`
`(12) United States Patent
`Singh et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,977,376 B2
`Jul. 12, 2011
`
`................ .. 210/638
`4,778,596 A * 10/1988 Linder etal.
`4,871,865 A
`10/1989 Lever, Jr. et al.
`549/354
`4,923,892 A
`5/1990 Lever, Jr. et al.
`514/450
`..
`5,116,863 A
`5/1992 O h
`t
`l.
`514/450
`5,164,194 A
`“/1992 HZHICIE:
`.... H
`424/489
`5,443,833 A *
`8/1995 Clark et al.
`.
`424/400
`5,478,565 A * 12/1995 Geri_a ..... ..
`424/434
`5A&J%1A:
`1H%6I@ndM. ..... H
`Hflwfii
`2:S§‘1:§12§ 2 >1
`3/£333 1‘:‘§:.¥f;‘ff}Z”21‘“§1?“'...:
`...::: 211/332
`6,146,622 A
`11/2000 Castillo etal.
`..
`424/78.02
`6,174,914 B1
`1/2001 Yanniet al.
`. . . . .
`. . . . .. 514/450
`6,207,684 B1
`3/2001 Aberg ......................... .. 514/324
`C t'
`d
`)
`( Oll lllllll
`FOREIGN PATENT DOCUMENTS
`0 048 023
`3/1982
`
`
`
`(Continued)
`
`OTHER PUBLICATIONS
`
`(54) OLOPATADINE FORMULATIONS FOR
`TOPICAL NASAL ADMINISTRATION
`
`(75)
`
`.
`.
`Inventors: Onkar N. Singh, Arlington, TX (US); G.
`Michael Wall, F011 Wonh, TX (US);
`Rajni Jani, Fort Worth, TX (US);
`NhmmdAJjmwm#¥mgmmTX
`(US): Wesley Wehsin Han=Ar1ina°n=
`TX (US)
`
`(73) Assignee: Novartis AG, Basal (CH)
`
`( * ) Notice:
`
`Subject. to any disclaimer, the term ofthis
`Iaatselét 11S5:X]:eI}3de<;208rdadJuSted under 35
`‘
`‘
`‘
`( ) y
`ayS'
`
`EP
`
`(21) Appl. No.: 11/703,373
`
`(22)
`
`Filed:
`
`Feb‘ 7’ 2007
`
`(65)
`
`Prior Publication Data
`
`PH Ratner, FC Hampel, NJ Amar, JH van Bevel, D Mohar, BF
`
`US 2007/0142458 A1
`
`Jun. 21, 2007
`
`Related US, Application Data
`(63) 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.
`
`Marple, PS Roland, GM Wall, MJ Brubaker, M Drake, D Turner, LH
`Silver. Safety and Efficacy of Olopatadine Hydrochloride Nasal
`Spray for tl1e Treatment of Seasonal Allergic Rhinitis to Mountain
`Allllllll Alllllgy Alllllllll lllllllllllol 2005' Vol 95’ pp llllll
`
`'
`
`(Continued)
`
`(60) Provisional application No. 60/301,315, filed on Jun.
`27,2001.
`
`Primary Examiner i Patricia A Duffy
`.
`.
`Ass1stantExammer — Isaac Shomer
`
`(51)
`
`Int CL
`A61K 31/335
`
`(2006.01)
`
`...................................... .. 514/450; 424/810
`(52) U.S. Cl.
`(58) Field of Classification Search ...................... .. None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,407,791 A
`10/1983 Stark ............................. .. 424/80
`4,749,700 A
`6/1988 Wenig ...................... .. 514/225.2
`
`(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
`olo atadine.
`ll
`
`2 Claims, 4 Drawing Sheets
`
`I4
`
`1
`
`0,8
`0'6
`
`0'4
`M
`
`Q
`
`§>
`
`
`
`V
`
`l
`.
`
`3
`r
`
`250
`
`?151)
`E
`g 1,00
`
`unl1lxl1l1l1l;l11$1l(l(l:l1l,)
`Zwitlcnun
`aw ~ummmn~~num~m~~~m~{fl@fi§%;$~~~w~~m~~~u —————————————————— --
`Wu
`.
`
`
`
`
`
`- —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
`
`—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
`
`°'°°
`
`"l"—'
`
`"""
`
`03.60
`
`400
`
`440
`
`480
`
`5.20
`
`5:)
`
`600
`
`5,40 73.110
`
`720
`
`760
`
`11.00
`
`000001
`
`ARGENTUM PHARM. 1047
`
`ARGENTUM PHARM. 1047
`
`000001
`
`
`
`US 7,977,376 B2
`Page 2
`
`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).
`Ohshima et al., “Synthesis and Antiallergic Activity of 11-(Am
`inoalkylidene)-6,11,dihydrodibenz[b,e]oxepin
`Derivatives,”
`.I.
`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).
`Pujara et al., “Effects of formulation variables on nasal epithelial cell
`integrity:
`Biochemical
`evaluations,”
`International
`.I.
`of
`Pharmaceutics, vol. 114, pp. 197-203 (1995).
`Sharif et al., “Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatadine (AL-4943A), a Novel Drug
`for Treating Ocular Allergic Diseases,” .I. 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.*
`Hamilton et al., “Comarison of a New Antihistaminic and
`Antiallergic Compound KW 46790 with Terfenadine and Placebo on
`Skin and Nasal Provocation in Atopic Individuals,” Clinical and
`ExperimentalAllergy, vol. 24, pp. 955-959, (1994).
`
`* cited by examiner
`
`U.S. PATENT DOCUMENTS
`
`........ .. 514/401
`11/2001 Hasiwanter et al.
`6,316,483 B1
`424/434
`12/2001 Santus et al.
`6,333,044 B1
`514/450
`2/2006 Castillo et al.
`6,995,186 B2 *
`514/218
`12/2001 Yarmi
`......... ..
`2001/0056093 A1
`5/2006 Cagle et al.
`................... .. 424/45
`2006/0110328 A1
`FOREIGN PATENT DOCUMENTS
`0 214 779
`3/1987
`0 235 796
`9/1987
`61926
`3/1995
`WO 00/03705
`1/2000
`WO 01/21209
`3/2001
`WO01/21210
`3/2001
`WO 01/35963
`5/2001
`WO 01/54687 A1
`8/2001
`WO 02/30395 A1
`4/2002
`W0 03/002093
`1/2003
`WO 03002093 A1 *
`1/2003
`WO 2004/043470
`5/2004
`
`
`
`EP
`EP
`JP
`W0
`W0
`WO
`W0
`W0
`W0
`W0
`W0
`W0
`
`OTHER PUBLICATIONS
`
`SM Berge, LD Bighley, DC Monkhouse. “Pharmaceutical Salts”
`Journal of Pharmaceutical Science, vol. 66, No. 1, pp. 1-19, Jan.
`1977.*
`Church, “Is Inhibition of Mast Cell Mediator Release Relevant 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 Individuals,” Clinical and
`ExperimentalAllergy, 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. 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-
`605 (1994) (abstract only).
`
`000002
`
`000002
`
`
`
`U.S. Patent
`
`Jul. 12, 2011
`
`Sheet 1 014
`
`US 7,977,376 B2
`
`Fig. IA
`
`2.50
`
`2.00
`
`A 1.50
`
`iE
`
`‘
`
`3 1.00
`
`Unionized COOH
`Ionized N(CH3)H *
`
`0 so
`‘
`
`"
`
`0.00
`
`Ionized COO’
`Zwitterion
`Unionized N(CH3)
`§‘—’“i?3°5!-(-:-(-)~9-5’5‘-d- ------------------------------------------------- ~-
`Ionized N(cH,)H*
`
`000003
`
`000003
`
`
`
`U.S. Patent
`
`Jul. 12, 2011
`
`Sheet 2 014
`
`US 7,977,376 B2
`
`Fig. 1B
`
`G5a___e__om
`
`0.7
`
`0.6
`
`5.4.3.2.0000
`
`0.1
`
`-O-0.41% NaCl
`
`960.5% Na2HPO4
`
`10
`
`11
`
`Time (minutes)
`
`000004
`
`
`
`
`
`A>\>cvu>_omm_Q2___§_ao_oR.
`
`000004
`
`
`
`
`U.S. Patent
`
`Jul. 12, 2011
`
`Sheet 3 014
`
`US 7,977,376 B2
`
`%lF Vehicle (0.01 %BAC +0.0l%EDTA)
`-13- 0.5% Na2HPO4 in Vehicle
`-0- 2.6% Mannitol in Vehicle
`
`—I- 0.41% NaCl in Vehicle
`-X-0.41% NaCl + 0.5% Na2HPO4 in Vehicle
`
`(w/v)
`
`
`
`%0lopatadineDissolved
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`Time (seconds)
`
`Fig. 4
`
`-%.2%NaC| —I-.4l%NaCl —A-.8%NaCl —)<-.41%NaCl+.l5%Na2HPO4
`
`-€K—.4l%NaCl+.5%Na2HPO4
`
`0.7
`
`
`
`°/oolopatadineDissolved
`
`(w/v)
`
`0
`
`1 00
`
`200
`
`300
`Time (seconds)
`
`400
`
`500
`
`600
`
`000005
`
`000005
`
`
`
`U.S. Patent
`
`Jul. 12, 2011
`
`Sheet 4 014
`
`US 7,977,376 B2
`
`1
`
`wlo phosphate
`
`\5O
`
`Fig.5
`
`wlphosphate buffer
`
`0
`
`2
`
`4
`
`6
`
`8
`
`I0
`
`I2
`
`14
`
`l6
`
`l8
`
`0. [N NaOH (mL)
`
`000006
`
`000006
`
`
`
`US 7,977,376 B2
`
`1
`OLOPATADINE FORMULATIONS FOR
`TOPICAL NASAL ADMINISTRATION
`
`This application is a continuation-in-part of Ser. No.
`11/079,996, filed Mar. 15, 2005, now U.S. Pat. No. 7,402,609
`which is a continuation of Ser. No. 10/175,106, filed Jun. 19,
`2002, now U.S. Pat. No. 6,995,186 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 antihistarnimc
`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
`
`Medicarnent 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.
`
`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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`000007
`
`000007
`
`
`
`US 7,977,376 B2
`
`Acid-Base Equilibrium of Olopatadine
`Zwitterion
`
`
`
`Anion
`
`CH3
`H3C\ /
`
`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)-11-(3-dimethylaminopropylidene)-6,1 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
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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.
`Phosphate buffer is commonly used in aqueous pharma-
`ceutical compositions formulated near neutral pH. Phosphate
`buffer (pKa1:2.l2, pKa2:7.l, pKa3:12.67) 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
`
`000008
`
`000008
`
`
`
`US 7,977,376 B2
`
`5
`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
`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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`6
`4. Allow adequate time between each addition for dissolution
`of each ingredient
`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
`
`following examples.
`
`Example 1
`
`phosphate salt in this vehicle is the same as that shown in
`water in Example 2.
`
`40
`
`Topically Administrable Nasal Solution
`
`Example 4
`
`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.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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.
`
`000009
`
`000009
`
`
`
`US 7,977,376 B2
`
`TABLE 2
`
`Formulation 2A
`% 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
`
`Formulation 2B
`% w/v
`
`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
`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
`
`Effect of Phosphate Buffer Added to Cloudy 0.6%
`Olopatadine Nasal Spray Composition
`
`30
`
`35
`
`Formulations 3A, 3B, and 3C shown in Table 3 were pre- 40
`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.
`
`TABLE 3
`
`Olopatadine HCl
`3enzalkonium
`Chloride
`Disodium EDTA
`Sodium Chloride
`
`Sodium
`{ydroxide
`{ydrochloric
`Acid
`
`’urified Water
`3atch Size
`
`Osmolality
`nitial pH
`
`Formulation 3A
`
`Formulation 3B
`
`Formulation 3C
`
`Formulation 3D
`
`0.665
`0.01 + 3% xs
`
`0.665
`0.01 + 3% xs
`
`0.665
`0.01 + 3% xs
`
`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
`
`0.01
`0.7
`
`pH to 3.7
`
`pH to 3.7
`
`qs 100%
`2000 mL
`250
`3.189
`
`0.01
`0.7
`
`pH to 3.7
`
`pH to 3.7
`
`qs 100%
`100 mL
`
`6.908
`
`0.01
`0.7
`
`pH to 3.7
`
`pH to 3.7
`
`qs 100%
`800 mL
`
`246
`3.176
`
`000010
`
`000010
`
`
`
`US 7,977,376 B2
`
`TABLE 3-continued
`
`Final pH
`Visual
`Observations:
`
`Formulation 3A
`
`Formulation 3B
`
`Formulation 3C
`
`Formulation 3D
`
`3.002
`
`3.664
`
`3.618
`
`3.7
`
`Upon addition of Olopatadine HCl, Upon addition of Olopatadine HCl,
`solution appeared cloudy, batch
`solution appeared cloudy, batch was
`was qs to 100% and
`qs to 90% and pH adjusted, solution
`still cloudy
`still cloudy
`After 2.5 hours of stirring, solution
`After 7 hours of stirring, the
`began to clear
`solution was still cloudy.
`but still many particles*
`in solution
`After 3.5 hours of stirring, solution
`appeared clear with particles*
`
`After 7 days of stirring, the solution
`was still cloudy with many particles*
`
`Alter overnight stirring, solution
`appeared clear with several
`particles*
`
`The batch was qs to 100% and still
`cloudy with
`many particles*
`
`Used dibasic sodium phosphate
`(0.5%) in attempts to clarify a
`portion of the cloudy solution
`(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**
`
`Upon addition of
`Olopatadine {C1,
`solution appeared
`cloudy
`After overnight
`stirring, the so ution
`remained cloudy with
`many particles*
`After final qs to 100%
`and pH adjus , the
`solution was still
`cloudy wi 1
`many partic es*
`After approx. 7 hours
`of stirring, the solution
`was cloudy with
`many partic es*
`
`*I_nsoluble drug related
`**Extraneous fibrous particles
`
`Example 7
`
`25
`
`addition) colunms. In each case, visual observations relating
`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
`tory equipment and glassware.)
`four sequences are indicated in Table 4 in the “OA” (order of
`TABLE 4
`
`Effect of Compounding Sequence on 0.6%
`Olopatadine Nasal Spray Composition
`
`Component
`
`Olopatadine HCl
`Benzalkonium Chloride
`Disodium 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
`
`pH
`Osmolality
`
`4A
`
`4B
`
`4C
`
`4D
`
`% w/v
`
`OA“
`
`% w/v
`
`OA""
`
`% w/v
`
`OA“
`
`% w/v
`
`OA“
`
`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
`
`NA”
`2
`NA
`
`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
`
`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 After 6 minutes - clear with a
`several suspended particles
`few suspended particles
`After 1 hour - clear with many After 1 hour - clear with a few
`suspended particles*
`suspended particles*
`Next day (approx 16 hours) -
`Next day (approx 16 hours) -
`clear with several particles*
`clear with a few particles*
`3.698
`3.692
`274
`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 a After 5 minutes - clear with a
`few suspended particles
`few suspended particles
`
`After 7 minutes - clear with a
`few suspended particles
`Alter 1 hour - clear with
`several suspended particles*
`Next day (approx 16 hours) -
`clear with a few particles*
`3.718
`279
`
`After 20 minutes - clear with
`a few suspended particles
`After 1 hour - clear with
`several suspended particles*
`Next day (approx 16 hours) -
`clear with a few particles*