`Castillo et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,995,186 B2
`Feb. 7, 2006
`
`US006995186B2
`
`(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 U.S. 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) U.S. 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
`5/1992 Oshima et al.
`........... .. 514/450
`5,116,863 A
`11/1992 Hettche .................... .. 424/489
`5,164,194 A
`6/1997 Hayakawa et al.
`....... .. 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
`
`3/2001 Aberg ...................... .. 514/324
`6,207,684 B1
`6,316,483 B1
`11/2001 Haslwanter et al.
`...... .. 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,” Arzneimittelforschung,
`vol. 45(9), p. 1005-1008 (1995).
`
`Ohshima et al., “Synthesis and Antiallergic Activity of
`11-(Aminoalkylidene)-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. of Pharma-
`cology 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 Ophthalmol-
`ogy & Wsual 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
`
`000001
`
`ARGENTUM PHARM. 1006
`
`ARGENTUM PHARM. 1006
`
`000001
`
`
`
`US 6,995,186 B2
`Page 2
`
`OIBER PUBLICATIONS
`
`Spitalny et al., "Olopatadine Ophthalmic Solution Decreases
`Itching and Redness Associated with Allergic Conjunctivi(cid:173)
`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
`
`000002
`
`
`
`US 6,995,186 B2
`
`1
`OLOPATADINE FORMULATIONS FOR
`TOPICAL ADMINISTRATION
`
`This application claims priority to U.S. Provisional
`Application Ser. No. 60/301,315, filed Jun. 27, 2001.
`
`BACKGROUND OF THE INVENTION
`
`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
`10 eye are desirable.
`
`5
`
`SUMMARY OF THE INVENTION
`
`The present invention provides topical olopatadine for(cid:173)
`mulations that are effective as once-a-day products for
`15 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 0.2-0.6%
`olopatadine. In addition to their relatively high concentra(cid:173)
`tion of olopatadine, they also contain an amount of polyvi(cid:173)
`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 0.2--0.6% olopatadine.
`
`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 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-
`dime thy laminopropy lidene )-6,11-dihydrodibenz[b,e] 20
`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(cid:173)
`taminic action because they are believed to inhibit the
`release of autacoids (i.e., histamine, serotonin, and the like) 25
`from mast cells and to inhibit directly histamine's effects on
`target tissues. The Burroughs Wellcome Patents teach vari(cid:173)
`ous pharmaceutical formulations containing the carboxylic
`acid derivatives of doxepin, including nasal spray and oph(cid:173)
`thalmic formulations. See, for example, Col. 7, lines 7-26, 30
`and Examples 8 (H) and 8 (I) of the '865 patent.
`U.S. Pat. No. 5,116,863, assigned to Kyowa Hakka
`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- 35
`dine is the cis form of the compound having the formula:
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`45
`
`Unless indicated otherwise, all component amounts are
`presented on a % (w/v) basis and all references to olopata(cid:173)
`dine 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 refer(cid:173)
`ence in the present specification. The solution formulations
`of the present invention contain 0.17--0.62% olopatadine.
`40 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(cid:173)
`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(cid:173)
`ceutically acceptable salts of olopatadine include inorganic
`acid salts such as hydrochloride, hydrobromide, sulfate and
`phosphate; organic acid salts such as acetate, maleate,
`50 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
`55 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-
`60 patadine is added to the compositions of the present inven(cid:173)
`tion in this salt form, 0.222% olopatadine hydrochloride is
`equivalent to 0.2% olopatadine free base, 0.443% olopata(cid:173)
`dine hydrochloride is equivalent to 0.4% olopatadine free
`base, and 0.665% olopatadine hydrochloride is equivalent to
`65 0.6% olopatadine free base.
`In addition to olopatadine, the aqueous solution compo(cid:173)
`sitions of the present invention comprise polyvinylpyrroli-
`
`Medicament forms taught by the Kyowa patent for the acetic
`acid derivatives of doxepin include a wide range of accept(cid:173)
`able carriers; however, only oral and injection administra(cid:173)
`tion forms are mentioned.
`U.S. Pat. No. 5,641,805, assigned to Alcon Laboratories,
`Inc. and Kyowa Hakka 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-
`
`000003
`
`
`
`US 6,995,186 B2
`
`10
`
`20
`
`3
`done or polystyrene sulfonic acid in an amount sufficient to
`enhance the physical stability of the composition. Polyvi(cid:173)
`nylpyrrolidone and polystyrene sulfonic acid are known
`polymers and both are commercially available from a vari(cid:173)
`ety of sources in different grades and in a number of 5
`molecular weights. For example, polyvinylpyrrolidone is
`available in many grades from International Specialty Prod(cid:173)
`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(cid:173)
`mers of vinylpyrrolidone and copolymers of vinylpyrroli(cid:173)
`done and vinyl acetate. Vinylpyrrolidone-vinyl acetate 15
`copolymers are known as "copovidone" and are commer(cid:173)
`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(cid:173)
`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=l,000,000). As used herein,
`"polystyrene sulfonic acid" includes homopolymers of sty(cid:173)
`rene sulfonic acid and salts, as well as copolymers of styrene
`sulfonic acid and maleic anhydride. The polystyrene sul(cid:173)
`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%.
`The compositions of the present invention comprise
`0.17--0.62% olopatadine and a polymeric physical stability(cid:173)
`enhancing ingredient consisting essentially of polyvinylpyr(cid:173)
`rolidone or polystyrene sulfonic acid in an amount sufficient
`to enhance the physical stability of the solution. The com(cid:173)
`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(cid:173)
`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(cid:173)
`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,
`
`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(cid:173)
`ent other than polyvinylpyrrolidone or polystyrene sulfonic
`acid.
`Particularly for compositions intended to be administered
`as eye drops, the compositions preferably contain a tonicity(cid:173)
`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(cid:173)
`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
`25 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-
`30 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
`35 above room temperature) prior to mixing with olopatadine in
`order to reduce the amount of peroxides in the polyvinylpyr(cid:173)
`rolidone ingredient and minimize the effect of peroxides on
`the chemical stability of olopatadine. While thermally treat(cid:173)
`ing an aqueous solution of polyvinylpyrrolidone for pro-
`40 longed periods will substantially reduce the amount of
`peroxides, it can lead to discoloration (yellow to yellowish(cid:173)
`brown) of the polyvinylpyrrolidone solution. In order to
`substantially reduce or eliminate peroxides without discol(cid:173)
`oring the polyvinylpyrrolidone solution, the pH of the aque-
`45 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(cid:173)
`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
`55 range of 60-121° C., preferably 65-80° C. and most pref(cid:173)
`erably 70-75° C. The elevated temperature should be main(cid:173)
`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
`60 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
`container that has been sterilized using ethylene oxide
`65 instead of gamma-irradiation. A preferred container for a
`nasal product is a high-density polyethylene container
`equipped with a nasal spray pump.
`
`50
`
`000004
`
`
`
`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.RC!
`("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 ± 0.2
`q.s. 100
`
`5
`
`10
`
`15
`
`20
`
`6
`to adjust the pH to approximately pH 6.5, then
`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(cid:173)
`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
`
`Preparation of Polyvinylpyrrolidone Stock Solution
`
`A 4% stock solution of polyvinylpyrrolidone is prepared by
`dissolving the polyvinylpyrrolidone in purified water, add(cid:173)
`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(cid:173)
`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
`
`A representative compounding procedure for the solution
`30 composition of this Example is provided below.
`
`25
`
`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(cid:173)
`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 35
`ingredient. NaOH is added to adjust the pH to approximately
`pH 7, then the drug is added, followed by final pH adjust(cid:173)
`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 40
`and transferred under sterile conditions into ethylene oxide(cid:173)
`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
`
`0.222*
`0.04
`0.5
`4.4
`0-0.02
`0.45
`0.05
`q.s. pH 6.5 ± 0.2
`q.s. 100
`
`*equivalent to 0.2% free base
`
`45
`
`50
`
`55
`
`60
`
`A representative compounding procedure for the solution
`composition of this Example is provided below.
`Compounding Procedure
`Purified water, mannitol, boric acid, edetate disodium, ben(cid:173)
`zalkonium chloride (as 1 % stock solution) and polystyrene 65
`sulfonic acid (as a powder) are added to a container, with
`mixing after adding each ingredient. Tromethamine is added
`
`000005
`
`
`
`US 6,995,186 B2
`
`7
`The solution composition of this Example may be pre(cid:173)
`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 µm 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
`5 (two vials each) was subjected to continuous low(cid:173)
`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
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`Polyvinyl Alcohol
`
`0.1
`
`(Airvol 2055)
`
`Hydroxypropyl
`
`Methylcellulose (2910)
`
`Xanthan Gum (AR)
`
`Carbopol 974P
`
`Polyvinyl pyrrolidone
`
`(wt. Avg. MW ~ 58K)
`
`Sodium Carboxymethyl-
`
`cellulose (7 62P)
`
`Benzalkonium
`
`Chloride
`
`0.05
`
`0.02
`
`0.01
`
`1.0
`
`1.8
`
`0.01 +
`
`1% XS
`
`0.01 +
`
`1% XS
`
`0.01 +
`
`1% XS
`
`0.6
`
`0.01 +
`
`1% XS
`
`0.6
`
`0.01 +
`
`1% XS
`
`0.6
`
`0.01 +
`
`1% XS
`
`0.6
`
`0.1
`
`0.01 +
`
`1% XS
`
`0.6
`
`Sodium Chloride
`
`Dibasic Sodium
`
`0.6
`
`0.5
`
`0.6
`
`0.5
`
`Phosphate (anhydrous)
`
`0.5
`
`0.5
`
`0.5
`
`0.5
`
`0.5
`
`NaOH/HCl
`
`q.s. pH 7
`
`q.s. pH 7
`
`q.s. pH 7
`
`q.s. pH 7
`
`q.s. pH 7
`
`q.s. pH 7
`
`q.s. pH 7
`
`Purified Water
`
`q.s. 100
`
`q.s. 100
`
`q.s. 100
`
`q.s. 100
`
`q.s. 100
`
`q.s. 100
`
`q.s. 100
`
`Viscosity* (cps)
`
`1.02
`
`1.40
`
`1.42
`
`0.97
`
`1.20
`
`1.45
`
`1.16
`
`*Brookfield viscometer (60 RPM, CP-42)
`
`TABLE 2
`
`Refrigeration - RT cycles
`
`Continuous low-temperature exposure
`
`Formulation One cycle
`
`Three cycles
`
`Day 7
`
`Day 14
`
`Day 28
`
`Clear, few
`particles (one
`vial)
`Clear,
`Clear, a
`crystal (2 mm) particles and
`crystals
`observed in
`one vial)
`Clear, crystals Clear, crystals Clear, crystals Clear, crystals
`
`Clear, fiber-
`like particles
`
`Clear,
`particles
`
`Clear, crystals Clear, crystals
`and fiber-like
`particles
`
`Clear, no
`particles
`
`Clear, no
`particles
`
`Clear, few
`particles
`
`A
`
`B
`
`c
`
`D
`
`E
`
`F
`
`G
`
`Clear, no
`particles
`Clear, lots of
`Clear, lots of
`Clear, lots of Clear, lots of
`crystals
`crystals
`crystals
`crystals
`Clear, no
`Clear, no
`Clear, no
`Clear, no
`Clear, no
`particles
`particles
`particles
`particles
`particles
`Clear, no
`Clear, no
`Clear, no
`Clear, no
`Clear, no
`particles
`particles
`particles
`particles
`particles
`Clear, no
`Clear, crystals Clear, crystals Clear, crystals Clear, crystals
`particles
`
`Clear, crystals
`
`000006
`
`
`
`US 6,995,186 B2
`
`9
`EXAMPLE 6
`
`Ingredient
`
`NaOH/HCl
`
`Purified Water
`
`The compositions shown in Table 3 below were subjected 5
`to freeze-thaw stability studies at two conditions (with and
`without seed; seed=0-¥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 compositions was filtered through a 0.2 µm 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.
`
`10
`
`10
`
`TABLE 3-continued
`
`FORMULATION
`
`H
`
`Concentration ( % w/w)
`
`Adjust pH
`7.0 ± 0.2
`QS to 100%
`
`Adjust pH
`7.0 ± 0.2
`QS to 100%
`
`Adjust pH
`7.0 ± 0.2
`QS to 100%
`
`TABLE 4
`
`FORMULATION
`
`OBSERVATION
`
`H
`
`No precipitation after 6 cycles with or without
`seed at either temperature
`Hazy from 1st 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
`
`TABLE 3
`
`FORMULATION
`
`H
`
`Ingredient
`
`Concentration ( % w/w)
`
`Olopatadine.HCl
`Benzalkonium
`Chloride
`Edetate Disodium
`Hydroxypropyl
`methyl-cellulose
`Carbopol 974P
`Polyvinyl alcohol
`(Airvol 205S)
`Sodium Chloride
`Dibasic Sodium
`Phosphate
`(Anhydrous)
`
`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
`
`0.01
`
`0.6
`
`0.55
`0.5
`
`1.8
`
`0.55
`0.5
`
`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
`temperatures (0° C. or -20° C.). In no case was the poly(cid:173)
`meric ingredient autoclaved and none of the compositions
`was filtered through a 0.2 µm filter. Each of the compositions
`35 (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
`
`INGREDIENT
`
`Concentration (% w/w)
`
`K
`
`L
`
`M
`
`N
`
`0
`
`p
`
`Q
`
`R
`
`s
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.222
`
`0.333
`
`0.333
`
`0.333
`
`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
`
`2
`
`0.01 +
`3% XS
`
`0.5
`
`0.55
`
`0.02
`
`2
`
`2
`
`0.01
`
`0.5
`
`0.3
`
`0.01
`
`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
`
`1.8
`
`2
`
`2
`
`0.01 +
`3% XS
`
`0.5
`
`0.01 +
`3% XS
`
`0.5
`
`1.8
`
`0.01 +
`3% XS
`
`0.5
`
`0.3
`
`0.01
`
`0.55
`
`0.02
`
`0.55
`
`0.02
`
`2
`
`2
`
`2
`
`0.01 +
`3% XS
`
`0.5
`
`0.6
`
`0.01 +
`3% XS
`
`0.5
`
`0.01
`
`0.01
`
`0.5
`
`0.5
`
`0.55
`
`0.02
`
`0.3
`
`0.01
`
`0.3
`
`0.01
`
`000007
`
`
`
`US 6,995,186 B2
`
`12
`
`11
`
`TABLE 6
`
`Observation (No. of vials showing precipitation)
`
`Formulation #cycles Seed 0° C. Seed -20° C. No Seed 0° C. No Seed -20° C.
`
`K
`L
`M
`N
`0
`p
`
`Q
`
`R
`s
`
`0/3
`0/3
`0/3
`0/3
`0/3
`1/3
`
`3/3
`
`0/3
`3/3
`(3 cycles)
`
`0/3
`0/3
`0/3
`0/3
`0/3
`0/3
`(6 cycles)
`0/3
`(6 cycles)
`0/3
`3/3
`
`0/3
`0/3
`0/3
`0/3
`0/3
`2/3
`
`3/3
`
`0/3
`3/3
`(3 cycles)
`
`6
`5
`
`5
`
`6
`5
`
`0/3
`0/3
`0/3
`0/3
`0/3
`2/3
`(6 cycles)
`0/3
`(6 cycles)
`0/3
`2/3
`
`EXAMPLE 8
`
`20
`
`TABLE 8
`
`FORMULATION
`
`OBSERVATION
`
`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
`(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 30
`are shown in Table 8.
`
`TABLE 7
`
`INGREDIENT
`
`Olopatadin.HCl
`Polystyrene Sulfonic Acid
`(Wt. Avg. MW ~ lOOOK)
`Benzalkonium Chloride
`Edetate Disodium
`Mannitol
`Boric Acid
`N-lauroylsarcosine
`Tromethamine/HCl
`Purified Water
`
`FORMULATION
`
`u
`T
`Concentration (% w/w)
`
`0.222
`0.25
`
`0.222
`0.5
`
`0.01
`0.05
`4.4
`0.45
`0.04
`q.s. pH 6.5
`q.s. 100
`
`0.01
`0.05
`4.4
`0.45
`0.04
`q.s. pH 6.5
`q.s. 100
`
`T
`u
`
`No precipitation at either temperature
`No precipitation at either temperature
`
`EXAMPLE 9
`
`Seven compositions were prepared and subjected to
`freeze-thaw stability studies. Each of the seven composi(cid:173)
`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