(12) United States Patent
`US 6,995,186 B2
`(10) Patent No.:
`Castillo et al.
`
`(45) Date of Patent: Feb. 7, 2006
`
`USOO6995186B2
`
`(54) OLOPATADINE FORMULATIONS FOR
`TOPICAL ADMINISTRATION
`
`(75)
`
`Inventors: Ernesto J. Castillo, Arlington, TX
`(US); Wesley Wehsin Han, Arlington,
`TX (US); Huixiang Zhang, Fort Worth,
`TX (US); Haresh G. Bhagat, Fort
`Worth, TX (US); Onkar N. Singh,
`Arlington, TX (US); Joseph Paul
`Bullock, Fort Worth, TX (US); Suresh
`C. Dixit, Fort Worth, TX (US)
`
`(73) Assignee: Alcon, Inc., Hunenberg (CH)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 511 days.
`
`(21) Appl. No.: 10/175,106
`
`(22)
`
`Filed:
`
`Jun. 19, 2002
`
`(65)
`
`Prior Publication Data
`US 2003/0055102 A1 Mar. 20, 2003
`
`(60)
`
`(51)
`
`Related US. Application Data
`Provisional application No. 60/301,315, filed on Jun. 27,
`2001.
`
`Int. Cl.
`A61K 31/335
`
`(2006.01)
`
`........................................ 514/450; 514/912
`(52) US. Cl.
`(58) Field of Classification Search ................. 514/450,
`514/912
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1988 Wenig ..................... 514/225.2
`4,749,700 A
`10/1989 Lever, Jr. et al.
`........... 549/354
`4,871,865 A
`5/1990 Lever, Jr. et al.
`514/450
`4,923,892 A
`
`............. 514/450
`5/1992 Oshima et al.
`5,116,863 A
`11/1992 Hettche ...................... 424/489
`5,164,194 A
`6/1997 Hayakawa et a1.
`......... 514/450
`5,641,805 A
`6,146,622 A * 11/2000 Castillo et al.
`.......... 424/78.02
`6,174,914 B1
`1/2001 Yanni et al.
`................ 514/450
`6,207,684 B1
`3/2001 Aberg ........................ 514/324
`6,316,483 B1
`11/2001 Haslwanter et a1.
`........ 514/401
`6,333,044 B1
`12/2001 Santus et al.
`............... 424/434
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`W0
`
`0 048 023
`0 214 779
`0 235 796
`WO 91/54687 A1
`
`3/1982
`3/1987
`9/1987
`8/2001
`
`OTHER PUBLICATIONS
`
`Church, “Is Inhibition of Mast Cell Mediator Release Rel-
`evant
`to the Clinical Activity of Anti—allergic Drugs?,”
`Agents and Actions, vol. 18, 3A, pp. 288—293 (1986).
`
`Clegg et al., “Histamine Secretion from Human Skin Slices
`Induced by Anti—IgE and Artificial Secretagogues and the
`Effects of Sodium Cromoglycate and Salbutanol,” Clin.
`Allergy, vol. 15, pp. 321—328 (1985).
`Hamilton et al., “Comarison of a New Antihistaminic and
`Antiallergic Compound KW 46790 With Terfenadine and
`Placebo on Skin and Nasal Provocation in Atopic Individu-
`als,” Clinical and Experimental Allergy, vol. 24, pp.
`955—959 91994).
`Ikeda et al., “Effects of Oxatomide and KW—4679 on
`Acetylcholine—Induced Responses in the Isolated Acini of
`Guinea Pig Nasal Glands,” Int. Arch. Immunol, vol. 106, p.
`157—162 (1995).
`
`Irani etal., “Mast Cell Heterogeneity,” Clinical and Experi-
`mental Allergy, vol. 19, pp. 143—155 (1989).
`
`Kamei et al., “Effects of Certain Antiallergic Drugs on
`Experimental Conjuctivitis in Guinea Pigs,” Atarashii
`Ganka, vol. 11(4), p. 603—605 (1994) (abstract only).
`
`Kamei et al., “Effect of (Z)—11—[3—(Dimethylamino) propy-
`lidene]—6,
`11—dihydrodibenz[b,e]oxepin—2—acetic Acid
`Hydrochloride on Experimental Allergic Conjuctivitis and
`Rhinitis in Rats and Guinea Pigs,” Arzneimittelforschang,
`vol. 45(9), p. 1005—1008 (1995).
`
`Ohshima et al., “Synthesis and Antiallergic Activity of
`11—(Aminoa1kylidene)—6,11,dihydrodibenz[b,e]oxepin
`Derivatives,” J. Medicinal Chemistry, vol. 35(11), p.
`2074—2084 (1992).
`
`Pearce et al., “Effect of Disodium Cromoglycate on Antigen
`Evoked Histamine Release in Human Skin,” Clinical Exp.
`Immunol, vol. 17, pp. 437—440 (1974).
`
`Sharif et al., “Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatadine (AL—4943A), a Novel
`Drug for Treating Ocular Allergic Diseases,” J. ofPharma-
`c0l0gy and Experimental Therapeaticsl, vol. 278(3), p.
`1252—1261 (1996).
`
`Sharif et al., “Olopatadine (AL—4943A): Pharmacological
`Profile of a Novel Anti—histaminic/Anti—allergic Drug for
`Use in Allergic Conjunctivitis,” Investigative Ophthalmol-
`ogy & Visual Sciencevol. 37(3), p. 1027 (1996) (abstract
`only).
`
`Siraganian, “An Automated Continuous Flow System for the
`Extraction and Fluorometric Analysis of Histamine,” Anal.
`Biochem., vol. 57, pp. 383—394 (1974).
`
`(Continued)
`
`Primary Examiner—Zohreh Fay
`(74) Attorney, Agent, or Firm—Patrick M. Ryan
`
`(57)
`
`ABSTRACT
`
`Topical formulations of Olopatadine for treatment of allergic
`or inflammatory disorders of the eye and nose are disclosed.
`The aqueous formulations contain approximately
`0.17—0.62% (W/v) of Olopatadine and an amount of polyvi-
`nylpyrrolidone or polystyrene sulfonic acid sufficient
`to
`enhance the physical stability of the formulations.
`
`16 Claims, No Drawings
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 001
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 001
`
`

`

`US 6,995,186 132
`Page 2
`
`OTHER PUBLICATIONS
`
`Spitalny et al., “Olopatadine Ophthalmic Solution Decreases
`Itching and Redness Associated With Allergic Conjunctivi-
`tis,” Investigative Ophthalmology & Visual Science, vol.
`37(3), p. 593 (1996) (abstract only).
`“The Lung,” Scientific Foundation, Raven Press, Ltd., New
`York, Ch. 3.4.11 (1991).
`Yanni et al., “The In Vitro and In Vivo Ocular Pharmacology
`of Olopatadine (AL—4943A), An Effective Anti—allergic/
`
`Anti—histaminic Agent,” Investigative Ophthalmology &
`Visual Science, vol. 37(3), p. 1028 (1996) (abstract only).
`Zhang et al., “Optically Active Analogues of Ebastine:
`Synthesis and Effect of Chirality on Their Antihistaminic
`and Antimuscarinic Activity,” Chirality, vol. 6(8), p.
`631—641 (1994).
`Astelin® Nasal Spray Product Insert.
`
`* cited by examiner
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1005 p. 002
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`

`

`US 6,995,186 B2
`
`1
`OLOPATADINE FORMULATIONS FOR
`TOPICAL ADMINISTRATION
`
`This application claims priority to US. Provisional
`Application Ser. No. 60/301,315, filed Jun. 27, 2001.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention relates to topical formulations used
`for
`treating allergic and inflammatory diseases. More
`particularly, the present invention relates to formulations of
`olopatadine and their use for treating and/or preventing
`allergic or inflammatory disorders of the eye and nose.
`2. Description of the Related Art
`As taught in US. Pat. Nos. 4,871,865 and 4,923,892, both
`assigned to Burroughs Wellcome Co.
`(“the Burroughs
`Wellcome Patents”), certain carboxylic acid derivatives of
`doxepin, including olopatadine (chemical name: Z-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepine-2-acetic acid), have antihistamine and antiasthmatic
`activity. These two patents classify the carboxylic acid
`derivatives of doxepin as mast cell stabilizers with antihis-
`taminic action because they are believed to inhibit
`the
`release of autacoids (i.e., histamine, serotonin, and the like)
`from mast cells and to inhibit directly histamine’s effects on
`target tissues. The Burroughs Wellcome Patents teach vari-
`ous pharmaceutical formulations containing the carboxylic
`acid derivatives of doxepin, including nasal spray and oph-
`thalmic formulations. See, for example, Col. 7, lines 7—26,
`and Examples 8 (H) and 8 (I) of the ”865 patent.
`US. Pat. No. 5,116,863, assigned to Kyowa Hakko
`Kogyo Co., Ltd., (“the Kyowa patent”), teaches that acetic
`acid derivatives of doxepin and, in particular, olopatadine,
`have anti-allergic and anti-inflammatory activity. Olopata-
`dine is the cis form of the compound having the formula:
`
`CHZCH2N(CH3)2
`
`CHZCOOH
`
`O
`
`Medicament forms taught by the Kyowa patent for the acetic
`acid derivatives of doxepin include a wide range of accept-
`able carriers; however, only oral and injection administra-
`tion forms are mentioned.
`
`US. Pat. No. 5,641,805, assigned to Alcon Laboratories,
`Inc. and Kyowa Hakko Kogyo Co., Ltd., teaches topical
`ophthalmic formulations containing olopatadine for treating
`allergic eye diseases. According to the ’805 patent,
`the
`topical formulations may be solutions, suspensions or gels.
`The formulations contain olopatadine, an isotonic agent, and
`“if required, a preservative, a buffering agent, a stabilizer, a
`viscous vehicle and the like.”See Col. 6,
`lines 30—43.
`“[P]olyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid
`or the like” are mentioned as the viscous vehicle. See Col.
`6, lines 55—57.
`PATANOL® (olopatadine hydrochloride ophthalmic
`solution) 0.1% is currently the only commercially available
`olopatadine product for ophthalmic use. According to its
`labelling information, it contains olopatadine hydrochloride
`equivalent
`to 0.1% olopatadine, 0.01% benzalkonium
`chloride, and unspecified amounts of sodium chloride, diba-
`
`2
`sic sodium phosphate, hydrochloric acid and/or sodium
`hydroxide (to adjust pH) and purified water. It does not
`contain polyvinyl alcohol, polyvinylpyrrolidone, poly-
`acrylic acid or any other polymeric ingredient.
`Topical olopatadine formulations that have prolonged
`therapeutic activity and are effective as products for treating
`allergic or inflammatory conditions in the eye and nose are
`desirable. Topical olopatadine formulations that are effective
`as once-a-day products for treating allergic conditions in the
`eye are desirable.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides topical olopatadine for-
`mulations that are effective as once-a-day products for
`treating allergic or inflammatory disorders of the eye and are
`effective for treating allergic or inflammatory disorders of
`the nose. The formulations of the present
`invention are
`aqueous solutions that comprise approximately 02—06%
`olopatadine. In addition to their relatively high concentra-
`tion of olopatadine, they also contain an amount of polyvi-
`nylpyrrolidone or polystyrene sulfonic acid sufficient
`to
`enhance the physical stability of the solutions.
`Among other factors, the present invention is based on the
`finding that polyvinylpryrrolidone and polystyrene sulfonic
`acid, unlike polyvinyl alcohol and the polyacrylic acid
`carbomer 974P, enhance the physical stability of solutions
`containing approximately 02—06% olopatadine.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Unless indicated otherwise, all component amounts are
`presented on a % (w/v) basis and all references to olopata-
`dine are to olopatadine free base.
`Olopatadine is a known compound that can be obtained
`by the methods disclosed in US. Pat. No. 5,116,863, the
`entire contents of which are hereby incorporated by refer-
`ence in the present specification. The solution formulations
`of the present invention contain 0.17—0.62% olopatadine.
`Preferably, the solution formulations intended for use in the
`eye contain 0.17—0.25% olopatadine, and most preferably
`0.18—0.22% olopatadine. Preferably, the solution formula-
`tions intended for use in the nose contain 0.38—0.62%
`olopatadine.
`Generally, olopatadine will be added in the form of a
`pharmaceutically acceptable salt. Examples of the pharma-
`ceutically acceptable salts of olopatadine include inorganic
`acid salts such as hydrochloride, hydrobromide, sulfate and
`phosphate; organic acid salts such as acetate, maleate,
`fumarate,
`tartrate and citrate; alkali metal salts such as
`sodium salt and potassium salt; alkaline earth metal salts
`such as magnesium salt and calcium salt; metal salts such as
`aluminum salt and Zinc salt; and organic amine addition salts
`such as triethylamine addition salt
`(also known as
`tromethamine), morpholine addition salt and piperidine
`addition salt. The most preferred form of olopatadine for use
`in the solution compositions of the present invention is the
`hydrochloride salt of (Z)-11-(3-dimethylaminopropylidene)-
`6,11-dihydro-dibenz-[b,e]oxepin-2-acetic acid. When olo-
`patadine is added to the compositions of the present inven-
`tion in this salt form, 0.222% olopatadine hydrochloride is
`equivalent to 0.2% olopatadine free base, 0.443% olopata-
`dine hydrochloride is equivalent to 0.4% olopatadine free
`base, and 0.665% olopatadine hydrochloride is equivalent to
`0.6% olopatadine free base.
`In addition to olopatadine, the aqueous solution compo-
`sitions of the present invention comprise polyvinylpyrroli-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
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`

`

`US 6,995,186 B2
`
`3
`done or polystyrene sulfonic acid in an amount sufficient to
`enhance the physical stability of the composition. Polyvi-
`nylpyrrolidone and polystyrene sulfonic acid are known
`polymers and both are commercially available from a vari-
`ety of sources in different grades and in a number of
`molecular weights. For example, polyvinylpyrrolidone is
`available in many grades from International Specialty Prod-
`ucts (Wayne, N.J.): Plasdone® C-15 (weight avg. MW=8K),
`K-26/28 (weight avg. MW=30K), K-29/32 (weight avg.
`MW=58K), K-30 (weight avg. MW=50K) and K-90 (weight
`avg. MW=1300K). Also, polyvinylpyrrolidone is available
`from BASF Corporation under the Kollidon brand name. As
`used herein, “polyvinylpyrrolidone” includes homopoly-
`mers of vinylpyrrolidone and copolymers of vinylpyrroli-
`done and vinyl acetate. Vinylpyrrolidone-vinyl acetate
`copolymers are known as “copovidone” and are commer-
`cially available from BASF Corporation as Kollidon VA 64.
`The polyvinylpyrrolidone ingredient included in the solution
`compositions of the present invention has a weight average
`molecular weight of 5000—1,600,000. Most preferred is
`polyvinylpyrrolidone having a weight average molecular
`weight of 50,000—60,000. In general, the amount of poly-
`vinylpyrrolidone contained in the compositions of the
`present invention will be 0.1—3%, preferably 0.2—2%, and
`most preferably 1.5—2%.
`Polystyrene sulfonic acid is commercially available in
`many grades, including for example the following grades
`available from Alco Chemical, a division of National Starch
`& Chemical Company: Versa TL-70 (weight avg. MW=75,
`000), Versa TL-125 (weight avg. MW=200,000), and Versa
`TL-502 (weight avg. MW=1,000,000). As used herein,
`“polystyrene sulfonic acid” includes homopolymers of sty-
`rene sulfonic acid and salts, as well as copolymers of styrene
`sulfonic acid and maleic anhydride. The polystyrene sul-
`fonic acid ingredient included in the solution compositions
`of the present invention has a weight average molecular
`weight of 10,000—1,500,000, preferably 75,000 to 1,000,
`000, and most preferably 75,000. In general, the amount of
`polystyrene sulfonic acid contained in the compositions of
`the present invention will be 0.1—1%, preferably 0.15—0.4%,
`and most preferably 0.25%.
`invention comprise
`The compositions of the present
`0.17—0.62% olopatadine and a polymeric physical stability-
`enhancing ingredient consisting essentially of polyvinylpyr-
`rolidone or polystyrene sulfonic acid in an amount sufficient
`to enhance the physical stability of the solution. The com-
`positions of the present invention do not contain polyvinyl
`alcohol, polyvinyl acrylic acid, hydroxypropylmethyl
`cellulose, sodium carboxymethyl cellulose, xanthan gum or
`other polymeric physical stability enhancing ingredient.
`The compositions of the present invention have a viscos-
`ity of 0.5—10 cps, preferably 0.5—5 cps, and most preferably
`1—2 cps. This relatively low viscosity insures that
`the
`product is comfortable, does not cause blurring, and is easily
`processed during manufacturing, transfer and filling opera-
`tions.
`
`In addition to the olopatadine and polyvinylpyrrolidone
`ingredients,
`the compositions of the present
`invention
`optionally comprise one or more excipients. Excipients
`commonly used in pharmaceutical compositions intended
`for topical application to the eyes or nose, such as solutions
`or sprays, include, but are not limited to, tonicity agents,
`preservatives, chelating agents, buffering agents, surfactants
`and antioxidants. Suitable tonicity-adjusting agents include
`mannitol, sodium chloride, glycerin, sorbitol and the like.
`Suitable preservatives include p-hydroxybenzoic acid ester,
`benzalkonium chloride, benzododecinium bromide,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`polyquaternium-1 and the like. Suitable chelating agents
`include sodium edetate and the like. Suitable buffering
`agents include phosphates, borates, citrates, acetates and the
`like. Suitable surfactants include ionic and nonionic
`surfactants, though nonionic surfactants are preferred, such
`as polysorbates, polyethoxylated castor oil derivatives and
`oxyethylated tertiary octylphenol formaldehyde polymer
`(tyloxapol). Suitable antioxidants include sulfites,
`ascorbates, BHA and BHT. The compositions of the present
`invention optionally comprise an additional active agent.
`With the exception of the optional preservative ingredient
`(e.g., polyquaternium-1),
`the compositions of the present
`invention preferably do not contain any polymeric ingredi-
`ent other than polyvinylpyrrolidone or polystyrene sulfonic
`acid.
`
`Particularly for compositions intended to be administered
`as eye drops, the compositions preferably contain a tonicity-
`adjusting agent in an amount sufficient to cause the final
`composition to have an ophthalmically acceptable osmola-
`lity (generally 150—450 mOsm, preferably 250—350 mOsm).
`The ophthalmic compositions of the present invention pref-
`erably have a pH of 4—8, preferably a pH of 6.5—7.5, and
`most preferably a pH of 6.8—7.2. Compositions of the
`present invention intended for use in the nose preferably
`have a pH of 3.5—8. Preferably, compositions intended to be
`administered to the nose have a pH of 3.5—4.5, and most
`preferably a pH of 3.8—4.4.
`When the compositions of the present invention contain
`polyvinylpyrrolidone, the polyvinylpyrrolidone ingredient is
`preferably selected or processed to minimize peroxide con-
`tent. Freshly produced batches of polyvinylpyrrolidone are
`preferred over aged batches. Additionally, particularly in
`cases where the composition will contain greater than 0.5%
`polyvinylpyrrolidone,
`the polyvinylpyrrolidone ingredient
`should be thermally treated (i.e., heated to a temperature
`above room temperature) prior to mixing with olopatadine in
`order to reduce the amount of peroxides in the polyvinylpyr-
`rolidone ingredient and minimize the effect of peroxides on
`the chemical stability of olopatadine. While thermally treat-
`ing an aqueous solution of polyvinylpyrrolidone for pro-
`longed periods will substantially reduce the amount of
`peroxides, it can lead to discoloration (yellow to yellowish-
`brown) of the polyvinylpyrrolidone solution. In order to
`substantially reduce or eliminate peroxides without discol-
`oring the polyvinylpyrrolidone solution, the pH of the aque-
`ous solution of polyvinylpyrrolidone should be adjusted to
`pH 11—13 before it is subjected to heat. Much shorter heating
`times are needed to achieve significant reductions in perox-
`ide levels if the pH of the polyvinylpyrrolidone solution is
`elevated.
`
`One suitable method of thermally treating the polyvi-
`nylpyrrolidone ingredient is as follows. First, dissolve the
`polyvinylpyrrolidone ingredient in purified water to make a
`4—6% solution,
`then raise the pH of the solution to pH
`11—13, preferably 11—11.5, then heat to a temperature in the
`range of 60—121° C., preferably 65—80° C. and most pref-
`erably 70—75° C. The elevated temperature should be main-
`tained for approximately 30—120 minutes (preferably 30
`minutes). After
`the heated solution cools to room
`temperature, add HCl to adjust the pH to 3.5—8, depending
`upon the target pH for the olopatadine composition.
`The compositions of the present invention are preferably
`packaged in opaque plastic containers. Apreferred container
`for an ophthalmic product is a low-density polyethylene
`container that has been sterilized using ethylene oxide
`instead of gamma-irradiation. A preferred container for a
`nasal product
`is a high-density polyethylene container
`equipped with a nasal spray pump.
`
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`

`US 6,995,186 B2
`
`5
`Certain embodiments of the invention are illustrated in the
`
`following examples.
`
`EXAMPLE 1
`
`Topically Administrable Ophthalmic Solution
`
`Ingredient
`
`(Z)—11-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b,e]oxepin-2—acetic
`acid.HCl
`(“Olopatadine.HCl”)
`Polyvinylpyrrolidone
`Sodium Chloride
`Benzalkonium Chloride
`Edetate Disodium
`Dibasic Sodium Phosphate (Anhydrous)
`NaOH/HCl
`Purified Water
`
`*equivalent to 0.2% free base
`
`Concentration (% w/v)
`
`0.222"
`
`1.6—2.0
`0.55
`0—0.02
`0.01
`0.5
`q.s. pH 7.0 1 0.2
`q.s. 100
`
`A representative compounding procedure for the solution
`composition of this Example is provided below.
`Preparation of Polyvinylpyrrolidone Stock Solution
`A 4% stock solution of polyvinylpyrrolidone is prepared by
`dissolving the polyvinylpyrrolidone in purified water, add-
`ing NaOH to raise the pH to 11.5, and heating for 30 minutes
`at 70—75° C. After cooling to room temperature, HCl is
`added to the stock solution to adjust the pH to 7.
`Compounding Procedure
`Purified water, dibasic sodium phosphate, sodium chloride,
`edetate disodium, benzalkonium chloride (as 1% stock
`solution) and polyvinylpyrrolidone (as 4% stock solution)
`are added to a container, with mixing after adding each
`ingredient. NaOH is added to adjust the pH to approximately
`pH 7, then the drug is added, followed by final pH adjust-
`ment to pH 7.0 and the addition of the remaining amount of
`purified water, with mixing after adding each ingredient. The
`resulting solution is then filtered through a sterilizing filter
`and transferred under sterile conditions into ethylene oxide-
`sterilized LDPE or polypropylene containers.
`
`EXAMPLE 2
`
`Topically Administrable Ophthalmic Solution
`
`Ingredient
`
`Concentration (% w/v)
`
`Olopatadine.HCl
`N-lauroylsarcosine
`Polystyrene Sulfonic Acid
`Mannitol
`Benzalkonium Chloride
`Boric Acid
`Edetate Disodium
`Tromethamine
`Purified Water
`
`*equivalent to 0.2% free base
`
`0.222"
`0.04
`0.5
`4.4
`0—0.02
`0.45
`0.05
`q.s. pH 6.5 1 0.2
`q.s. 100
`
`A representative compounding procedure for the solution
`composition of this Example is provided below.
`Compounding Procedure
`Purified water, mannitol, boric acid, edetate disodium, ben-
`zalkonium chloride (as 1% stock solution) and polystyrene
`sulfonic acid (as a powder) are added to a container, with
`mixing after adding each ingredient. Tromethamine is added
`
`6
`then
`the pH to approximately pH 6.5,
`to adjust
`N—lauroylsarcosine and then the drug is added, followed by
`final pH adjustment to pH 6.5 and addition of the remaining
`amount of purified water, with mixing after adding each
`ingredient. The resulting solution is then filtered through a
`sterilizing filter and transferred under sterile conditions into
`ethylene oxide-sterilized LDPE or polypropylene contain-
`ers.
`
`EXAMPLE 3
`
`Topically Administrable Nasal Solution
`
`Ingredient
`
`Concentration (% w/v)
`
`Olopatadine.HCl
`Polyvinylpyrrolidone
`Sodium Chloride
`Benzalkonium Chloride
`Edetate Disodium
`Dibasic Sodium Phosphate (Anhydrous)
`NaOH/HCl
`Purified Water
`
`0.222"
`1.6—2.0
`0.3—0.6
`0—0.02
`0.01
`0.5
`q.s. pH 3.8—7
`q.s. 100
`
`*equivalent to 0.2% free base
`
`15
`
`20
`
`25
`
`30
`
`A representative compounding procedure for the solution
`composition of this Example is provided below.
`
`Preparation of Polyvinylpyrrolidone Stock Solution
`
`A 4% stock solution of polyvinylpyrrolidone is prepared by
`dissolving the polyvinylpyrrolidone in purified water, add-
`ing NaOH to raise the pH to 11.5, and heating for 30 minutes
`at 70—75° C. After cooling to room temperature, HCl is
`added to the stock solution to adjust the pH to 7.
`
`Compounding Procedure
`
`Purified water, dibasic sodium phosphate, sodium chloride,
`edetate disodium, benzalkonium chloride (as 1% stock
`solution), polyvinylpyrrolidone (as 4% stock solution), and
`the drug are added to a container, with mixing after adding
`each ingredient. NaOH/HCl is added to adjust the pH to
`approximately pH 4, and the remaining amount of purified
`water is added. The resulting solution is then filtered through
`a sterilizing filter and aseptically transferred into high-
`density polyethylene, spray-pump containers.
`
`EXAMPLE 4
`
`Topically Administrable Nasal Solution
`
`Ingredient
`
`Concentration (% w/v)
`
`Olopatadine.HCl
`Polyvinylpyrrolidone
`Sodium Chloride
`Benzalkonium Chloride
`Edetate Disodium
`Dibasic Sodium Phosphate (Anhydrous)
`NaOH/HCl
`Purified Water
`
`0.443"
`1.6—2.0
`0.3—0.6
`0.01 + 3% xs
`0.01
`0.5
`q.s. pH 3.8—4.4
`q.s. 100
`
`*equivalent to 0.4% free base
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 005
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 005
`
`

`

`US 6,995,186 B2
`
`7
`The solution composition of this Example may be pre-
`pared using the procedure described above for the solution
`composition of Example 3.
`
`EXAMPLE 5
`
`The compositions shown in Table 1 below were prepared
`and subjected to stability studies. In no case was the poly-
`
`8
`meric ingredient autoclaved and none of the compositions
`was filtered through a 0.2 pm filter. One set of samples (two
`vials each) of each of the compositions was subjected to
`three refrigeration-room temperature cycles and a second set
`(two vials each) was subjected to continuous low-
`temperature exposure. The results are shown in Table 2
`below.
`
`TABLE 1
`
`FORMULATION
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`G
`
`INGREDIENT
`Concentration (% w/w)
`
`
`Olopatadine.HCl
`Polyvinyl Alcohol
`(Airvol 2055)
`Hydroxypropyl
`Methylcellulose (2910)
`Xanthan Gum (AR)
`Carbopol 974P
`Polyvinyl pyrrolidone
`(wt. Avg. MW = 58K)
`Sodium Carboxymethyl-
`cellulose (762P)
`Benzalkonium
`Chloride
`Sodium Chloride
`Dibasic Sodium
`
`Phosphate (anhydrous)
`NaOH/HCl
`Purified Water
`Viscosity" (cps)
`
`0.222
`0.1
`
`—
`
`—
`—
`—
`
`0.222
`0.222
`0.222
`0.222
`0.222
`0.222
`
`
`
`
`0.05
`
`—
`—
`—
`
`0.02
`—
`—
`
`—
`0.01
`—
`
`—
`—
`1.0
`
`—
`—
`1.8
`
`
`
`—
`—
`—
`
`0.1
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`0.01 +
`1% xs
`0.6
`0.5
`
`q.s. pH 7
`q.s. 100
`1.02
`
`q.s. pH 7
`q.s. 100
`1.40
`
`q.s. pH 7
`q.s. 100
`1.42
`
`q.s. pH 7
`q.s. 100
`0.97
`
`q.s. pH 7
`q.s. 100
`1.20
`
`q.s. pH 7
`q.s. 100
`1.45
`
`q.s. pH 7
`q.s. 100
`1.16
`
`*Brookfield viscometer (60 RPM, CP-42)
`
`TABLE 2
`
`Refrigeration - RT cycles
`
`Continuous ow-temperature exposure
`
`Formulation One cycle
`
`Tiree cycles
`
`Day 7
`
`Day 14
`
`C ear, no
`Jar ic es
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`G
`
`
`
`C ear, few
`particles (one
`vial)
`C ear, a
`crystal (2 mm)
`observed in
`one vial)
`C ear, crystals
`
`
`
`C ear, few
`particles
`
`C ear,
`particles and
`crystals
`
`C ear, crystals
`
`C ear, lots of
`crystals
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`
`
`
`
`C ear, fiber-
`li§e particles
`
`C ear, crystals
`and fiber-like
`particles
`
`C ear, crystals
`
`C ear, lots of
`crystals
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`Day 28
`
`C ear,
`particles
`
`C ear, crystals
`
`C ear, crystals
`
`C ear, crystals
`
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`
`
`C ear, no
`Jar ic es
`
`
`
`
`
`
`
`C ear, no
`Jar ic es
`C ear, lots of C ear, lots of
`crysta s
`crystals
`C ear, no
`C ear, no
`Jar ic es
`particles
`C ear, no
`C ear, no
`Jar ic es
`particles
`C ear, no
`C ear, crystals
`Jar ic es
`
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`
`1005 p. 006
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 006
`
`

`

`US 6,995,186 B2
`
`9
`EXAMPLE 6
`
`10
`
`TABLE 3-continued
`
`FORMULATION
`
`The compositions shown in Table 3 below were subjected 5
`to freeze-thaw stability studies at two conditions (with and
`without seed; seed=0—1/2 Canyon pumice (from Charles B.
`Chrystal Co., Inc., New York, NY.) at 1 mg in 5 mL of
`formulation) and two temperatures (0° C. or —20° C.). In no 10
`case was the polymeric ingredient autoclaved and none of
`the compositions was filtered through a 0.2 pm filter. Each
`of the compositions (two Vials each) was subjected to siX
`freeze-thaw cycles where one cycle was three days at low
`temperature (i.e., either 0° C. or —20° C.), followed by one 15
`day at uncontrolled room temperature. The compositions
`were Visually inspected and the results recorded. The results
`are shown in Table 4 below.
`
`TABLE 3
`
`FORMULATION
`
`H
`
`I
`
`J
`
`Concentration ( % w/w)
`
`0.222
`0.01 + 3% XS
`
`0.222
`0.01 + 3% XS
`
`0.222
`0.01 + 3% XS
`
`0.01
`1.8
`
`—
`—
`
`0.55
`0.5
`
`0.01
`—
`
`0.6
`—
`
`0.55
`0.5
`
`0.01
`—
`
`—
`1.8
`
`0.55
`0.5
`
`20
`
`25
`
`30
`
`35
`
`Ingredient
`
`Olopatadine.HCl
`Benzalkonium
`Chloride
`
`Edetate Disodium
`HydrOXypropyl
`methyl-cellulose
`Carbopol 974P
`Polyvinyl alcohol
`(Airvol 205S)
`Sodium Chloride
`DibaSic Sodium
`
`Phosphate
`(Anhydrous)
`
`Ingredient
`
`NaOH/HCl
`
`Purified Water
`
`H
`
`I
`Concentration ( % w/w)
`
`J
`
`Adjust pH
`7.0 1 0.2
`QS to 100%
`
`Adjust pH
`7.0 1 0.2
`QS to 100%
`
`Adjust pH
`7.0 1 0.2
`QS to 100%
`
`TABLE 4
`FORMULATION
`OBSERVATION
`
`H
`
`I
`
`J
`
`No precipitation after 6 cycles with or without
`seed at either temperature
`Hazy from 1“ cycle onward with or without
`seed at both temperatures
`No precipitation after 6 cycles with or without
`seed at either temperature
`
`EXAMPLE 7
`
`The compositions shown in Table 5 below were subjected
`to freeze-thaw stability studies at two conditions (with and
`without seed; seed=same as in Example 4 above) and two
`temperatures (0° C. or —20° C.). In no case was the poly-
`meric ingredient autoclaved and none of the compositions
`was filtered through a 0.2 pm filter. Each of the compositions
`(three Vials each) was subjected to up to siX freeze-thaw
`cycles where one cycle was three days at low temperature
`(i.e., either 0° C. or —20° C.), followed by one day at
`uncontrolled room temperature. The compositions were
`Visually inspected and the results recorded. The results are
`shown in Table 6 below.
`
`TABLE 5
`
`FORMULATION
`
`K
`
`L
`
`M
`
`P
`
`Q
`
`R
`
`S
`
`INGREDIENT
`
`0.222
`2
`
`Olopatadine.HCl
`Polyvinyl pyrrolidone
`(wt. Avg. MW = 58K)
`Polyethylene Glycol (400) —
`Polyvinyl pyrrolidone
`—
`(wt. avg. MW = 1300K)
`Benzalkonium Chloride
`
`DibaSic Sodium
`
`Phosphate (Anhydrous)
`Sodium Chloride
`Edetate Disodium
`
`NaOH/HCl
`Purified Water
`
`N
`
`O
`
`Concentration (% w/w)
`
`0.222
`1.8
`
`_
`—
`
`0.01 +
`3% XS
`0.5
`
`0.55
`0.02
`
`0.222
`—
`
`_
`1.8
`
`0.01 +
`3% XS
`0.5
`
`0.55
`0.02
`
`0.222
`—
`
`_
`—
`
`0.01 +
`3% XS
`0.5
`
`0.6
`—
`
`0.333
`2
`
`_
`—
`
`0.01 +
`3% XS
`0.5
`
`0.55
`0.02
`
`0.333
`2
`
`0.333
`—
`
`2
`—
`
`0.01
`
`0.5
`
`0.3
`0.01
`
`_
`2
`
`0.01
`
`0.5
`
`0.3
`0.01
`
`0.222
`2
`
`2
`—
`
`0.01
`
`0.5
`
`0.3
`0.01
`
`0.222
`—
`
`2
`—
`
`0.01 +
`3% XS
`0.5
`
`0.3
`0.01
`
`0.01 +
`3% XS
`0.5
`
`0.55
`0.02
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
`q.S. pH 7
`q.S. 100
`
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`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1005 p. 007
`
`

`

`US 6,995,186 B2
`
`12
`
`11
`
`TABLE 6
`
`Observation No. of vials showing precipitation
`
`Formulation # cycles Seed 00 C.
`K
`6
`0/3
`L
`6
`0/3
`M
`6
`0/3
`N
`6
`0/3
`0
`6
`0/3
`P
`5
`1/3
`
`Q
`
`R
`S
`
`5
`
`6
`5
`
`3/3
`
`0/3
`3/3
`(3 cycles)
`
`Seed —200 C.
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`(6 cycles)
`0/3
`(6 cycles)
`0/3
`3/3
`
`EXAMPLE 8
`
`No Seed 00 C. No Seed —200 C.
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`2/3
`2/3
`(6 cycles)
`0/3
`(6 cycles)
`0/3
`2/3
`
`3/3
`
`0/3
`3/3
`(3 cycles)
`
`20
`
`TABLE 8
`
`FORMULATION
`
`OBSERVATION
`
`T
`U
`
`NO precipitation at either temperature
`N0 PreCiPitatiOH at either temperature
`
`The formulations shown in Table 7 were prepared and
`subjected to freeze-thaw testing for 5.5 cycles. For one set
`of samples, one cycle was defined as one week at 0° C. 25
`followed by one week at uncontrolled room temperature
`EXAMPLE 9
`(approx. 21° C.). For another set of samples, one cycle was
`Seven compositions were prepared and subjected to
`defined as one week at —20 C. followed by one week at
`uncontrolled room temperature (approx. 21° C.). The results 30 freeze-thaw stability studies. Each of the seven composi-
`are shown in Table 8~
`tions contained purified water, 0.222% (w/w) Olopatadine
`HCl, 0.01% (w/w) (+3% excess) benzalkonium chloride,
`0.06% (w/w) sodium chloride 0.5% (w/w) dibasic sodium
`phosphate, and NaOH/HCl to adjust pH to 7. The seven
`35 samples were differentiated by their amount or grade
`(molecular weight) of polyvinylpyrrolidone ingredient, as
`shown in Table 9. In no case was the polymeric ingredient
`autoclaved and the compositions were filtered through a 0.2
`um filter. The seven samples were placed in scmtillation
`.
`.
`.
`.
`.
`40 Vials containing stir bars and were subjected to freeze-thaw
`stability studies at
`two conditions and two temperatures
`o
`o
`.
`.
`.
`.
`(3—4 C. or —21 C.). After s1x cycles of 3 days at low
`temperature and one day at room temperature (w1th stirring),
`the samples were subjected to 3.5 cycles of one week at low
`45 temperature, followed by one week at room temperature (no
`.
`.
`stirring). Although fibers were observed in a few samples
`during the study, no crystals were observed in any samples
`.1 h
`d f h
`d A h
`d f h
`d
`h
`. b
`unti t een o t estu y.
`tt een o t estu y,t estir ars
`were removed and the samples (replicate samples of each
`composition) were Visually inspected. The results are shown
`in Table 9.
`
`TABLE 7
`
`FORMULATION
`
`U
`_
`T
`concentrauon (% W/W)
`0222
`0222
`0.25
`0.5
`
`0.01
`0.05
`4 4
`0'45
`0.04
`'
`
`0.01
`0.05
`4 4
`0'45
`0.04
`'
`
`q.s.