, analogs thereof, derivatives
`thereof, metabolites thereof, salts thereof, or combinations
`thereof, which are effective to treat elevated intraocular
`pressures. Another group of embodiments are methods of
`reducing intraocular pressure and treating glaucoma by
`topical application of the aforementioned ophthalmic com-
`positions. However, a person having ordinary skill in the art
`may vary some of the elements of the embodiments without
`departing from the spirit and scope of the invention.
`One embodiment of the invention is a composition which
`has a reduced concentration of strong preservative, and
`correspondingly, generates less ocular
`irritation.
`Unexpectedly,
`it has been found that the use of certain
`non-ionic tonicity adjusting agents enhances the preserva-
`tive effectiveness of strong preservatives in compositions
`containing docosanoid active agents. This allows for a
`reduced concentration of strong preservatives in the com-
`position. In addition, chelating agents may be added to
`further boost preservative efficacy and reduce the required
`concentration of strong preservative. Thus, one embodiment
`of the invention is a composition which includes (1) a
`docosanoid active agent (e.g. isopropyl unoprostone), (2) a
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`US 6,770,675 B2
`
`3
`
`strong preservative (e.g., benzalkonium chloride), and (3) a
`non-ionic tonicity enhancing agent (e.g., a simple sugar such
`as mannitol) effective in increasing the preservative efficacy
`relative to a composition including solely a strong preser-
`vative.
`
`In particular, the complete eradication of Psuedomonas
`Aeriginosa is desired. While benzalkonium chloride (BAK)
`kills nearly all Psuedomonas, there may remain some which
`are resistant to BAK. Over time, the BAK-resistant Psue-
`domonas may propagate to a concentration which is unac-
`ceptable. Thus,
`it
`is preferable to include a preservative
`efficacy enhancer to eliminate BAK-resistant Psuedomonas.
`It is preferable that the preservative efficacy enhancer or
`second preservative be a well tolerated component which
`acts via a mechanism which differs from BAK. The strong
`preservative (e.g., BAK) will handle the bulk of the biobur-
`den. The use of the second well tolerated preservative or
`enhancer insures complete kill of contaminating microbes
`and yet minimizes ophthalmic irritation as compared to
`using abnormally high concentrations of BAK.
`A preferred class of preservative efficacy enhancers are
`chelating agents, such as calcium chelating agents. A pre-
`ferred calcium chelating agent is ethylene diamine tetraac-
`etate (EDTA). EDTA has been shown to assist
`in the
`eradication of BAK-resistant Psuedomonas without substan-
`
`tially altering ophthalmic compatibility or docosanoid effi-
`cacy. In addition, EDTA offers the advantage of simulta-
`neously acting as a buffer.
`the composition
`Thus,
`in a preferred embodiment,
`includes (1) a docosanoid active agent,
`(2) a strong
`preservative, and (3) a non-ionic tonicity enhancing agent,
`(4) a chelating agent (e.g., edetate sodium). These compo-
`sitions are especially advantageous in that preservative
`effectiveness is improved relative to a composition contain-
`ing a strong preservative alone. This allows for a reduction
`in the required concentration of the strong preservative, and
`accordingly less ophthalmic irritation.
`Another embodiment of the invention is a composition
`containing a docosanoid active agent which has an advan-
`tageously reduced total surfactant concentration. It is gen-
`erally desirable to minimize the concentration additives to
`an ophthalmic formulation in order to minimize potential
`ocular irritation associated with the additives. However, in
`order to solubilize docosanoid active agents, a surfactant is
`typically required. It has been unexpectedly discovered that
`the combination of two or more non-ionic surfactants, as
`opposed to a single surfactant, can reduce the total concen-
`tration of surfactant required to achieve a given level of
`solubility of the docosanoid active agent. Thus, this embodi-
`ment of the invention relates to a composition which
`includes (1) a docosanoid active agent, (2) a first non-ionic
`surfactant (e.g., Polysorbate 80), (3) a second non-ionic
`surfactant (e.g., a BRIJ surfactant) and (4) an ophthalmically
`acceptable carrier. This embodiment of the invention offers
`advantages in reduced ocular irritation and reduced raw
`material (surfactant) requirements.
`Yet another embodiment of the invention relates to the
`
`difficulties in achieving solubility of docosanoid active
`agents. In order to solubilize the active agent, a non-ionic
`surfactant, preferably Polysorbate 80, is added to the for-
`mulation. Thus, increasing the docosanoid concentration to
`the preferred ranges described herein requires a correspond-
`ing increase in the surfactant concentration,
`in order to
`maintain the docosanoid in solution. However, the Polysor-
`bate 80 surfactant deactivates the commonly used oph-
`thalmic preservative benzalkonium chloride (BAC). Thus,
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`an increase in surfactant reduces the preservative effective-
`ness. In sum, an increase in therapeutic efficacy which is
`achieved by increasing active agent concentration results in
`the need for an increase in Polysorbate 80 concentration and
`therefore a decrease in preservative effectiveness.
`Accordingly, improvements in both preservative effective-
`ness and efficacy of the cited formulations are difficult to
`achieve.
`
`However, it has been unexpectedly found that the use of
`non-ionic tonicity adjusting agents appreciably improves the
`action of the preservative in the presence of surfactant. Thus,
`in order to minimize the aforementioned preservative deac-
`tivation problem, a preferred composition includes (1) a
`docosanoid active agent, (2) a strong preservative (e.g.,
`BAK), (3) a non-ionic surfactant which increases solubility
`of the docosanoid active agent but decreases the preservative
`effectiveness of the strong preservative (e.g., Polysorbate
`80), and (4) a preservative enhancer which increases the
`effectiveness of the strong preservative (e.g., mannitol or
`EDTA), and (5) an ophthalmically acceptable carrier. Thus,
`the efficacy and preservative effectiveness may be simulta-
`neously improved in the present formulations, while main-
`taining a solution form, by optimizing the concentrations of
`active agent, surfactant, non-ionic tonicity adjusting agent,
`and preservative.
`Some prior art anti-glaucoma pharmaceutical formula-
`tions have used salts such as sodium chloride to adjust
`tonicity to ophthalmically acceptable levels (e.g., about 0.8
`to about 1.0 mg/ml NaCl equivalents). However,
`ionic
`tonicity adjusting agents have been found by the present
`inventors to reduce the solubility of the docosanoid active
`agents. Thus, another advantage of the use of non-ionic
`tonicity adjusting agents (e.g., mannitol) in the present
`invention is the increased solubility of salts of the active
`agent.
`In accordance with several preferred inventive embodi-
`ments disclosed herein, a preferred composition includes:
`(a) about 0.06 to about 0.24 weight percent isopropyl
`unoprostone;
`
`(b) about 0.3 to about 2 weight percent of two non-ionic
`surfactant selected from the group consisting of CRE-
`MOPHOR RH, BRIJ 97, BRIJ 98, CREMOPHOR EL,
`Polysorbate 80 and mixtures thereof;
`(c) about 0.01 to about 0.20 weight percent benzalkonium
`chloride;
`
`(d) about 0.01 to about 0.1 weight percent EDTA;
`(e) about 0.10 to about 10.0 weight percent mannitol;
`(f) about 0.01 to about 0.05 molar of an ophthalmically
`acceptable buffer;
`(g) an ophthalmically acceptable carrier;
`in which the pH is adjusted to about 4.5 to about 8.0.
`The active agents useful in accordance with the invention
`may be selected from the group consisting of docosanoids,
`metabolites thereof, analogs thereof, derivatives thereof,
`salts thereof, docosanoid prodrugs, and mixtures thereof,
`referred to herein as “docosanoid active agent” or merely
`“active agent”. Thus, the active agent is not limited by the
`specific form of the active, i.e., whether in free acid or salt
`form. Rather, the docosanoid active agent is active in that the
`agent causes a reduction of intraocular pressure (IOP) when
`applied to the ocular environment of a patient in need of
`reduction of intraocular pressure.
`A docosanoid, as used herein, refers to a group of com-
`pounds related to docosahexaneoic acid. Docosanoids are
`found in human and animal tissues and organs and may be
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`US 6,770,675 B2
`
`5
`synthetically produced. The preferred docosanoids are those
`which are useful
`in therapeutic ophthalmic applications,
`especially those which reduce intraocular pressure.
`A group of docosanoids which have been found to be
`useful in decreasing intraocular pressure are disclosed in
`US. Pat. Nos. 4,599,353; 5,296,504; 5,422,368; and 5,578,
`618. These patents are incorporated herein by reference for
`the teaching and examples of docosanoid active agents
`which are useful in reducing intraocular pressure.
`A particularly preferred group of active agents are
`described more fully in US. Pat. Nos. 5,106,869; 5,221,763
`5,208,256; 5,001,153; 5,151,444; 5,166,178 and 5,212,200,
`each of which is incorporated herein by reference for the
`disclosure of compounds useful in the present invention.
`Docosanoids of the present invention may be docosanoid
`salts, or those docosanoids with an esterified carboxyl group.
`Suitable docosanoid salts are ophthalmically acceptable
`salts, including without limitation thereto, salts of alkali
`metals such as sodium or potassium; salts of an alkaline
`earth metal such as calcium or magnesium; salts of
`ammonia, methylamine, dimethylamine, cyclopentylamine,
`benzylamine, piperidine, monoethanolamine,
`diethanolamine, monomethylmonoethanolamine,
`tromethamine, lysine and tetralkylammonia; and the like and
`mixtures thereof Suitable docosanoid esters are ophthalmi-
`cally acceptable esters, including without limitation thereto,
`methyl, ethyl, propyl, butyl, isopropyl, t-butyl, 2-ethylhexyl,
`straight or branched-chain alkyl esters which may contain an
`unsaturated bond. Suitable esters include an ester having an
`alicyclic group such as a cyclopropyl, cyclopentyl, olr
`cyclohexyl group; an ester containing an aromatic group
`such as a benzyl or phenyl group (wherein the aromatic
`group may contain one or more substituents); a hydroxy-
`alkyl or alkoxyalkyl ester such as hydroxyethyl,
`hydroxyisopropyl, polyhydroxyisopropyl, methoxyethyl,
`ethaoxyethyl or methoxyisopropyl groups; an alkysilyl ester
`(e.g., a trimethylsilyl or triethylsilyl ester); and a tetrahy-
`dropyranyl ester.
`Most preferred are docosanoids as disclosed in US. Pat.
`No. 5,208,256, which is incorporated herein by reference for
`its disclosure of docosanoid compounds. A particularly
`preferred docosanoid is isopropyl unoprostone. The struc-
`ture of isopropyl unoprostone is given below and a method
`of preparation is outlined in US. Pat. No. 5,212,200, which
`is incorporated by reference.
`
` H6
`
`The preferred docosanoid concentration is an amount which
`will substantially reduce intraocular pressure (IOP) of an eye
`which has elevated IOP, especially in a patient suffering
`from glaucoma. Clearly the required concentration depends
`on a number of factors,
`including the efficacy of the
`docosanoid in the presence of the other components, the
`volumetric amount of medicament applied, and the fre-
`quency and duration of application.
`It has been determined that concentrations of active
`
`agents within the range of about 0.001 to about 0.30 weight
`percent are more efficacious for reducing intraocular pres-
`sure than concentrations above or below this range.
`In
`particular, a concentration of about 0.06 to about 0.24 weight
`
`6
`percent active agent is preferred, while a concentration of
`about 0.10 to about 0.20 is more preferred. However, the
`preferred concentration in any specific application depends
`on a number of factors, such as the concentrations and
`chemical nature of other ingredients as well as the delivery
`method and conditions. Moreover, quite unexpectedly, fur-
`ther increases in active agent concentrations outside these
`preferred ranges may actually cause less of the desired
`decrease in intraocular pressure than the concentrations in
`the preferred ranges.
`A surfactant, as used herein, refers to a surface active
`agent which improves the solubility of a substance, e.g. an
`active or drug, in a solvent. A non-ionic surfactant, as used
`herein, refers to a surfactant which possesses no easily
`ionizable groups.
`US. Pat. No. 5,208,256 discloses the use of Polysorbate
`80 as a surfactant for docosanoid-containing ophthalmic
`compositions. Polysorbate 80 improves the solubility of
`isopropyl unoprostone, so that a higher concentration of
`isopropyl unoprostone can be used in a solution form.
`However, it has been discovered that while increasing the
`Polysorbate 80 concentration allows for increases in the
`docosanoid concentration in solution, the preservative effec-
`tiveness decreases with increasing Polysorbate 80 concen-
`trations. Moreover, it is desired to increase both the efficacy
`(e.g., by increasing the docosanoid concentration) and pre-
`servative effectiveness of the known docosanoid-containing
`ophthalmic formulations. Thus, it has been determined that
`use of more Polysorbate 80 has the disadvantage of decreas-
`ing preservative effectiveness, while less Polysorbate 80 has
`the disadvantage of reducing prostaglanin in solution and
`thereby reducing efficacy.
`One embodiment of the present invention offers a solution
`to these problems by using a combination of two or more
`non-ionic surfactants. Certain combinations of non-ionic
`surfactants have been found to increase docosanoid active
`
`agent solubility without reducing preservative effectiveness
`as much as Polysorbate 80 alone in the same concentration.
`A preferred group of non-ionic surfactants are those
`which exhibit better ophthalmic tolerance than Polysorbate
`80 alone and/or which do not reduce preservative effective-
`ness or reduce preservative effectiveness less than Polysor-
`bate 80 alone in the same concentration.
`
`The first and second non-ionic surfactants may be selected
`from a group of non-ionic surfactants including, without
`limitation thereto, polyoxyethylene sorbitan fatty acid esters
`such as Polysorbates 20, 60 and 80; polyoxyethylene alkyl
`ethers such as Brij’s (e.g., BRIJ 97 or BRIJ 98 from ICI
`Surfactants, Wilmington, Del.), Cremophors (such as Cre-
`mophor RH or Cremophor EL), Volpo (e.g., VOLPO 10 and
`VOLPO 20 from Croda, Inc., Parsippany, N.J.) and equiva-
`lents thereof. Apreferred group includes polyoxyethylene 20
`oleate (e.g., Polysorbate 80), Polyoxyl 10 oleyl ethers (e.g.,
`Brij 97) and Polyoxyl 20 oleyl ethers (e.g., Brij 98).
`A particularly preferred combination of surfactants is the
`combinations of a polyoxyethylene sorbitan fatty acid ester
`(especially Polysorbate 80) with a polyoxyethylene alkyl
`ethers (especially BRIJ 97 or BRIJ 98).
`Thus, use of at least two surfactants together provides an
`unexpected synergistic result in that the total concentration
`of surfactant required to achieve a desired docosanoid active
`agent solubility is less that the concentration required for an
`individual surfactant. In addition, certain combinations of
`surfactants actually improve the preservative effectiveness.
`Specifically, the combination of Polysorbate 80 with a BRIJ
`surfactant improves BAC preservative effectiveness relative
`to the same concentration of Polysorbate 80 alone.
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`Furthermore, this combination of surfactants improves the
`emulsion stability of the formulation.
`The total concentration of surfactant used depends, in
`large part, on the solubilizing character of the particular
`surfactant or surfactants and the concentration and chemical
`
`nature of the particular docosanoid active agent which the
`surfactant is intended to solubilize. In general,
`the total
`surfactant concentration may range from about 0.1 to 5
`weight percent. Apreferred surfactant concentration is about
`0.3 to 2.0 weight percent. More preferably, the surfactant
`concentration is about 0.5 to 1.5 weight percent.
`A “preservative”, as used herein, refers to an additive
`which inhibits both microbial growth and kills microorgan-
`isms which inadvertently contaminate the ophthalmic solu-
`tion upon exposure to the surroundings. The preservative
`may be selected from a variety of well known preservatives,
`including hydrophobic or non-charged preservatives,
`anionic preservatives, and cationic preservatives. A “preser-
`vative enhancing agent”, as used herein, refers to an additive
`which increases the preservative effectiveness of a
`preservative, or the preservative effectiveness of a preserved
`formulation, but which would not typically be used solely to
`preserve an ophthalmic formulation.
`Cationic preservatives include, without limitation thereto,
`polymyxin B sulfate, quaternary ammonium compounds,
`poly(quaternary
`ammonium)
`compounds,
`p-hydroxybenzoic acid esters, certain phenols and substi-
`tuted alcohols, benzalkonium chloride, benzoxonium
`chloride, cetylpridinium chloride, benzethonium chloride,
`cetyltrimethyl ammonium bromide, chlorhexidine, poly
`(hexamethylene biguanide), and mixtures thereof. Poly
`(quaternary ammonium) compounds include BUSAN 77,
`ONAMER M, MIRAPOL A15,
`IONENES A,
`POLYQUATERNIUM 11, POLYQUATERNIUM 7,
`BRADOSOL, AND POLYQUAT D-17-1742. A preferred
`preservative for the ophthalmic field is benzalkonium chlo-
`ride.
`
`Anionic preservatives include, without limitation thereto,
`1-octane sulfonic acid (monosodium salt); 9-octadecenoic
`acid (sulfonated); ciprofloxacin; dodecyl diphenyloxide-
`disulfonic acid; ammonium, potassium, or sodium salts of
`dodecyl benzene sulfonic acid; sodium salts of fatty acids or
`tall oil; naphthalene sulfonic acid; sodium salts of sulfonated
`oleic acid; organic mercurials such as thimerosal (sodium
`ethylmercurithiosalicylate);
`thimerfonate sodium (sodium
`p-ethylmercurithiophenylsulfonate).
`Hydrophobic or non-ionic preservatives include, without
`limitation thereto, 2,3-dichloro-1,4-naphthoquinone;
`3-methyl-4-chlorophenol
`(PREVENTOL CMK);
`8-hydroxyquinoline and derivatives thereof; benzyl alcohol;
`bis(hydroxyphenyl) alkanes; bisphenols; chlorobutanol;
`chloroxylenol; dichlorophen[2,2'-methylene-bis(4-
`chlorophenol)]
`(PANACIDE); ortho-alkyl derivatives of
`para-bromophenol and para-chlorophenol; oxyquinoline;
`para-alkyl derivatives of ortho-chlorophenol and ortho-
`bromophenol; pentachlorophenyl laurate (MYSTOX LPL);
`phenolic derivatives such as 2-phenylphenol, 2-benzyl-4-
`chlorophenol, 2-cyclopentyl-4-chlorophenol, 4-t-
`amylphenol, 4-t-butylphenol, and 4- and 6-chloro-2-
`pentylphenol; phenoxy fatty acid polyester (PREVENTOL
`B2); phenoxyethanol; and phenylethyl alcohol.
`In one embodiment,
`the preservative is present in the
`solution in an amount sufficient to kill microbes which may
`inadvertently enter the dispensing container over the period
`of use. The desirable concentration will depend on a number
`of factors, including the strength of the preservative, the
`conditions of dispenser use, and the length of time the
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`dispenser and solution will be in service. Generally, the
`strong preservative may be present in a concentration from
`about 0.00005 to about 0.2 weight percent, more preferably
`the concentration is about 0.005 to about 0.2 weight percent,
`and even more preferably, the strong preservative concen-
`tration is about 0.01 to about 0.015 weight percent.
`An ophthalmically acceptable agent which enhances the
`effectiveness of the preservative may be advantageously
`added to the formulation. Examples of preservative enhanc-
`ing agents useful in accordance with the present invention
`include, without limitation thereto, chelating agents such as
`ethylene diamine tetraacetic acid (EDTA), derivatives
`thereof, salts thereof and mixtures thereof.
`The preservative enhancing agent is intended to overcome
`any remaining microbial burden which the strong preserva-
`tive did not. For example, while BAK kills nearly all
`Psuedomonas, there may remain some resistant strain or
`strains, which may propagate over time. Thus, it is desirable
`to add a preservative enhancing agent, such as EDTA, to kill
`the remaining BAC-resistant Psuedomonas. It is believed
`that EDTA destroys the Psuedomonas by chelation with
`Ca+ions. Accordingly, a preferred class of weak preserva-
`tives are chelating agents, especially calcium chelating
`agents.
`The use of EDTA is particularly preferred in part because
`EDTA prevents the growth of BAK-resistant Psuedomonas.
`However, EDTA has also been found to have advantages in
`addition to its preservative enhancing function. EDTA can
`be used to buffer the formulation to achieve the desired pH.
`Further, EDTA may provide a stabilization function for the
`docosanoid active agent, thereby inhibiting degradation and
`increasing shelf life.
`The concentration of preservative enhancing agent which
`is preferred will depend on a number of factors, such as the
`efficacy of the strong preservative at the chosen concentra-
`tion and the preservative enhancing effectiveness of the
`preservative enhancing agent. The concentration of preser-
`vative enhancer should be high enough to deactivate
`amounts of Psuedomonas which are dangerous to the
`patient, but the concentration should be low enough to avoid
`any substantial ocular discomfort.
`If a chelating agent such as EDTA is used, a concentration
`of about 0.01 to about 0.1 weight percent is preferred. More
`preferably, the concentration is about 0.03% to about 0.07%.
`Another additive which was determined, quite
`unexpectedly, to enhance the preservative effectiveness of
`formulations containing docosanoid active agents is manni-
`tol. It is known to use mannitol to adjust tonicity of an
`solution to improve ophthalmic compatibility, e.g., by
`adjusting to nearly an isotonic state. However, the preser-
`vative enhancing effect was unexpectedly found in formu-
`lations containing docosanoid active agents. In general, it is
`believed that other non-ionic tonicity adjusting agents, espe-
`cially other simple sugars, may perform the same function.
`Thus, use of one or more preservative enhancers can
`provide at least two advantages. First, the amount of strong
`preservative, which may cause irritation to some patients,
`required for a given level of preservation is reduced. Second,
`the preservative enhancers may be chosen so that they serve
`functions in addition to improving preservation of the for-
`mulation.
`
`An additional weaker preservative may be added to the
`container. The weaker preservative, at the concentrations of
`use, should not be sufficiently potent to cause irritation of the
`target tissue which the solution will contact. Examples of
`weaker preservatives useful in accordance with the present
`invention include, without
`limitation thereto, peroxides,
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`9
`such as hydrogen peroxide;. peroxide-generating species,
`such as an alkali perborate or a combination of sodium
`perborate, boric acid, and sodium borate; urea peroxide;
`sodium peroxide carbonate; sodium persulfate; sodium per-
`phosphate; and poly(vinyl pyrrolidone) hydrogen peroxide.
`Apreferred weak preservative is a perborate such as sodium
`perborate.
`If a peroxide or peroxide-generating species is used, the
`peroxide concentration should be less than about 0.1 weight
`percent, preferably about 0.004 to 0.05 weight percent, more
`preferably about 0.001 to 0.02 weight percent.
`The addition of a buffer offers at least two advantages.
`First, the buffer helps maintain the pH of the formulation at
`an ophthalmically acceptable level for instillation directly
`into the eye. Second, incorporating a buffer early in the
`manufacturing process reduces the complexity of control-
`lin