(12) United States Patent
`Singh et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,399,508 B2
`*Mar. 19, 2013
`
`US008399508B2
`
`(54)
`
`(75)
`
`(73)
`
`(*)
`
`(21)
`(22)
`(65)
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`OLOPATADINE FORMULATIONS FOR
`TOPICAL NASAL ADMINISTRATION
`
`Inventors: Onkar N. Singh, Arlington, TX (US); G.
`Michael Wall, Fort Worth, TX (US);
`Rajni Jani, Fort Worth, TX (US);
`Masood A. Chowhan, Arlington, TX
`(US); Wesley Wehsin Han, Arlington,
`TX (US)
`Alcon Pharmaceuticals Ltd., Fribourg
`(CH)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 90 days.
`
`Assignee:
`
`Notice:
`
`This patent is subject to a terminal dis-
`claimer.
`
`Appl. No.: 13/173,608
`Filed:
`Jun. 30, 2011
`Prior Publication Data
`
`US 2011/0306659 A1
`
`Dec. 15,2011
`
`Related U.S. Application Data
`
`Continuation of application No. 11/703,373, filed on
`Feb. 7, 2007, now Pat. No. 7,977,376, which is a
`continuation-in-part of application No. 11/079,996,
`filed on Mar. 15, 2005, now Pat. No. 7,402,609, which
`is a continuation of application No. 10/175,106, filed
`on Jun. 19, 2002, now Pat. No. 6,995,186.
`
`Provisional application No. 60/301,315, filed on Jun.
`27, 2001.
`
`Int. Cl.
`
`(2006.01)
`A 61K 31/335
`U.S. Cl.
`...................................... .. 514/450; 424/810
`Field of Classification Search ...................... .. None
`
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`10/1983 Stark
`6/1988 Wenig
`
`4,407,791 A
`4,749,700 A
`
`10/1988 Linder et al.
`4,778,596 A
`10/1989 Lever, Jr. et al.
`4,871,865 A
`5/1990 Lever, Jr. et al.
`4,923,892 A
`5/1992 Oshima et al.
`5,116,863 A
`11/1992 Hettche
`5,164,194 A
`8/1995 Clark et al.
`5,443,833 A
`12/1995 Geria
`5,478,565 A
`1/1996 Igari et al.
`5,482,706 A
`6/1997 Hayakawa et al.
`5,641,805 A
`4/2000 Francois et al.
`6,054,462 A
`11/2000 Castillo et al.
`6,146,622 A
`1/2001 Yanni et al.
`6,174,914 B1
`3/2001 Aberg
`6,207,684 B1
`8/2001 Jonasse et al.
`6,274,626 B1
`11/2001 Haslwanter et al.
`6,316,483 B1
`12/2001 Santus et al.
`6,333,044 B1
`2/2006 Castillo et al.
`6,995,186 B2
`12/2001 Yanni
`2001/0056093 A1
`5/2006 Cagle et al.
`2006/0110328 A1
`FOREIGN PATENT DOCUMENTS
`0048023
`3/1982
`0214779
`3/1987
`0235796
`9/1987
`61926
`3/1995
`WO0003705
`1/2000
`WO0121209
`3/2001
`
`EP
`EP
`EP
`JP
`WO
`WO
`
`(Continued)
`
`OTHER PUBLICATIONS
`
`Church, Martin K., Is Inhibition of Mast Cell Mediator Release
`Relevant to the Clinical Activity ofAnti-Allergic Drugs?, Agents and
`Actions, 1986, pp. 288-293, vol. 18, 3/4.
`
`(Continued)
`
`Primary Examiner — Brian Gulledge
`Assistant Examiner — Isaac Shomer
`
`(74) Attorney, Agent, or Firm — Patrick M. Ryan
`
`(57)
`
`ABSTRACT
`
`Topical formulations of olopatadine for treatment of allergic
`or inflammatory disorders of the nose are disclosed. The
`aqueous formulations contain approximately 0.6% (w/v) of
`olopatadine.
`
`2 Claims, 6 Drawing Sheets
`
`Solubility
`
`(%)
`
`360
`
`4.00
`
`4.40
`
`4,50
`
`5.20
`
`6.00
`
`6.24::
`
`3.30
`
`7.20
`
`7.80
`
`8.00
`
`PH
`
`000001
`
`ARGENTUM PHARM. 1048
`
`ARGENTUM PHARM. 1048
`
`000001
`
`

`
`US 8,399,508 B2
`Page 2
`
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`WO0121210
`3/2001
`WO0135963
`5/2001
`WO0154687 A1
`8/2001
`WO0230395 A1
`4/2002
`WO03002093 A1
`1/2003
`WO2004043470 A1
`5/2004
`
`OTHER PUBLICATIONS
`
`Clegg, L.S., et al., Histamine Secretion From Human Skin Slices
`Induced by Anti-IgR and Artificial Secretagogues and the Effects of
`Sodium Cromoglycate and Salbutamol, Clinical Allergy, 1985, pp.
`321-328, vol. 15.
`Hamilton, S,A., et al., Comparison of a New Antihistaminic and
`Antiallergic Compound KW 4679 with Terfenadine and Placebo on
`Skin and Nasal Provocation in Atopic Individuals, Clinical and
`Experimental Allergy, 1994, pp. 955-959, vol. 24.
`Ikeda, Katsuhisa, 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., 1995, pp. 157-162, vol.
`106.
`Irani, Anne-Marie A., et al., Mast Cell Heterogeneity, Clinical and
`Experimental Allergy, 1989, pp. 143-155, vol. 19.
`Kamei, C., et al.; Effect of (Z)-1 1 -[3 -(Dimethylamino) propylidene]-
`6, 11-dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride on
`Experimental Allergic Conjunctivitis and Rhinitis in Rats and Guinea
`Pigs, Arzneimittelforschung, 1995, pp. 1005-1008, vol. 45(9).
`Kamei, Chiaki, et al., Effects of Certain Antiallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs, Atarashii Ganka, 1994,
`pp. 603-605, vol. 11(4) (abstract only).
`Ohshima, Etsuo, et al., Synthesis and Antiallergic Activity of
`11-(Arninoalkylidene)-6, 11, dihydrodibenz[b,e]oxepin Derivatives,
`J. Medicinal Chemistry, 1992, pp. 2074-2054, vol. 35(11).
`Pearce, Cheryl A., et al., Effect of Disodium Cromoglycate on Anti-
`gen-Evoked Histamine Release From Human Skin, Clinical Exp.
`Immunol., 1974, pp. 437-440, vol. 17.
`
`Pujara, et al., Effects of Formulation Variables on Nasal Epithelial
`Cell
`Integrity: Biochemical Evaluations,
`International
`J. of
`Pharmaceutics, 1995, pp. 197-203, vol. 114.
`Sharif. N.A., et al., Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatedine (AL-4943A), a Novel Drug
`for Treating Ocular Allergic Diseases, J. of Pharmacology and
`Experimental Therapeutics, 1996; pp. 1252-1261, vol. 278(3).
`Sharif, N.A., et al., Olopatadine (AL-4943A): Pharmacological Pro-
`file of a Novel Anti-Histaminic/Anti-Allergic Drug for Use in Aller-
`gic Compounds, Investigative Ophthalmology & Visual Science,
`1996, p. 1027, Vol, 37(3) (abstract only).
`Siraganian, Reuben P., An Automated Continuous Flow System for
`the Extraction and Fluorometric Analysis of Histamine, Anal.
`Biochem., 1974, pp. 383-394, vol. 57.
`Spitalny, L., et al., Olopatadine Ophthalmic Solution Decreases Itch-
`ing and Redness Associated with Allergic Conjunctivitis, Investiga-
`tive Ophthalmology & Visual Science, 1996, p. 593, vol. 37(3)
`(abstract only).
`LB Schwartz, TF Huff. “Mast Cells.” The Lung, Scientific Founda-
`tion, 1991, Ch. 3.4.11, Raven Press, Ltd., NewYork, pp. 601-615.
`Yanni; J.M., et al., The In Vitro and In Vivo Ocular Pharmacology of
`Olopatadine (AL-4943A), An Effective Anti-Allergic/Anti-Hista-
`mine Agent, Investigative Ophthalmology &Visual Science, 1996, p.
`1028, vol. 37(3) (abstract only).
`Zhang, Ming-Qiang, et al., Optically Active Analogues of Ebastine:
`Synthesis and Effect of Chirality on Their Antihistaminic Activity,
`Chirality, 1994, p. 631-641, vol. 6(8).
`Astelin® Nasal Spray Product Insert, Jun. 7, 2002, 1 1 printed pages.
`Ratner, P.H., et al., Safety and Efficacy ofOlopatadine Hydrochloride
`Nasal Spray for the Treatment of Seasonal Allergic Rhinitis to Mount
`Cedar, Annals Allergy Asthsma Immunol., 2005, pp. 474-479, vol.
`95.
`Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical
`Science, Jan. 1977, pp. 1-19, vol. 66, No. 1.
`
`000002
`
`000002
`
`

`
`U.S. Patent
`
`Mar. 19, 2013
`
`Sheet 1 of6
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`US 8,399,508 B2
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`U.S. Patent
`
`Mar. 19, 2013
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`U.S. Patent
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`Mar. 19, 2013
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`US 8,399,508 B2
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`U.S. Patent
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`Mar. 19, 2013
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`
`U.S. Patent
`
`Mar. 19, 2013
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`
`US 8,399,508 B2
`
`1
`OLOPATADINE FORMULATIONS FOR
`TOPICAL NASAL ADMINISTRATION
`
`This application is a continuation application of Ser. No.
`11/703,373, filed Feb. 7, 2007, which is a continuation-in-
`part application of Ser. No. 11/079,996, filed Mar. 15, 2005,
`which is a continuation of Ser. No. 10/175,106, filed Jun. 19,
`2002, which claims priority to U.S. Provisional Application
`Ser. No. 60/301,315, filed Jun. 27, 2001, all of which are
`.
`.
`incorporated herein by reference.
`
`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 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 histarnine’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
`
`O
`
`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.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`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 60
`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 65
`the like” are mentioned as the viscous vehicle. See Col. 6,
`lines 55-57.
`
`2
`
`PATANOL® (olopatadine hydrochloride ophthalmic solu-
`tion) 0.1% is currently the only commercially available olo-
`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.
`Topical olopatadine formulations that are effective as prod-
`ucts for treating allergic or inflammatory conditions in the
`nose are desirable.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides topical olopatadine formu-
`lations that are effective as products for treating allergic or
`inflammatory disorders of the nose. The formulations of the
`present
`invention are aqueous
`solutions that comprise
`approximately 0.6% olopatadine. Despite their relatively
`high concentration of olopatadine, they do not contain any
`polymeric ingredient as a physical stability enhancing ingre-
`dient. The formulations contain a phosphate salt that permits
`the pH of the formulations to be maintained within the range
`3.5-3.95 and that also aids in solubilizing the olopatadine
`drug in the presence of sodium chloride.
`Among other factors, the present invention is based on the
`finding that stable, nasal spray, solution formulations of olo-
`patadine can be prepared within a pH range of 3 .5-3 .95 using
`a phosphate buffer without the need for any polymeric ingre-
`dient to enhance the solubility or physical stability of the
`formulation.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGS. 1A and 1B show the pH-solubility profile of olo-
`patadine.
`FIG. 2 shows the effect of NaCl and Na2HPO4 on the
`dissolution of olopatadine in water.
`FIG. 3 shows the effect of NaCl and Na2HPO4 on the
`dissolution of olopatadine in a nasal vehicle.
`FIG. 4 shows the effect of NaCl and Na2HPO4 concentra-
`tions on the dissolution rate of olopatadine in a nasal vehicle.
`FIG. 5 shows the buffer capacity of an olopatadine nasal
`spray composition.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Unless indicated otherwise, all component amounts are
`presented on a % (w/v) basis and all references to amounts of
`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 0.54-0.62% olopatadine. Prefer-
`ably, the solution formulations contain 0.6% olopatadine.
`Olopatadine has both a carboxylic functional group
`(pKa1:4.18) and a tertiary amino group (pKa2:9.79). It exists
`in different ionic forms depending upon the pH of the solu-
`tion. Olopatadine exists predominantly as a zwitterion in the
`pH range between the two pKa values with a negatively-
`charged carboxylic group and a positively-charged tertiary
`amino group. The iso-electric point of the olopatadine zwit-
`terion is at pH 6.99. At a pH lower than pKa1, cationic olo-
`patadine (with ionized tertiary amino group) is dominant. At
`a pH higher than pKa2, anionic olopatadine (with ionized
`carboxylic group) is dominant.
`
`000009
`
`000009
`
`

`
`3
`Acid-Base Equilibrium of Olopatadine
`
`US 8,399,508 B2
`
`H3C
`\N+
`H30’
`\H
`
`
`
`Zwitterion
`
`In many zwitterionic molecules, such as various amino
`acids, intra-molecular ionic interactions are not significant or
`do not exist. But the structure of olopatadine is such that
`intra-molecular interactions exist and are significant, possi-
`bly due to the distance and bonding angle between the oppo-
`sitely charged functional groups. This interaction effectively
`reduces the ionic and dipole character of the molecule. The
`net effect of the intra-molecular interactions between the
`
`oppositely charged functional groups is the reduction of
`aqueous solubility of olopatadine. Olopatadine has the pH-
`solubility profile shown in FIGS. 1A (theoretical) and 1B
`(obtained using phosphate buffer).
`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 tromethamine), 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)-l l -(3 -dimethylaminopropylidene)-6,l l-dihydro-
`dibenz-[b,e]oxepin-2-acetic acid. When olopatadine is added
`to the compositions of the present invention in this salt form,
`0.665% olopatadine hydrochloride is equivalent to 0.6% olo-
`patadine free base. Preferably the compositions ofthe present
`invention comprise approximately 0.665% olopatadine
`hydrochloride.
`In addition to olopatadine, the aqueous solution composi-
`tions of the present invention comprise a phosphate salt. The
`phosphate salt not only helps maintain the pH of the compo-
`sitions within the targeted pH range of 3.5-3.95 by contrib-
`uting to the buffer capacity ofthe compositions, but also helps
`solubilize olopatadine. Suitable phosphate salts for use in the
`compositions of the present invention include monobasic
`sodium phosphate, dibasic sodium phosphate,
`tribasic
`sodium phosphate, monobasic potassium phosphate, dibasic
`potassium phosphate, and tribasic potassium phosphate. The
`most preferred phosphate salt is dibasic sodium phosphate.
`The compositions of the present
`invention comprise an
`amount of phosphate salt equivalent (on an osmolality con-
`tribution basis) to 0.2-0.8%, preferably 0.3-0.7%, and most
`preferably 0.4-0.6% of dibasic sodium phosphate. In a pre-
`ferred embodiment, the phosphate salt is dibasic sodium
`phosphate at a concentration of 0.4-0.6% (w/v). In a most
`preferred embodiment, the compositions contain 0.5% (w/v)
`dibasic sodium phosphate.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Phosphate buffer is commonly used in aqueous pharma-
`ceutical compositions formulated near neutral pH. Phosphate
`buffer (pKa1:2.l2, pKa2:7.l, pKa3:l2.67) would not nor-
`mally be chosen for an aqueous composition with a target pH
`range of 3.5-3.95 because it has low buffer capacity in that
`region. Other buffering agents are commonly used in aqueous
`pharmaceutical compositions, including acetate, citrate and
`borate buffers, but are not suitable for use in the topical nasal
`compositions of the present invention. Borate buffers are not
`suitable because they do not have any significant buffer
`capacity in the pH range 3 .5-3.95. Though acetate and citrate
`buffers have buffer capacity in this region, they are not pre-
`ferred because they have the potential to cause irritation to
`nasal mucosal tissues and undesirable taste and/or smell.
`
`In addition to olopatadine and phosphate salt, the compo-
`sitions ofthe present invention comprise sodium chloride as a
`tonicity-adjusting agent. The compositions contain sodium
`chloride in an amount sufficient to cause the final composition
`to have a nasally acceptable osmolality, preferably 240-350
`mOsm/kg. Most preferably, the amount of sodium chloride in
`the compositions of the present invention is an amount sulfi-
`cient to cause the compositions to have an osmolality of
`260-330 mOsn1/kg. In a preferred embodiment, the compo-
`sitions contain 0.3-0.6% sodium chloride. In a more preferred
`embodiment, the compositions contain 0.35-0.55% sodium
`chloride, and in a most preferred embodiment, the composi-
`tions contain 0.35-0.45% sodium chloride.
`
`The compositions of the present invention also contain a
`pharmaceutically acceptable pH-adjusting agent. Such pH-
`adjusting agents are known and include, but are not limited to,
`hydrochloric acid (HCl) and sodium hydroxide (NaOH). The
`compositions of the present invention preferably contain an
`amount of pH-adjusting agent sufficient to obtain a compo-
`sition pH of3.5-3.95, and more preferably, a pH of 3.6-3.8.
`In one embodiment,
`the aqueous compositions of the
`present invention consist essentially of olopatadine, phos-
`phate buffer, sodium chloride, a pH-adjusting agent, and
`water, and have a pH from 3.5-3.95. These compositions can
`be manufactured as sterile compositions and packaged in
`multi-dose, pressurized aerosol containers to avoid microbial
`contamination. In another embodiment, the aqueous compo-
`sitions of the present invention contain a preservative and a
`chelating agent such that the compositions pass United States
`Pharmacopeia/National Formulary XXX criteria for antimi-
`crobial effectiveness, and more preferably the Pharm. Eur. 5”’
`Edition criteria for antimicrobial preservation (Pharm. Eur. B
`preservative effectiveness standard). Suitable preservatives
`include p-hydroxybenzoic acid ester, benzalkonium chloride,
`benzododecinium bromide, and the like. Suitable chelating
`agents include sodium edetate and the like. The most pre-
`ferred preservative ingredient for use in the compositions of
`
`000010
`
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`
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`
`US 8,399,508 B2
`
`5
`the present invention is benzalkonium chloride (“BAC”). The
`amount of benzalkonium chloride is preferably 0.005-
`0.015%, and more preferably 0.01%. The most preferred
`chelating agent is edetate disodium (“EDTA”). The amount of
`edetate disodium in the compositions of the present invention
`is preferably 0.005-0.015%, and more preferably 0.01%.
`The aqueous solution compositions of the present inven-
`tion do not contain a polymeric ingredient
`intended to
`enhance the solubility of olopatadine or the physical stability
`of the solution. For example, the compositions of the present
`invention do not contain polyvinylpyrrolidone, polystyrene
`sulfonic acid, polyvinyl alcohol, polyvinyl acrylic acid,
`hydroxypropylmethyl cellulose, sodium carboxymethyl cel-
`lulose or xanthan gum.
`The compositions of the present invention are preferably
`packaged in opaque plastic containers. A preferred container
`is a high-density polyethylene container equipped with a
`nasal spray pump. Preferably, the package is designed to
`provide the spray characteristics described in commonly-
`assigned, co-pending, U.S. Patent Application Publication
`No. 2006/0110328, which is incorporated herein by refer-
`ence.
`
`The present invention also relates to a method of treating
`allergic rhinitis comprising topically administering to the
`nasal cavities a composition containing 0.6% olopatadine,
`phosphate buffer, sodium chloride, a pH-adjusting agent, and
`water. The compositions optionally contain one or more pre-
`servative ingredients. Preferably,
`the compositions are
`administered such that 1200 mcg of olopatadine (e.g., 600/
`mcg per 100 microliter spray><two sprays) is delivered to each
`nostril twice per day.
`Certain embodiments of the invention are illustrated in the
`
`following examples.
`
`Example 1
`
`Topically Administrable Nasal Solution
`
`TABLE 1
`
`Ingredient
`
`Olopatadine Hydrochloride
`Benzalkonium Chloride
`Edetate Disodium, Dihydrate
`Sodium Chloride
`Dibasic Sodium Phosphate, Anhydrous
`Hydrochloric Acid and/or Sodium Hydroxide
`Purified Water
`
`Amount (%, w/v)
`
`0.665“
`0.01
`0.01
`0.41
`0.5
`Adjust to pH 3.7 1 0.1
`qs to 100
`
`“0.665% w/V olopatadine hydrochloride (665 mcg/100 microliter spray) is equivalent to
`0.6% w/V olopatadine as base (600 mcg/100 microliter spray).
`
`An exemplary compounding procedure for the nasal compo-
`sition shown in Table 1 is described as below.
`
`1. Tare a suitable compounding vessel with magnetic stir bar.
`Add approximately 80% of the batch weight of purified
`water.
`
`2. While stirring, add dibasic sodium phosphate (anhydrous),
`sodium chloride, edetate disodium, benzalkonium chloride
`and olopatadine HCl.
`3. Add equivalent to approximately 0.55 g, 6N hydrochloric
`acid per 100 ml batch.
`4. Allow adequate time between each addition for dissolution
`of each ingredient
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`5. Add purified water to approximately 90% of final batch
`weight.
`6. Measure pH and adjust, ifnecessary, to 3.7 with 6N (and/or
`1N) hydrochloric acid and 1N sodium hydroxide.
`7. Adjust to final batch weight with purified water (QS).
`8. Measure final pH.
`9. Filter through 0.2 um filtration membrane.
`
`Example 2
`
`Effect of NaCl and Phosphate Buffer on Dissolution
`of Olopatadine Hydrochloride
`
`The effect of NaCl on the dissolution rate of olopatadine
`hydrochloride in water was determined. NaCl caused a sig-
`nificant reduction in the rate of dissolution of olopatadine.
`With addition of Na2HPO4, however, the dissolution of olo-
`patadine was dramatically improved. The complete dissolu-
`tion of 0.6% olopatadine solution without Na2HPO4 would
`take at least several hours assuming that the entire amount of
`olopatadine would eventually dissolve, but with Na2HPO4 it
`takes less than one minute. The results are shown in FIG. 2.
`
`Example 3
`
`Effect of NaCl and Na2HPO4 on the Dissolution
`Olopatadine Hydrochloride in a Nasal Vehicle
`
`The effect of NaCl, Na2HPO4, and mannitol on the disso-
`lution rate of olopatadine hydrochloride in a nasal formula-
`tion containing 0.01% EDTA and 0.01% BAC was deter-
`mined. The results are shown in FIG. 3. The effect of
`
`phosphate salt in this vehicle is the same as that shown in
`water in Example 2.
`
`Example 4
`
`Effect of NaCl and Na2HPO4 Concentrations on
`Dissolution
`
`The effect of NaCl and Na2HPO4 concentrations on the
`dissolution rate of olopatadine hydrochloride in a nasal for-
`mulation containing 0.01% EDTA and 0.01% BAC was deter-
`mined. The results are shown in FIG. 4. The aqueous solubil-
`ity of olopatadine HCl
`decreases with
`increasing
`concentration ofNaCl. However, increasing phosphate buffer
`correlates with increased aqueous solubility of olopatadine
`HCl in the presence of NaCl.
`
`Example 5
`
`Effect of Phosphate Buffer on Olopatadine Nasal
`Spray Composition
`
`The two compositions shown in Table 2 below were pre-
`pared using the procedure described in Example 1 and visual
`observations of the compositions clarity were made at differ-
`ent points during the compounding procedure. The results are
`shown in Table 2.
`
`000011
`
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`
`

`
`US 8,399,508 B2
`
`7
`
`TABLE 2
`
`Formulation 2A
`% w/v
`
`Formulation 2B
`% w/v
`
`0.665
`0.01 + 3% xs
`0.01
`0.37
`0.5
`pH to 3.7
`pH to 3.7
`qs 100
`2000 mL
`266
`6.704
`3.699
`
`0.665
`0.01 + 3% xs
`0.01
`0.7
`absent
`pH to 3.7
`pH to 3.7
`qs100
`2000 mL
`250
`3.189
`3.618
`
`Solution appeared clear
`with a few particles
`
`Solution became cloudy
`with many particles
`Solution began to clear
`during pH adjust down
`to 3.7
`Solution remained clear
`
`Solution appeared cloudy
`with many particles
`suspended
`Solution remained cloudy
`with many particles
`Solution remained cloudy
`even after pH adjust down
`to 3.6
`Solution was still cloudy
`with many particles
`
`Component
`
`Olopatadine HCl
`Benzalkonium Chloride
`Disodium EDTA
`Sodium Chloride
`Dibasic Sodium Phosphate
`Sodium Hydroxide
`Hydrochloric Acid
`Purified Water
`Batch Size
`Osmolality
`Initial pH
`Final pH
`Visual Observations:
`
`Upon addition of HCl
`
`After overnight stirring
`
`Final pH adjustment
`
`Add final batch quantity of water
`(approximately 10%)
`
`The results for FormulationA show that it is a clear solution.
`The results for Formulation B show that despite the pH-
`solubility profile indicating 0.6% olopatadine should dissolve
`at pH 3.189, the olopatadine did not go into solution. These 30
`results demonstrate that, without phosphate buffer, 0.665%
`olopatadine hydrochloride did not completely dissolve in
`water in the presence of0.7% NaCl at a pH as low as 3 .6 using
`the compounding procedure described in Example 1.
`
`Example 6
`
`35
`
`Effect of Phosphate Buffer Added to Cloudy 0.6%
`Olopatadine Nasal Spray Composition
`
`40
`
`Formulations 3A, 3B, and 3C shown in Table 3 were pre-
`pared without phosphate buffer and, despite extensive stir-
`ring, the olopatadine HCl was not completely solubilized. A
`portion ofFormulation 3C was removed and phosphate buffer
`was added to form Formulation 3D. The results, summarized
`in Table 3, demonstrate that 0.665% olopatadine hydrochlo- 45
`ride is not soluble in the tested nasal vehicle without a phos-
`phate salt.
`
`Formulation 3A
`
`0.665
`0.01 + 3% xs
`
`0.01
`0.33
`pH to 3.7
`pH to 3.7
`qs 100%
`300 mL
`137
`3.002
`3.002
`
`Olopatadine HCl
`Benzalkonium
`Chloride
`Disodium EDTA
`Sodium Chloride
`Sodium Hydroxide
`Hydrochloric Acid
`Purified Water
`Batch Size
`Osmolality
`Initial pH
`Final pH
`Visual
`Observations:
`
`TABLE 3
`
`Formulation 3B
`
`0.665
`0.01 + 3% xs
`
`Formulation 3C
`
`0.665
`0.01+ 3% xs
`
`0.01
`0.7
`pH to 3.7
`pH to 3.7
`qs 100%
`800 mL
`246
`3.176
`3.664
`
`pH to 3.7
`pH to 3.7
`qs 100%
`2000 mL
`
`3.189
`3.618
`
`Formulation 3D
`
`0.665
`0.01 + 3% xs
`
`0.01
`0.7
`pH to 3.7
`pH to 3.7
`qs 100%
`100 mL
`
`6.908
`3.7
`
`Upon addition of Olopatadine Upon addition of Olopatadine
`HCl, solution appeared
`HCl, solution appeared
`cloudy, batch was qs to
`cloudy, batch was qs to
`
`Upon addition of Olopatadine
`HCl, solution appeared
`cloudy
`
`Used dibasic sodium phosphate
`(0.5%) in attempts to clarify a
`portion of the cloudy solution
`
`000012
`
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`
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`
`US 8,399,508 B2
`
`TABLE 3-continued
`
`10
`
`Formulation 3A
`
`Formulation 3B
`
`Formulation 3C
`
`100% and still cloudy
`
`After 2.5 hours of stirring,
`solution began to clear
`but still many particles *
`in solution
`After 3.5 hours of stirring,
`solution appeared clear
`with particles *
`
`90% and pH adjusted,
`solution still cloudy
`After 7 hours of stirring,
`the solution was still
`cloudy.
`
`After 7 days of stirring,
`the solution was still
`cloudy with many particles *
`
`After overnight stirring,
`solution appeared clear
`with several particles *
`
`The batch was qs to 100%
`and still cloudy with
`many particles *
`
`After overnight stirring,
`the solution remained
`cloudy with many particles *
`
`After final qs to 100% and
`pH adjust, the solution was
`still cloudy with many
`particles *
`After approx. 7 hours of
`stirring, the solution was
`cloudy with many particles *
`
`Formulation 3D
`
`(Formulation 3C)
`
`Within a minute of stirring, the
`solution became clear with a few
`particles ** in solution (mostly
`fibrous in appearance)
`After qs to 100% (using solution
`from the original batch), the
`solution remained clear with a few
`fibrous particles **
`
`* Insoluble drug related
`** Extraneous fibrous particles
`
`Example 7
`
`Effect of Compounding Sequence on 0.6%
`Olopatadine Nasal Spray Composition
`
`addition) colunms. In each case, visual observations relating
`20 to the composition’s clarity were recorded. The results are
`shown in Table 4. In all four cases (Formulations 4A-4D), at
`the end of the compounding procedure, the solutions were
`clear. (The solutions contained some extraneous fibrous par-
`ticles that did not appear to be related to the drug or the
`The composition of Example 1 above was prepared using
`formulation excipients and were likely attributable to labora-
`four different sequences for the addition of ingredients. The
`four sequences are indicated in Table 4 in the “OA” (order of
`tory equipment and glassware.)
`TABLE 4
`
`Component
`
`% w/v
`
`OA“
`
`% w/v
`
`OA‘’’ ‘
`
`% w/v
`
`OA“
`
`% w/v
`
`OA“
`
`4A
`
`4B
`
`4C
`
`4D
`
`0.665
`0.01
`0.01
`0.41
`0.5
`
`3
`4
`5
`6
`1
`
`0.665
`0.01
`0.01
`0.41
`0.5
`
`5
`4
`3
`2
`1
`
`0.665
`0.01
`0.01
`0.41
`0.5
`
`2
`3
`4
`5
`6
`
`0.665
`0.01
`0.01
`0.41
`0.5
`
`2
`4
`5
`6
`1
`
`Olopatadine HCl
`Benzalkonium Chloride
`Disoditun EDTA
`Sodium Chloride
`Dibasic Sodium
`Phosphate (Anhydrous)
`Sodium Hydroxide
`Hydrochloric Acid
`Purified Water
`Batch Size
`Sodium Hydroxide added
`Hydrochloric Acid added
`Initial Observations
`Additional observations
`
`NAZ’
`2
`NA
`
`pH to 3.7
`pH to 3.7
`qs 100%
`100 mL
`0.238 g (1N)
`0.576 g (6N)
`Cloudy, many suspended
`particles
`After 10 minutes - solution
`began to clear, many
`suspended particles
`After 30 minutes - clear with
`several suspended particles
`After 1 hour - clear with
`many suspended particles*
`Next day (approx 16 hours) -
`clear with several particles*
`
`pH
`Osmolality
`
`3 .698
`274
`
`bNA = not applicable
`Treferred method of manufacturing
`*Extraneous fibrous particles
`
`NA’’
`6
`NA
`
`pH to 3.7
`pH to 3.7
`qs 100%
`100 mL
`None
`0.550 g (6N)
`Cloudy, many suspended
`particles
`After 1 minute - clear with
`several suspended particles
`After 6 minutes - clear with a
`a few suspended particles
`After 1 hour - clear with a few
`suspended particles*
`Next day (approx 16 hours) -
`clear with a few particles*
`3.692
`283
`
`NA’’
`3
`NA
`
`NA’’
`1
`NA
`
`pH to 3.7
`pH to 3.7
`pH to 3.7
`pH to 3.7
`qs 100%
`qs 100%
`100 mL
`100 mL
`None
`None
`0.550 g (6N)
`0.550 g (6N)
`Cloudy, many suspended
`Cloudy, many suspended
`particles
`particles
`After 2 minutes - clear with After 5 minutes - clear with
`a few suspended particles
`a few suspended particles
`After 7 minutes - clear with a After 20 minutes - clear with
`few suspended particles
`a few suspended particles
`After 1 hour - clear with
`After 1 hour - clear with
`several suspended particles*
`several suspended particles*
`Next day (approx 16
`Next day (approx 16
`hours) -
`hours) -
`clear with a few particles*
`clear with a few particles*
`3.718
`3 .724
`279
`280
`
`60
`
`Example 8
`
`Effect of Various Buffer Systems
`
`The composition of Example 1 above was prepared but
`acetate, borate and citrate buffers, respectively, were substi-
`55 tuted in place of the phosphate buffer. Visual observations
`regarding the clarity of each of the compositions were
`recorded and are shown in Table 5.
`
`000013
`
`000013
`
`

`
`Component
`
`Olopatadine HCl
`Benzalkonium
`Chloride
`Disodium EDTA
`Sodium Chloride
`Sodium Acetate
`Sodium Borate
`Sodium Citrate
`Sodium Hydroxide
`Hydrochloric Acid“
`Purified Water
`Batch Size
`Sodium Hydroxide
`added
`Hydrochloric Acid
`added
`pH
`Osmolality
`Visual Observations:
`
`Observations: Initial
`
`Additional
`obser