US007402609B2
`
`(12) Ulllted States Patent
`Castillo et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,402,609 B2
`*Jul. 22, 2008
`
`(54) OLOPATADINE FORMULATIONS FOR
`TOPICAL ADMINISTRATION
`
`(75)
`
`Inventors: Ernesto J_ Castilloafllingtona TX (US);
`Wesley Wehsin Han, Arlington, TX
`(US); Huixiang Zhang, Fm Womb, 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, F611
`Womb’ TX (US)
`(73) Assignee: Alcon, Inc., Hunenberg (CH)
`.
`.
`.
`.
`.
`( * ) Notice:
`Subject. to any dlsclalmer, the term of this
`patent is extended or adjusted under 35
`USC 15409) by 0 days
`
`6,274,626 131 =1
`6,316,483 B1
`6,333,044 B1
`
`............ .. 514/568
`3/2001 Jonasse 6161.
`11/2001 Hasiwanter 6161.
`....... .. 514/401
`12/2001 Santus et al.
`.............. .. 424/434
`
`2001/0056093 A1
`
`12/2001 Yanni
`
`....................... .. 514/218
`
`FOREIGN PATENT DOCUMENTS
`0 048 023
`3/1982
`0 214 779
`3/1987
`0 235 795
`9/1987
`W0 W6); :
`WO 01/21209
`3/2001
`
`WO 01/54687 A1
`WO 91/54687 A1
`W0 02/3039 5 A1
`W0 03/002093
`WO 2004/043470
`
`8/2001
`8/2001
`4/2002
`1/2003
`5/2004
`
`EP
`EP
`EP
`$0
`W0
`
`W0
`W0
`W0
`W0
`W0
`
`This patent is subject to a terminal dis-
`claimer.
`
`OTHER PUBLICATIONS
`
`(21) Appl. No‘, 11/079,996
`
`(22)
`
`Filed:
`
`Mar. 15, 2005
`
`(65)
`
`Prior Publication Data
`US 2005/0158387 A1
`Jul. 21, 2005
`
`Related US_ Application Data
`
`(63) Continuation of application No. 10/175,106, filed on
`Jun. 19, 2002, now Pat. No. 5,995,185.
`
`(60)
`
`Pr0ViSi0I1a1 application NO. 60/301315, filed on Jun.
`27, 2001.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/333
`(52) U.S. Cl.
`.................................................... .. 514/450
`(58) Field of Classification Search ..................... .. None
`See application file for complete search history.
`References Cited
`
`(56)
`
`Church, “Is Inhibition ofMast Cell Mediator Release Relevant to the
`Clinical Activity of Anti-allergic Drugs?,” Agents and Actions, vol.
`18, 3/4, 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
`(198?)
`_
`_
`_
`_
`_
`Hamilton et
`a1., “Comarlson of a New Antlhlstamlnlc and
`
`Antlallerglc Compound KW 46790 with Terfenadlne and Placebo on
`Skin and Nasal Provocation in Atopic Individuals,” Clinical and
`Experimental Allergy, V01. 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. Allergy Immunol., vol. 106, p. 157-162 (1995).
`Irani et al., “Mast Cell Heterogeneity,” Clinical and Experimental
`Allergy, vol. 19, pp. 143-155 (1989).
`Kamei et al., “Effects of Certain Antiallergic Drugs on Experimental
`Conjunctivitis in Guinea Pigs,” Atarashii Ganka, vol. 11(4), p. 603-
`505 (1994) <abS”a°‘ °“1Y)~
`
`(Continued)
`Z hr hA F
`P .
`E
`.
`ay
`rlmary xammer— o
`e
`(74) Attorney, Agent, or Firm—Patrick M. Ryan
`
`U.S. PATENT DOCUMENTS
`4,407,791 A
`10/1983 Stark ......................... .. 424/80
`
`(57)
`
`ABSTRACT
`
`
`
`5/1988 Wenig ---------------- -~ 514/2252
`Topical formulations of olopatadine for treatment of allergic
`10/1989 LGVCL J“ et 31'
`549/354
`or inflammatory disorders of the eye and nose are disclosed.
`5/1990 Levin’ Jr’ et a1’
`514/450
`The aqueous formulations contain approximately 0.17-
`. . . . . .
`5/1992 Oshlma et al.
`. . . .. 514/450
`0
`.
`.
`11/1992 Hettche .................... .. 424/489
`0'62 A’ (W/V) Of Olopatadme afld all amounl Of p°1yVmy1pyr'
`6/1997 Hayakawa eta1'
`........ N 514/450
`rolldone orpolystyrene sulfomc acld sufficlent to enhance the
`11/2000 Castillo et a1.
`......... .. 424/78.02
`Physlcal Stablhty Ofthe f°1'm“1a“°nS~
`1/2001
`1 Claim, No Drawings
`3/2001
`
`4749700 A
`458715865 A
`4923392 A
`5,116,863 A
`5,164,194 A
`5,641,805 A
`6,146,622 A
`6,174,914 B1
`6,207,684 B1
`
`000001
`
`ARGENTUM PHARM. 1049
`
`ARGENTUM PHARM. 1049
`
`000001
`
`

`
`US 7,402,609 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Kamei et al., “Effect of (Z)-11-[3-(Dimethylamino) propylidene]-
`6,11-dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride on
`Experimental Allergic Conjunctivitis and Rhinitis in Rats and Guinea
`Pigs,”Arzneimitteh’orschung, vol. 45(9), p. 1005-1008 (1995).
`Ohshin1a
`et
`al.,
`“Synthesis
`and Antiallergic Activity of
`1 1-(Aminoalkylidene)-6,1 1,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'. of Pharmacology and
`Experimental Therapeuticsl, 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 Ophthalmology & Wsual Science, vol.
`37(3), p. 1027 (1996) (abstract only).
`
`Siraganian, “An Automated Continuous Flow System for the Extrac-
`tion and Fluorometric Analysis of Histamine,” Anal. Biochem., vol.
`57, pp. 383-394 (1974).
`Spitalny et al., “Olopatadine Ophthalmic Solution Decreases Itching
`and Redness Associated with Allergic Conjunctivitis,” Investigative
`Ophthalmology & Wsual Science, vol. 37(3), p. 593 (1996) (abstract
`only).
`“The Lung,” Scientific Foundation, Raven Press, Ltd., NeWYork, 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-hista-
`minic Agent,” Investigative Ophthalmology & Wsual 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
`
`000002
`
`000002
`
`

`
`US 7,402,609 B2
`
`1
`OLOPATADINE FORMULATIONS FOR
`TOPICAL ADMINISTRATION
`
`This application is a continuation application of U.S. Ser.
`No. 10/175,106, filed June 19, 2002 now U.S. Pat. No. 6,995,
`186.
`
`This application claims priority to U.S. Provisional Appli-
`cation, 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 particu-
`larly, the present invention relates to formulations of olopata-
`dine 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 U.S. 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, 1 1 -dihydrodibenz[b,e]ox-
`epine-2-acetic acid), have antihistamine and antiasthmatic
`activity. These two patents classify the carboxylic acid deriva-
`tives of doxepin as mast cell stabilizers with antihistarninic
`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 tis-
`sues. The Burroughs Wellcome Patents teach various phar-
`maceutical
`formulations containing the carboxylic acid
`derivatives of doxepin, including nasal spray and ophthalmic
`formulations. See, for example, Col. 7,
`lines 7-26, and
`Examples 8 (H) and 8 (I) of the ’865 patent.
`U.S. Pat. No. 5,116,863, assignedto Kyowa Hakko Kogyo
`Co., Ltd., (“the Kyowa patent”), teaches that acetic acid
`derivatives of doxepin and, in particular, olopatadine, have
`anti-allergic and anti-inflarnmatory activity. Olopatadine is
`the cis form of the compound having the formula:
`
`CH2CH2N(CH3)2
`
`CHZCOOH
`
`Medicament forms taught by the Kyowa patent for the acetic
`acid derivatives ofdoxepin include a wide range ofacceptable
`carriers; however, only oral and injection administration
`forms are mentioned.
`
`U.S. Pat. No. 5,641,805, assigned to Alcon Laboratories,
`Inc. and Kyowa Hakko Kogyo Co., Ltd., teaches topical oph-
`thalmic formulations containing olopatadine for treating
`allergic eye diseases.According to the ’805 patent, the topical
`formulations may be solutions, suspensions or gels. The for-
`mulations contain olopatadine, an isotonic agent, and “if
`required, a preservative, a buffering agent, a stabilizer, a vis-
`cous 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 solu-
`tion) 0.1% is currently the only commercially available olo-
`
`2
`
`patadine product for ophthalmic use. According to its label-
`ling information,
`it contains olopatadine hydrochloride
`equivalent to 0.1% olopatadine, 0.01% benzalkonium chlo-
`ride, and unspecified amounts of sodium chloride, dibasic
`sodium phosphate, hydrochloric acid and/or sodium hydrox-
`ide (to adjust pH) and purified water. It does not contain
`polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic 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 formu-
`lations that are effective as once-a-day products for treating
`allergic or inflammatory disorders ofthe eye and are effective
`for treating allergic or inflammatory disorders of the nose.
`The formulations of the present invention are aqueous solu-
`tions that comprise approximately 0.2-0.6% olopatadine. In
`addition to their relatively high concentration of olopatadine,
`they also contain an amount ofpolyvinylpyrrolidone or poly-
`styrene sulfonic acid suflicient to enhance the physical sta-
`bility 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 car-
`bomer 974P, enhance the physical stability of solutions con-
`taining approximately 0.2-0.6% olopatadine.
`DETAILED DESCRIPTION OF THE INVENTION
`
`Unless indicated otherwise, all component amounts are
`presented on a % (w/v) basis and all references to olopatadine
`are to olopatadine free base.
`Olopatadine is a known compound that can be obtained by
`the methods disclosed in U.S. Pat. No. 5,116,863, the entire
`contents of which are hereby incorporated by reference in the
`present specification. The solution formulations of the
`present invention contain 0.17-0.62% olopatadine. Prefer-
`ably, 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 formulations
`intended for use in the nose contain 0.38-0.62% olopatadine.
`Generally, olopatadine will be added in the form of a phar-
`maceutically acceptable salt. Examples of the pharmaceuti-
`cally acceptable salts of olopatadine include inorganic acid
`salts such as hydrochloride, hydrobromide, sulfate and phos-
`phate; 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 triethy-
`lamine addition salt (also known as trometharnine), morpho-
`line addition salt and piperidine addition salt. The most pre-
`ferred form of olopatadine for use in the
`solution
`compositions of the present invention is the hydrochloride
`salt of
`(Z)-1 1-(3-dimethylarninopropylidene)-6,11-dihy-
`drodibenz-[b,e]oxepin-2-acetic acid. When olopatadine is
`added to the compositions of the present invention in this salt
`form, 0.222% olopatadine hydrochloride is equivalent to
`0.2% olopatadine free base, 0.443% olopatadine hydrochlo-
`ride is equivalent to 0.4% olopatadine free base, and 0.665%
`olopatadine hydrochloride is equivalent to 0.6% olopatadine
`free base.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`000003
`
`000003
`
`

`
`US 7,402,609 B2
`
`3
`In addition to olopatadine, the aqueous solution composi-
`tions of the present invention comprise polyvinylpyrrolidone
`or polystyrene sulfonic acid in an amount sufiicient
`to
`enhance the physical stability of the composition. Polyvi-
`nylpyrrolidone and polystyrene sulfonic acid are known poly-
`mers and both are commercially available from a variety of
`sources in different grades and in a number of molecular
`weights. For example, polyvinylpyrrolidone is available in
`many grades from International Specialty Products (Wayne,
`N.J.): Plasdone® C-15 (weight avg. MW:8 K), K-26/28
`(weight avg. MW:30 K), K-29/32 (weight avg. MW:58 K),
`K-30 (weight avg. MW:50 K) and K-90 (weight avg.
`MW:1300 K). Also, polyvinylpyrrolidone is available from
`BASF Corporation under the Kollidon brand name. As used
`herein, “polyvinylpyrrolidone” includes homopolymers of
`vinylpyrrolidone and copolymers of vinylpyrrolidone and
`vinyl acetate. Vinylpyrrolidone-vinyl acetate copolymers are
`known as “copovidone” and are commercially available from
`BASF Corporation as Kollidon VA 64. The polyvinylpyrroli-
`done 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 hav-
`ing a weight average molecular weight of 50,000-60,000. In
`general, the amount of polyvinylpyrrolidone contained in the
`compositions of the present invention will be 0.1 -3%, prefer-
`ably 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 sulfonic
`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 sul-
`fonic acid contained in the compositions of the present inven-
`tion will be 0.1-1%, preferably 0.15-0.4%, and most prefer-
`ably 0.25%.
`The compositions of the present invention comprise 0.17-
`0.62% olopatadine and a polymeric physical stability-en-
`hancing ingredient consisting essentially ofpolyvinylpyrroli-
`done or polystyrene sulfonic acid in an amount sufficient to
`enhance the physical stability of the solution. The composi-
`tions of the present invention do not contain polyvinyl alco-
`hol, polyvinyl acrylic acid, hydroxypropylmethyl cellulose,
`sodium carboxymethyl cellulose, xanthan gun1 or other poly-
`meric physical stability enhancing ingredient.
`The compositions of the present invention have a viscosity
`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 operations.
`In addition to the olopatadine and polyvinylpyrrolidone
`ingredients, the compositions ofthe present invention option-
`ally 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 antioxi-
`dants. Suitable tonicity-adjusting agents include mannitol,
`sodium chloride, glycerin, sorbitol and the like. Suitable pre-
`servatives include p-hydroxybenzoic acid ester, benzalko-
`nium chloride, benzododecinium bromide, polyquater-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`nium-1 and the like. Suitable chelating agents include sodium
`edetate and the like. Suitable buffering agents include phos-
`phates, borates, citrates, acetates and the like. Suitable sur-
`factants include ionic and nonionic surfactants, though non-
`ionic
`surfactants are preferred,
`such as polysorbates,
`polyethoxylated castor oil derivatives and oxyethylated ter-
`tiary octylphenol formaldehyde polymer (tyloxapol). Suit-
`able antioxidants include sulfites, ascorbates, BHA and BHT.
`The compositions of the present invention optionally com-
`prise an additional active agent. With the exception of the
`optional preservative ingredient (e.g., polyquatemium- 1), the
`compositions of the present invention preferably do not con-
`tain any polymeric ingredient other than polyvinylpyrroli-
`done 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 osmolality
`(generally 150-450 mOsm, preferably 250-350 mOsm). The
`ophthalmic compositions of the present invention preferably
`have a pH of 4-8, preferably a pH of 6.5-7.5, and most pref-
`erably 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 per-
`oxides,
`it can lead to discoloration (yellow to yellowish-
`brown) of the polyvinylpyrrolidone solution. In order to
`substantially reduce or eliminate peroxides without discolor-
`ing the polyvinylpyrrolidone solution, the pH of the aqueous
`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 peroxide
`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 ofthe solution to pH 11-13,
`preferably 1 1-1 1 .5, then heat to a temperature in the range of
`60-121 ° C., preferably 65-80° C. and most preferably 70-75°
`C. The elevated temperature should be maintained 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. A preferred container
`for an ophthalmic product is a low-density polyethylene con-
`tainer 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.
`
`000004
`
`000004
`
`

`
`5
`Certain embodiments of the invention are illustrated in the
`
`6
`Compounding Procedure
`
`US 7,402,609 B2
`
`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 chlo-
`ride, edetate disodium, benzalkonium chloride (as 1% stock
`solution) andpolyvinylpyrrolidone (as 4% stock solution) are
`added to a container, with mixing after adding each ingredi-
`ent. NaOH is added to adjust the pH to approximately pH 7,
`then the drug is added, followed by final pH adjustment 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 trans-
`ferred 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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
`to adjust the pH to approximately pH 6.5, then N-lauroylsar-
`cosine and then the drug is added, followed by final pH
`adjustment to pH 6 .5 and addition ofthe 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 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
`
`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 1 1.5, 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 chlo-
`ride, 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
`
`Olopatadine - HCl
`Polyvinylpyrrolidone
`Sodium Chloride
`Benzalkonium Chloride
`Edetate Disodium
`
`Concentration (% w/v)
`
`0.443*
`1.6-2.0
`0.3-0.6
`0.01 + 3% xs
`0.01
`
`000005
`
`000005
`
`

`
`7
`
`-continued
`
`US 7,402,609 B2
`
`8
`EXAMPLE 5
`
`Ingredient
`
`Dibasic Sodium Phosphate (Anhydrous)
`NaOH/HCl
`Purified Water
`
`Concentration (% w/v)
`0.5
`q.s. pH 3.8-4.4
`q.s. 100
`
`*equivalent to 0.4% free base
`
`5
`
`C OW WCI'C prepare
`C COIIIPOSI IOIIS S OWI1 III
`a C
`d
`1 b 1
`.t.
`Th
`h
`, T b1
`and subjected to stability studies. In no case was the poly-
`meric ingredient autoclaved and none of the compositions
`was filtered through a 0.2 um filter. One set of samples (two
`vials each) of each ofthe compositions was subjected to three
`
`The solution composition ofthis Example may be prepared 10 refrigerati011‘r00111 temperature eyeles and 3 Seeend Set
`(two vials each) was subj ected to continuous low-temperature
`using the procedure described above for the solution compo-
`sition of Example 3.
`exposure. The results are shown in Table 2 below.
`
`TABLE 1
`
`FORMULATION
`
`INGREDIENT
`
`Olopatadine.HCl
`Polyvinyl Alcohol
`(Airvol 2055)
`Hydroxypropyl
`Me rylcellulose
`(29 0)
`Xanthan Gum
`(AR)
`Caraopol 974P
`Polyvinyl
`pyrrolidone (wt.
`Avg. MW = 58K)
`So ium
`Car3oxymethyl-
`cellulose
`(762P)
`Benzalkonium
`Chloride
`So ium Chloride
`Dibasic Sodium
`Phosphate
`(an rydrous)
`NaOH/HCl
`Purified Water
`Viscosity* (cps)
`
`A
`
`B
`
`0.222
`0.1
`
`—
`
`—
`
`—
`—
`
`0.222
`
`0.05
`
`—
`
`—
`—
`
`C
`
`D
`Concentration (% w/w)
`0.222
`0.222
`0.222
`
`E
`
`F
`
`G
`
`0.222
`
`0.222
`
`0.02
`
`—
`—
`
`—
`
`0.01
`—
`
`—
`
`—
`1 .0
`
`—
`
`—
`1 .8
`
`—
`
`—
`—
`
`0.1
`
`0.01 + 1% 0.01 + 1% 0.01 + 1% 0.01 + 1% 0.01 + 1% 0.01 + 1% 0.01 + 1%
`xs
`xs
`xs
`xs
`xs
`xs
`xs
`0.6
`0.6
`0.6
`0.6
`0.6
`0.6
`0.6
`0.5
`0.5
`0.5
`0.5
`0.5
`0.5
`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
`
`T rree cycles
`
`Day 7
`
`Day 14
`
`C ear, no
`aartic es
`C ear, lots of C ear, lots of
`crysta s
`crystals
`C ear, no
`C ear, no
`aartic es
`particles
`C ear, no
`C ear, no
`aartic es
`particles
`C ear, no
`C ear, crystals
`aartic es
`
`C ear, crystals
`
`C ear, crystals
`
`C ear, crystals
`
`C ear, lots of
`crystals
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`C ear, lots of
`crystals
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`C ear, crystals
`
`C ear, no
`particles
`C ear, no
`particles
`C ear, crystals
`
`000006
`
`C ear, few
`particles
`
`C ear, fiber-
`ll{C particles
`
`C ear,
`particles and
`crystals
`
`C ear, crystals
`and fiber-like
`particles
`
`Day 28
`
`C ear,
`particles
`
`C ear, crystals
`
`C ear, no
`aartic es
`
`C ear, no
`aartic es
`
`C ear, few
`particles (one
`vial)
`C ear, a
`crystal (2 mm)
`observed in
`one vial)
`C ear, crystals
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`G
`
`000006
`
`

`
`US 7,402,609 B2
`
`9
`EXAMPLE 6
`
`The compositions shown in Table 3 below were subjected
`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, N.Y.) at 1 mg in 5 mL of
`formulation) and two temperatures (0° C. or —20° C.). In no
`.
`.
`.
`case was the polymeric ingredient autoclaVed and none of the
`
`Ingredient
`
`Concentration (% w/w)
`
`10
`
`TABLE 3-continued
`
`FORMULATION
`
`H
`
`I
`
`J
`
`Adjust PH
`7 0 + 0 2
`t
`S‘
`_10'O0/
`Q 0
`0
`
`Adjust PH
`7 0 + 0 2
`t
`S‘
`_10'O0/
`Q 0
`0
`
`Adjust PH
`7 0 + 0 2
`t
`S‘
`_10'O0/
`Q 0
`0
`
`TABLE 4
`
`filter. Each of the 10 NaOH/HCl
`compositions was filtered through a 0.2
`compositions (two Vials each) was subjected to SIX freeze-
`.
`.
`thaw cycles where one cycle was three days at low tempera-
`ture (i.e., either 0° C. or —20° C.), followed by one day at
`uncontrolled room temperature. The compositions were Visu-
`ally inspected and the results recorded. The results are shown
`in Table 4 below.
`
`P
`
`t
`_fi dw
`um C
`a er
`
`15
`
`TABLE 3
`
`FORMULATION
`
`H
`
`1
`
`J
`
`ngredient
`
`Concentration (% w/w)
`
`Olopatadine - HCl
`
`0.222
`
`0.222
`
`0.222
`
`3enzalkonium
`Chloride
`
`Edetate Dimdium
`{ydI°Xy1’r°1’y1
`methY1°e“”1°Se
`C5Ib°P°1 9741’
`’01yV1Hy1 31001101
`(A1I‘/01 2053)
`Sodium Chloride
`Dibasic Sodium
`’hosphate
`(Anhydrous)
`
`0.01 + 3% xs
`
`0.01 + 3% xs
`
`0.01 + 3% xs
`
`0'01
`1'8
`
`*
`—
`
`0.55
`0.5
`
`0'01
`”
`
`0-5
`‘
`
`0.55
`0.5
`
`0'01
`”
`
`*
`1-3
`
`0.55
`0.5
`
`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
`
`20
`
`25
`
`30
`
`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
`35 temperatures (0° C. or —20° C.). In no case was the polymeric
`ingredient autoclaVed and none of the compositions was fil-
`tered through a 0.2 um 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
`40 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
`
`K
`
`L
`
`M
`
`FORMULATION
`
`O
`N
`Concentration (% w/w)
`
`P
`
`Q
`
`R
`
`S
`
`0.222
`—
`
`0.333
`2
`
`0.333
`2
`
`0.333
`—
`
`0.222
`2
`
`0.222
`2
`
`—
`
`—
`
`0.01 + 3%
`xs
`0.5
`
`2
`
`—
`
`0.01
`
`0.5
`
`NGREDIENT
`
`Olopatadine.HCl
`’olyVinyl
`ayrrolidone (wt.
`Avg. MW = 58K)
`’olyethylene
`Glycol (400)
`’olyVinyl
`ayrrolidone (wt.
`avg. MW = 1300K)
`3enZalkonium
`Chloride
`Dibasic Sodium
`’hosphate
`(Anhydrous)
`Sodium Chloride
`Edetate Disodium
`NaOH/HCl
`’urified Water
`
`0.222
`—
`
`2
`
`—
`
`0.222
`1.8
`
`—
`
`—
`
`0.222
`—
`
`—
`
`1.8
`
`—
`
`—
`
`—
`
`—
`
`0.01 + 3% 0.01 + 3% 0.01 + 3% 0.01 + 3% 0.01 + 3%
`xs
`xs
`xs
`xs
`xs
`0.5
`0.5
`0.5
`0.5
`0.5
`
`2
`
`—
`
`0.01
`
`0.5
`
`—
`
`2
`
`0.01
`
`0.5
`
`0.55
`0.02
`q.s. pH 7
`q.s. 100
`
`0.3
`0.01
`q.s. pH 7
`q.s. 100
`
`0.3
`0.01
`q.s. pH 7
`q.s. 100
`
`0.55
`0.02
`q.s. pH 7
`q.s. 100
`
`0.55
`0.02
`q.s. PH 7
`q.s. 100
`
`0.6
`—
`q.s. pH 7
`q.s. 100
`
`0.55
`0.02
`q.s. pH 7
`q.s. 100
`
`0.3
`0.01
`q.s. pH 7
`q.s. 100
`
`0.3
`0.01
`q.s. pH 7
`q.s. 100
`
`000007
`
`000007
`
`

`
`US 7,402,609 B2
`
`12
`
`11
`
`TABLE 6
`
`were placed in scintillation vials containing stir bars and were
`subjected to freeze-thaw stability studies at two conditions
`and two temperatures (3-4° C. or —21° C.). After six cycles of
`3 days at low temperature and one day at room temperature
`(with stirring), the samples were subjected to 3.5 cycles of
`one week at low 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 until the end ofthe study. At the end ofthe study,
`the stir bars were removed and the samples (replicate samples
`of each composition) were visually inspected. The results are
`shown in Table 9.
`
`TABLE 9
`
`Polyvinylpyrrolidone
`(w/w);
`Sarnple wt. avg. MW)
`
`Fibers/
`Amorphous
`particles
`
`C arity
`
`Particulates
`
`Refrigeration Condition (3-4° C.)
`
`9.1A None
`9.1 3 None
`
`None
`Crystals
`
`C ear
`Fibers
`Amorphous Hazy
`Particles
`C ear
`Fibers
`C ear
`Fibers
`Maybe fibers C ear
`None
`C ear
`None
`C ear
`None
`C ear
`None
`C ear
`None
`C ear
`None
`C ear
`None
`C ear
`Fibers
`C ear
`
`Formu-
`lation
`K
`L
`M
`N
`O
`P
`
`Q
`R
`S
`
`Observation No. ofvials showing precipitation
`Seed
`Seed
`No Seed
`No Seed
`0° C.
`—20° C.
`0° C.
`—20° C.
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`1/3
`0/3
`2/3
`2/3
`(6 cycles)
`(6 cycles)
`0/3
`0/3
`(6 cycles)
`(6 cycles)
`0/3
`0/3
`3/3
`2/3
`
`3/3
`0/3
`3/3
`(3 cycles)
`
`3/3
`0/3
`3/3
`(3 cycles)
`
`# cycles
`6
`6
`6
`6
`6
`5
`
`5
`6
`5
`
`EXAMPLE 8
`
`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. followed
`by one week at uncontrolled room temperature (approx. 21°
`C.). For another set of samples, one cycle was defined as one
`week at —20° C. followed by one week at uncontrolled room
`temperature (approx. 21° C.). The results are shown in Table
`8.
`
`TABLE 7
`
`FORMULATION
`
`U
`T
`Concentration (% w/w)
`
`0.222
`0.25
`0.01
`0.05
`4.4
`0.45
`0.04
`q.s. pH 6.5
`q.s. 100
`
`0.222
`0.5
`0.01
`0.05
`4.4
`0.45
`0.04
`q.s. pH 6.5
`q.s. 100
`
`INGREDIENT
`
`Olopatadine - HCl
`Polystyrene Sulfonic Acid
`(Wt. Avg. MW = 1000K)
`Benzalkoniurn Chloride
`Edetate Disodium
`Mannitol
`Boric Acid
`N-lauroylsarcosine
`Trornetharnine/HCl
`Purified Water
`
`TABLE