United States Patent
`(12)
`(10) Patent No.:
`US 6,984,628 B2
`Bakhitet al.
`(45) Date of Patent:
`Jan. 10, 2006
`
`
`US006984628B2
`
`(54) OPHTHALMIC COMPOSITIONS
`COMPRISING TREFOIL FACTOR FAMILY
`PEPTIDES N
`
`(75)
`
`Inventors: Peter G. Bakhit, Huntington Beach,
`CA (US); Orest Olejnik, Coto De
`Caza, CA (US); Richard Graham,
`:
`Irvine, CA (US)
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`21)
`(21)
`
`Appl. No.: 10/621,053
`App
`/621,
`
`(22)
`
`Filed:
`
`Jul. 15, 2003
`
`(65)
`
`(51)
`
`(56)
`
`Prior Publication Data
`US 2005/0014691 A1
`Jan. 20. 2005
`“
`—
`Int. Cl.
`(2006.01)
`AOIK 38/02
`(2006.01)
`AOIK 38/17
`(52) US. CM. eccccccsescresseesesevesesseeesvvvee 514/21; 5514/2
`(58) Field of Classification Search
`514/2
`.
`- es514/8 D a
`.
`oe
`one
`See applicationfile for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`
`2003/0153496 Al*
`8/2003 Thim et al. oe 514/12
`FOREIGN PATENT DOCUMENTS
`0473159
`3/1992
`0590655
`4/1994
`WO 02/46226 A2
`6/2002
`we talttoaeo wo
`19/2003
`/
`WO 02/102403
`12/2002
`OTHER PUBLICATIONS
`
`EP
`EP
`wo
`wo
`wo
`
`Allen, et al., The mucusbarrier, its role in gastroduodenal
`mucosal protection,
`J. Clin Gastroenterol, 1998;
`10
`(Suppl1): S93-S98;.
`Babyatsky, M.W., et al.,Oral trefoil peptides protect against
`ethanol-and indomethacin-induced
`gastric injury
`in rats,
`g
`jury
`Gastroenterology, 1996, vol. 110, pp. 489-497.
`Carr, M. D., et al., Solution Structure of Trefoil factor family
`proteins, Univ. of Kent , 3 pgs, www.biochem.ucl.ac.uk,
`(Feb. 13, 2003).
`purification,
`al, Ocular mucins:
`et
`Corfield, AP.
`metabolism and functions, Progress in Retinal and Eye
`Research, vol. 16, No. 4, pp 627-656, 1997.
`Danjo,Y., et al., Alteration of mucin in human conjunctival
`epihtelia in dry eve, Invest Ophthalmol Vis Sci, 1998, V 39,
`PP. 2602-09.
`ao.
`re
`Dignass, A., et al., Trefoil peptides promote epithelial migra-
`tion through a transforming growth factor f-independent
`pathway, J. Clin. Invest. 94, 376-383, (Jul. 1994).
`Gipson, I.K., et al., Mucin genes expressed by the ocular
`surface epithelium, Progress in Retinal and eye research,
`vol. 16, No. 1, pp. 81-98, 1997.
`Good, R.J., Surface free energy of solids and liquids:
`thermodynamics, molecular forces, and structures, J. Col-
`loid Interface Sci.; 1977, 59:398-419.
`Goke,M., et al., Trefoil peptides promote restitution of
`wounded corneal
`cpithclial
`cells, Experimental Cell
`Research, 2001, V. 264, pp. 337-344.
`Hauser, F., ef al., Hp1.b, A human P-domain peptide
`homologous with rat intestinal trefoil factor, is expressed
`also in the ulcer-associated cell lineage and the uterus, Proc
`Natl Acad Sci USA, 1993, V. 90, pp. 6961-6965.
`
`(Continued)
`
`FAMY CARE- EXHIBIT 1029-0001
`
`
`
`. 514/12
`
`
`
`
`0011111122
`
`*
`
`*
`
`AAAAA
`
`AAAAA
`
` 10
`
`2233332223
`
`6/1989
`Kaswatl ow... eee 514/11
`4,839,342
`
`12/1995
`vee S411
`Dinget al.
`5,474,979
`4/1997 Sullivan wees 514/178
`5,620,921
`7/1997 Pflugfelder et al.
`............ 514/2
`§,652,209
`.
`11/1997 Sullivan .........
`5,688,765
`5/1999 Yerxa et al.
`.
`ve. 514/47
`5,900,407 A
`9/1999 Sullivan ......
`. SI4/L77
`5,958,912
`11/1999 Ding et al.
`..
`. 514/785
`5,981,607
`5/2000 Saettone et al.
`424/78.04
`6,056,950
`5/2000
`Podolsky ......0.....
`ee 514/2
`6,063,755
`8/2000
`Sullivan .........
`514/178
`6,107,289
`11/20
`6,153,607 A
`Pflugfelderetal.
`4/200
`6,221,840 BL
`Podolsky .
`Primary Examiner—Jeftrey Edwin Russel
`Yerxa ......
`8/201
`6,277,855 B1
`(74) Attorney, Agent, or Firm—Brent A. Johnson; RobertJ.
`6,316,218 B1=11/20
`Podolsky.....
`Baran; Martin A. Voet
`.
`Yerxa et al.
`6,319,908 B1
`11/200
`
`.
`Yerxa et al.
`6,323,187 B1=11/20
`(57)
`ABSTRACT
`Yerxa et al.
`
`6,331,529 B1=12/20 toe
`Denick, Jr. et al.
`.
`6,348,508 Bl
`2/2002
`This invention relates to compositions comprising trefoil
`6,348,589 B1
`2/20
`Pendergastet al.
`family factor peptides which are useful in preventing or
`6,432,934 B1*
`8/2002 Gilbard ..........
`treating dry eye by topical administration of the composition
`6,436,910 B1
`8/2002 Yerxa et al. ws. 514/47
`to eye of the patient. One aspect of this invention relates to
`6,455,583 B1
`9/2002
`Pflugfelder ct al. ws... 514/528
`6,525,018 B1
`2/2003
`Podolsky veces 514/2
`topical ophthalmic compositions comprising a trefoil factor
`Yerxa .........
`. 536/25.6
`6,548,658 B2
`4/200
`536/26.22
`family peptide, and preferably, a mucoadhesive component,
`Rideout ct al.
`.
`6,555,675 B2
`4/20
`as described herein. Another aspect of this invention relates
`6,585,987 B1
`7/201
`Fransoni ......
`.. 424/401
`
`to the use of these compositions to treat or prevent dry eye
`.....eeeeeeeees 514/8
`2002/0037842 Al
`3/2002
`Leahyet al.
`in a patient.
`Rosenthal ct al.
`2002/0119104 Al
`8/20
`424/49
` Thim el al.
`.....
`.
`2002/0151472 Al—10/20
`2003/0032585 Al*
`2/200
`Thim et al. wee 514/8
`3 Claims, No Drawings
`
`FAMY CARE - EXHIBIT 1029-0001
`
`

`

`US 6,984,628 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Jagla, W., et al., Localization of TFF3 peptide to porcine
`conjunctival goblet cells, Cell tissue res (1999) 296:525-
`530.
`Langer, G., Secretory peptides TFF1 and TFF3 synthesized
`in human conjunctival goblet cells, Jnvest Ophthalmol Vis
`Sci, 1999, V. 40, pp 2220-2224.
`Langer, G., Et AL, TIT’ Peptides, New Mucus-Associated
`Secretory Products Of The Conjunctiva, Opthalmologe,
`2001-98:976-979.
`against
`protection
` Sucralfate
`al.
`Ligumsky,
`et
`gastrointestinal damage: possible role of prostanoids, Isr J
`Med Sci 1986; 22:801-806.
`Paulsen, F.P., et al., TFF peptides in the humanefferent tear
`ducts, Invest Ophthalmol Vis Sci, 2002, V 43, pp. 3359-
`3364.
`
`Playford, R.J., Trefoil peptides: what are they and what do
`they do?, Journal of the Royal College of Physicians of
`London, vol. 31, pp. 37-40, (Jan./Feb. 1997).
`Rachmilewitz, D., Trefoil peptides: a novel modality to
`prevent gastric injury’, Gastroenterology, vol. 110, No. 2,
`pp. 632-635, (Feb. 1996).
`
`Tabor, et al., Surface Forces and Surface Interactions, J.
`Colloid Interface Sci, 1977, 58:2-13.
`Tran, CP, et al., Trefoil peptide TFF2 (spasmolytic
`polypeptide) potently accelerates healing and reduces
`inflammation in a rat modelof colitis, OVID: Tran: Gut, vol.
`44(5) May 1999, 636-642.
`Uebermuth, C., Mucins of
`1999—96:563-569.
`
`eye, Ophthalmologe,
`
`the
`
`Wong, W.M., et al., Trefoil Peptides, Gur, vol. 44(6) Jun.
`1999, 890-895.
`Williams, et al., Trefoil factor family domain peptides,
`Virchows arch, 1997 431:299-304.
`tamily factors with
`Wright, N.A., Interaction of trefoil
`mucins: clues to their mechanism of action?, Gur, vol. 48(3)
`Mar. 2001, pp 293-294.
`Teraing and Dry Eyes, Ocular Times, Eye News and
`Information;
`www.geocities.com/ocular_times/tearing.
`html, Feb. 14, 2003, 4 pgs.
`
`* cited by examiner
`
`FAMY CARE- EXHIBIT 1029-0002
`
`FAMY CARE - EXHIBIT 1029-0002
`
`

`

`US 6,984,628 B2
`
`1
`OPHTHALMIC COMPOSITIONS
`COMPRISING TREFOIL FACTOR FAMILY
`PEPTIDES
`
`FIELD OF‘THE INVENTION
`
`The present invention relates to pharmaccutical compo-
`sitions. In particular, the present invention relates to topical
`ophthalmic compositions comprising a trefoil factor family
`peptide.
`
`BACKGROUND OF THE INVENTION
`
`Description of Related Art
`
`Dry eye disease is a general term for a variety of condi-
`tions characterized by abnormalities in the tear film, which
`affects three million people in the United States alone. Dry
`cyc is characterized by symptoms such as a sandy-gritty
`feeling in the eye, burning,
`irritation, or a foreign-body
`sensation that worsens during the day. Patients suffering
`from dry eye disease complain of mild to severe symptoms,
`and those with severe symptoms may experience constant
`and disabling eye irritation, and develop ocular surface
`epithelial disease and sight-threatening sterile or microbial
`corneal ulceration.
`The tear film consists of an inner mucouslayer, a middle
`aqueous layer which forms the bulk of the tear film, and an
`outer lipid layer. The aqueous layer is secreted by the
`lacrimal gland and the accessory lacrimal glands, and the
`tear fluid is drained by the efferent tear ducts. While the
`underlying causes of dry eye diseases are largely unknown,
`it is generally accepted that they are associated with abnor-
`malities in the tear composition or flow, which are affected
`by a variety of factors including aqueous layer secretion
`through lacrimal gland and drainage throughthe cfferent tear
`passage. In addition to abnormalities in the lacrimal glands,
`abnormalities in the meibomian glands (which secrete the
`lipid layer), and abnormalities in drainage through the
`efferent tear duct passage, changes in mucin composition
`and mucous viscosity may also affect tear flow [Langer G,
`et al,
`Invest Ophthalmol Vis Sci, 1999, vol. 40, pp.
`2220-2224; Danjo Y, et al, Invest OphthalmolVisSci, 1998,
`vol. 39, pp. 2602-2609; and Paulson FP, et al., Invest
`Ophthalmol Vis Sci, 2002, vol. 43, pp. 3359-3364].
`Until recently,
`the only methods used to treat dry eye
`disease were topical administration of over-the-counter
`compositions that serve asartificial tears (such as Refresh®
`marketed by Allergan, Inc), or surgery to close efferent
`drainage. Recently, a topical ophthalmic product containing
`Cyclosporin A, marketed by Allergan Inc., as Restasis®, was
`introduced, which has shownto beeffective in treating many
`cases of dry cyc. However,
`to maximize the number of
`options available to the physician and the patient any new
`and effective treatment for dry eye disease is highly desir-
`able.
`Trefoil peptides, or trefoil factor family (TFF) peptides
`are a class of peptides which comprise a commonstructural
`motif, knownasthe trefoil domain,as part of their structure.
`The trefoil motif comprises about 20 to about 60 aminoacid
`residues (usually about 40) containing six cysteine residues.
`The six cysteine residues form three disulfide bridges that
`complete three loops in the peptide chain so that the roughly
`40 residues have a clover-like shape, knownas the trefoil
`domain. TFF-peptides can have one or two trefoil domains
`per molecule, and may comprise additional amino acid
`residues which are not part of the trefoil domain. To date,
`three type of TI'T'-peptides have been isolated from humans-
`TFF1 (also known as pS2), TFF2 (also known as SP), and
`TFF3 (also known as ITF). TFF1 and TFF3 peptides cach
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`65
`
`2
`contain one trefoil domain, while TFF2 peptides contain two
`trefoil domains. TFF1 and TFF2 peptides are both produced
`by mucus-producing cells of stomach, while TFF3 peptides
`are produced by goblet cells of small and large intestine.
`All three forms of TFF-peptides are known to be produced
`in epithelial cells around areas of damage to mucus mem-
`brane, suggesting that trefoils have a role in healing injury,
`particularly to epithelial cells.
`It
`is believed that TFF-
`peptidesassist healing by both stabilizing mucus membrane
`al the injury site and by stimulating repair. It has been shown
`that TFF-peptides noncovalently link mucin, thus influenc-
`ing the rheology (e.g. increases viscosity) of mucus gels.
`[Hauser F, Poulsom R, Chinery R, et al, Proc Natl Acad Sci
`USA, 1993, vol. 90, pp. 6961-6965; and Babyatsky M W,
`deBeaumont M, Thim T., Podolky D K, Gastroenterology,
`1996,vol. 110, pp. 489-497]. TFF-peptides also appear to be
`responsible for promoting the migration of epithelial cells to
`the site of injury, thus stimulating repair. [Goke M,etal,
`Experimental Cell Research, 2001, vol 264, pp. 337-344;
`and Playford R J, Journal of the Royal College of Physicians
`of London, vol 31, pp. 37-40]
`Althoughthereis still a great deal unknown about the role
`of TFF peptides on the ocular surface, in the lacrimal gland,
`in the efferent passages, and in surrounding tissue,
`it is
`believed that ‘IF-peptides may be present during healing
`and other related processes in the eye. Biosynthesis and
`storage TFF1 and TFF3 peptides, but not TFF2, is known to
`occurin the human conjunctival epithelium [LangerG,etal,
`Invest Ophthalmol Vis Sci, 1999, vol. 40, pp. 2220-2224],
`and in vitro studies have shown that
`‘TFE2 and ‘TEE3
`peptides promote the migration of wounded corneal epithe-
`lial cells from rabbits [Géke M, ct al, Experimental Cell
`Research, 2001, vol 264, pp. 337-344]. However,to the best
`of our knowledge, no direct relationship has been unam-
`biguously established between 'TEF-peptides and any patho-
`logical condition affecting the eye.
`As mentioned previously, some cases of dry eye may be
`related to mucin composition and the Theological properties
`of the corresponding mucous membrane. Some work has
`also suggested that TTF-peptide secretion might be influ-
`enced byalterations in mucinsas they occurin patients with
`dry eye symptoms [Danjo and Paulson]. However, to the
`best of our knowledge, there is no direct evidence in any
`prior art demonstrating that TFF-peptide secretion abnor-
`malities contribute ta the symptoms or cause of dry eye
`discasc. In making the above statements,
`the applicants
`make no admission as to whether anyof the references cited
`herein are prior art.
`
`SUMMARY OF THE INVENTION
`
`Surprisingly, compositions comprising trefoil family fac-
`tor peptides will be useful in preventing or treating dry eye
`by topical administration of the composition to eye of the
`patient. One aspect of this invention relates to a topical
`ophthalmic composition comprising a therapeutically ettec-
`tive amount of a trefoil factor family (TFF) peptide. Another
`aspect of this invention relates a method of preventing or
`treating dry eye in a person comprising topically adminis-
`tering to the eye of said person a composition comprising a
`therapeutically effective amount of a trefoil factor family
`peptide. Another aspect of this invention relates to a phar-
`maceutical product comprising a composition having a
`therapeutically effective concentration of a trefoil factor
`family peptide which is dispensed from a package suitable
`for ophthalmic use, wherein the use of the composition for
`the prevention or treatment of dry cye is indicated thercon.
`
`FAMY CARE- EXHIBIT 1029-0003
`
`FAMY CARE - EXHIBIT 1029-0003
`
`

`

`US 6,984,628 B2
`
`3
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The term trefoil factor family (TFF) peptide as used
`herein refers to any peptide, whether natural or synthetic,
`which comprises the trefoil motif described previously
`herein. That is, the TFF-peptide comprises a residue com-
`prising from 20 to about 60 amino acids, including six
`cysteine residues. The cysteine residues form disulfide
`bonds which cause the peptide residue to have a clover-like
`shape comprising three loops. The methods of preparing of
`TFF-peptides, such as recombinant expression of peptides
`and synthetic peptide synthesis, are well known in theart.
`For example, methods of preparing TFF-peptides are
`included in the following references: U.S. Pat. No. 6,525,
`018; Allen,et. al., J Clin Gastroenterol 1998; 10 (Suppl1):
`$93-S98; Ligumsky,
`et. al.
`Isr J Med Sci
`1986;
`22:801-8006; Dignass, et. al., J. Clin. Invest., 94, 376-383;
`Babyatsky,et. al., Gastroenterology, 110, 489-497; Hauser,
`et. al., Proc. Natl. Acad. Sci. USA, vol. 90, pp. 6961-6965,
`August 1993; WO 02102403; and WO02085402, incorpo-
`rated herein by reference. A therapeutically effective amount
`of a TFF-peptide can be determined by a person of ordinary
`skill in the art without unduc experimentation. Although any
`TFF-peptide can be used in any of the compositions
`described herein related to this invention,it is preferable that
`TFF1 or TFF3 be used, and more preferred that TFF1 be
`used. In compositions of this invention the concentration of
`the TFF-peptide is preferably from about 0.001% to about
`1%. More preterred is a concentration of about 0.01% to
`about 0.5%, and even more preferred is a concentration of
`about 0.1% to about 0.2%. In the most preferred embodi-
`mentof the invention, the concentration of the TFF-peptide
`is about 0.15%.
`
`In relation to any of the compositions described herein
`related to this invention,it is prefcrable the composition also
`comprise a mucoadhesive component. With respect to this
`invention,
`the term “mucoadhesive” means a natural or
`synthetic component, including macromolecules, polymers,
`and oligomers, or mixtures thereof, that can adhere to a
`subject’s mucous membrane. Adhesion of mucoadhesives to
`the mucous membrane occurs primarily through noncova-
`lent interactions, such as hydrogen bonding and Van der
`Waalforces (laboret al., 1977 J. Colloid Interface Sci. 58:2
`and Good 1977 J. Colloid Interface Sci. 59:398). While not
`intending to be bound in any waybytheory,it is believed
`that mucoadhesives will be synergistic with TFF-peptides
`because they provide targeted delivery of the peptides to the
`mucous membrane by virtue of their adhesion. This synergy
`will be particularly pronounced in the case of topical oph-
`thalmic administration of a TIT'-peptide because of the
`otherwise short contact time between the TFF-peptide and
`the surface of the cyc. Another advantage of using mucoad-
`hesive agents in the compositions of this invention is that
`they help to improve the protective layer on the ocular
`surface. Examples of mucoadhesives for use in the present
`invention include, but are not limited to, Carbopol®, pectin,
`alginic acid, alginate, chitosan, hyaluronic acid, polysor-
`bates, such as polysorbate-20, -21, -40, -60, -61, -65, -80,
`-81, -85; poly(ethyleneglycol), such as PEG-7,-14,-16, -18,
`-55, -90, -100, -135, -180, -4, -240,-6, -8, -9, -10, -12, -20,
`or -32; oligosaccharides and polysaccharides, such as Tama-
`rind seed polysaccharide, gellan, carrageenan, xanthan gum,
`gum Arabic, and dextran; cellulose esters and cellulose
`ethers; modified cellulose polymers, such as carboxymeth-
`ylcellulose, hydroxyethylcellulose, hydroxypropyl methyl-
`cellulose, hydroxyethyl ethylcellulose; polyether polymers
`and oligomers, such as polyoxyethylene; condensation prod-
`ucts of poly(ethyleneoxide) with various reactive hydrogen
`containing compounds having long hydrophobic chains(c.g.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`4
`for
`aliphatic chains of about 12 to 20 carbon atoms),
`example, condensation products of poly(ethylene oxide)
`with fatty acids, fatty alcohols, fatty amides, polyhydric
`alcohols; polyether compounds, such as poly(methyl vinyl
`ether), polyoxypropylene of less than 10 repeating units;
`polyether compounds, such as block copolymersof ethylene
`oxide and propylene oxide; mixtures of block copolymers of
`ethylene oxide and propylene oxide with other excipients,
`for example poly(vinyl alcohol); polyacrylamide; hydro-
`lyzed polyacrylamide; poly(vinyl pyrrolidone); poly(meth-
`acrylic acid); poly(acrylic acid) or crosslinked polyacrylic
`acid, such as Carbomer®, i.e., a homopolymer of acrylic
`acid crosslinked with either an allyl ether of pentaerythritol,
`an allyl ether of sucrose, or an allyl ether of propylene.
`Preferably, the mucoadhesive componentis Tamarind sced
`polysaccharide, carboxymethylcellulose, hydroxymethyl-
`cellulose, Carbopol, hyaluronic acid, xanthan gum,or algi-
`nate. The most preferred mucoadhesive componentis Tama-
`rind seed polysaccharide, which is a galactoxyloglucan
`that’s extracted from the seed kernel of Tamarindus Indica,
`and can be purchased from ‘Cl America of Portland, Oreg.
`In certain situations it is also advantageous to include a
`second therapeutically active agent in any of the composi-
`tions described herein related to this invention. The second
`therapeutically active agent could be any drug which might
`be useful in treating the symptoms of dry eye, or any ofits
`underlying causes. In addition, the second therapeutically
`active agent could be any drug whichis useful in preventing
`or treating any disease which might occur simultaneously to
`dry eye disease, whether or not the disease is related. In
`another useful aspect ofthis invention, the second therapeu-
`tically active agent could be a drug whichis used in topical
`ophthalmic compositions which might cause, contribute to,
`or aggravate dry cyc discasc as a side cffect ofits usc. In this
`aspect, this invention is useful in reducing or eliminating
`said side effect.
`
`Oneclass of useful second therapeutically active agents in
`relation to this invention is nucleotide purinergic receptor
`agonists such as uridine 5'-triphosphate, dinucleotides, cyti-
`dine 5'-diphosphosphate, adenosine 5'-diphosphate, P*-(cy-
`tidine 5'-)-P-(uridine 5'-)tetraphosphates, P*, P’-di(uridine
`5')-tctraphosphates, or their therapeutically cffcctive ana-
`logues or derivatives, which may affect
`tear secretion,
`particularly the mucous layer of tears, and thus may have
`potential in treating dry eye disease. These compoundsare
`described in the following patents, all of which are incor-
`porated herein by reference: U.S. Pat. No. 6,555,675; U.S.
`Pat. No. 6,548,658; U.S. Pat. No. 6,436,910; U.S. Pat. No.
`6,348,589; U.S. Pat. No. 6,331,529; U.S. Pat. No. 6,323,187;
`U.S. Pat. No. 6,319,908; and U.S. Pat. No. 5,900,407.
`Another useful class of compounds that are useful as
`second therapeutically active agents is nicotinic receptor
`agonists such as nicotine andits analogs, trans-metanicotine
`and its analogs, epibatidine and its analogs, pyridol deriva-
`tives, piperidine alkaloids such as lobeline and its analogs,
`certain para-alkylthiophenol derivatives, and imidacloprid
`and its analogs. These compoundsare believed to stimulate
`secretion of mucin by the conjunctival goblet cells, and thus
`may be useful in treating dry eye, as disclosed in US. Pat.
`No. 6,277,855, which is incorporated herein by reference.
`Another useful class of second therapeutically active
`agents in relationto this inventionis tetracycline, derivatives
`or analoguesoftetracycline, or chemically modified tetra-
`cycline. These compoundsare believed to have potential in
`correcting, delayed tear clearance, as described in U-S. Pat.
`No. 6,455,583 B1, incorporated herein by reference, which
`is related to some cases of dry eye.
`Another class of compounds that are useful as second
`therapeutically active agents is corticosteroids such as meth-
`yiprednisolonc sodium succinate, prednisolone acctatc,
`
`FAMY CARE- EXHIBIT 1029-0004
`
`FAMY CARE - EXHIBIT 1029-0004
`
`

`

`US 6,984,628 B2
`
`5
`fluo-
`fluorometholone,
`prednisolone sodium phosphate,
`rometholone acetate, dexamethasone sodium phosphate,
`hydroxymethylprogesterone, rimexolane, budesonide, and
`tixocortol pivalatein, which are believed to be useful in
`treating dry eye as disclosed in U.S. Pat. No. 6,153,607,
`incorporated herein by reference.
`Another class of compounds which are useful as second
`therapeutically active agents is products of human lacrimal
`gland acinar epithelia such as growth [actors or cytokines
`including the transforming growth factor beta (TGF®),
`whichare disclosed to be useful in treating dry eye in U.S.
`Pat. No. 5,652,209, incorporated herein by reference.
`Anotherclass useful second therapeutically active agents
`is androgens or androgen analogues such as 17a-methyl-
`17P-hydroxy-2-oxa-5a-androstan-3-one,
`testosterone
`or
`testosterone derivatives, 4,5a-dihydrotestosterone or deriva-
`tives, 178-hydroxy-5a-androstane and derivatives, 19-nort-
`estosterone or derivatives, and nitrogen-substituted andro-
`gens, which are taught to be useful in treating dry eye
`disease in the following patents which are incorporated
`herein by reference, U.S. Pat. No. 6,107,289; U.S. Pat. No.
`5,958,912; U.S. Pat. No. 5,688,765; and U.S. Pat. No.
`5,620,921.
`Another useful class of second therapeutically active
`agents is cyclosporin and cyclosporin derivatives, such as
`cyclosporin A, cyclosporin B, cyclosporin C, cyclosporin D,
`and cyclosporin G.
`In relationship to any of the compositions described
`herein, it is preferable that an effective amount of buffer be
`included to maintain the pH from about 6 to about 8,
`prefcrably about 7. Buffcrs used arc thosc known to those
`skilled in the art, and, while not intending to be limiting,
`some examples are acetate, borate, carbonate, citrate, and
`phosphate buffers. Preferably, the buffer comprises borate.
`An effective amount of buffer necessary for the purposes of
`this invention can be readily determined bya person skilled
`in the art without undue experimentation. In cases where the
`buffer comprises borate, it is preferable that the concentra-
`tion of the borate buffer be about 0.6%.
`In any of the compositions related described herein
`related to this invention,it 1s preferable for a tonicity agent
`to be used. Tonicily agents are used in ophthalmic compo-
`sitions to adjust the concentration of dissolved material to
`the desired isotonic range. Tonicity agents are known to
`those skilled in the ophthalmic art, and, while not intending
`to be limiting, some examples include glycerin, mannitol,
`sorbitol, sodium chloride, and other electrolytes. Preferably,
`the tonicity agent is sodium chloride.
`In any of the compositionsrelated to the present invention
`whichare described herein, it is preferable for a preservative
`to be used when the composition is intended for multiple
`use. There mayalsobe reasons touse a preservative in single
`use compositions depending on the individual circum-
`stances. The term preservative has the meaning commonly
`understood in the ophthalmic art. Preservatives are used to
`prevent bacterial contamination in multiple-use ophthalmic
`preparations, and, while not
`intending to be limiting,
`examples include benzalkonium chloride, stabilized oxy-
`chloro complexes (otherwise known as Purite®), phenylm-
`ercuric acetate, chlorobutanol, benzyl alcohol, parabens, and
`thimerosal. Preferably,
`the preservative is benzalkonium
`chloride (BAK).
`Undercertain circumstances,a surfactant might be used in
`any of the compositions related to this invention which are
`described herein. The term surfactant used herein has the
`meaning commonly understood in the art. Surfactants are
`used to help solubilize the therapeutically active agent or
`other insoluble components of the composition, and may
`serve other purposes as well. Anionic, cationic, amphoteric,
`zwittcrionic, and nonionic surfactants mayall be usedin this
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`invention. For the purposesofthis invention,it is preferable
`that a nonionic surfactant, such as polysorbates, poloxamers,
`alcohol ethoxylates, ethylene glycol-propylene glycol block
`copolymers, fatty acid amides, alkylphenol ethoxylates, or
`phospholipids, is used in situations where it is desirable to
`use a surfactant.
`Another type of compound that might be used in any
`composition of this invention described hereinis a chelating
`agent. The term chelating agent refers to a compoundthatis
`capable of complexing a metal, as understood by those of
`ordinary skill in the chemicalart. Chelating agents are used
`in ophthalmic compositions to enhance preservative effec-
`tiveness. While not intending to be limiting, some useful
`chelating agents for the purposes of this invention are
`cdetate salts, like cdctate disodium, cdctate calcium diso-
`dium, edetate sodium, edetate trisodium, and edetate dipo-
`tassium.
`A particularly preferred embodiment of this invention
`comprises a trefoil factor family peptide,
`tamarind sced
`polysaccharide, about 0.5% sodium chloride, about 0.005%
`benzalkonium chloride, and about 0.6% of a borate buffer
`wherein the pH of the composition is adjusted to from about
`6 to about8.
`Another aspect of this invention involves a method of
`preventing or treating dry eye in a person, comprising
`topically administering to the eye of said person any one of
`the compositions described herein as related to this inven-
`tion, which composition comprises a therapeutically effec-
`tive amountofa trefoil factor family peptide.
`Another aspect of this invention involves a pharmaceuti-
`cal product comprising any one of
`the compositions
`described herein as related to this invention, which compo-
`sition comprises a therapeutically effective concentration of
`a trefoil factor family peptide, which is dispensed from a
`package suitable for ophthalmic use, and wherein the use of
`the composition for the prevention or treatmentof dry eye is
`indicated thereon.
`The best mode of making and using the present invention
`are described in the following examples. These examples are
`given onlyto provide direction and guidance in how to make
`and use the invention,and are not intendedto limit the scope
`of the invention in any way.
`
`EXAMPLE1
`
`Compositionsrelated to this invention are prepared by the
`following procedure. Unless otherwise indicated,all proce-
`dural steps are carried out at room temperature.
`Part T
`
`TSPis added to purified water at the concentration indicated
`in the 'Yable 1, and the solution is brought to a boil and
`maintained at a gentle boil for about 30 minutes. The
`solution is then allowed to cool to room temperature, and
`water is added to compensate for evaporative loss during
`boiling. The solution is then filtered through a 20 micron
`clarity filter followed by a 0.45 micronsterilizingfilter.
`Part II
`
`Each componentlisted in Table | is added in amount needed
`to provide the indicated concentration to a fixed volume of
`the solution from partI, in the following order: 'I'FF 1, boric
`acid, sodium borate decahydrate, sodium chloride, and
`BAK.After the addition of cach componcnt, the mixture is
`stirred until the solute is completely dissolved before the
`next componentis added. Whenall of the componentsofthe
`formulation have been added and dissolved, the pH is then
`adjusted to 7.0 with NaOH or HCI. The solution is then
`sterile filtered.
`
`FAMY CARE- EXHIBIT 1029-0005
`
`FAMY CARE - EXHIBIT 1029-0005
`
`

`

`US 6,984,628 B2
`
`TABTE 1
`
`TABLE 4-continued
`
`Component
`
`Function
`
`% (wiv)
`
`Component
`
`Function
`
`Benzalkonium Chloride (BAK)
`Purified Water
`HC! or NaOH.
`
`Buffer
`
`Butter
`
`EXAMPLE 5
`
`% (why)
`
`0.005
`Qs.
`adjust to pH 7.0
`
`A formulation having the composition according to Table
`5 is prepared according to the method described in U.S. Pat.
`No. 5,981,607, incorporated herein by reference, with the
`cyclosporin A being added to the castor oil before introduc-
`ing the oil into the emulsion. An aqueoussolution of the
`trefoil factor family peptide is sterile filtered into the emul-
`sion after the emulsion has cooled.
`
`TABLE 5
`
`Component
`
`Function
`
`TEF 3
`Cyclosporin A
`
`Castoroil
`Polysorbate-80
`Pemulen TR-2
`Glycerin
`Purified Water
`HC! or NaOH
`
`TFF-peptide
`Second
`Therapeutically
`Active Agent
`Oil phase
`Surfactant
`Emulsion stabilizer
`Tonicity agent
`
`Buffer
`
`% (wir)
`
`0.15
`0.05
`
`1.25
`1.0
`0.05
`2.2
`Qs.
`adjust to pH 7.4
`
`EXAMPLE6
`
`TEFF-peptide
`TFFL
`
`Tamarind Seed Polysaccharide (TSP) Mucoadhesive
`Boric Acid
`Butter
`Sodium Borate Decahydrate
`Butter
`Sodium Chloride
`Tonicity Agent
`Benzalkonium Chloride (BAK)
`Buffer
`Purified Water
`HCl or NaOH
`
`Buffer
`
`0.15
`05
`0.6
`0.035
`0.53
`0.005
`Qs.
`adjust to pH 7.0
`
`EXAMPLE2
`
`A formulation having the composition of Table 2 is
`prepared according to an analogous procedure to that of
`Example 1.
`
`TABLE 2
`
`Component
`
`Function
`
`% (wiv)
`
`TEF-peptide
`TEF3
`
`Tamarind Seed Polysaccharide (TSP) Mucoadhesive
`Borie Acid
`Buller
`Sodium Borate Decahydrate
`Buffer
`Sodium Chloride
`Tonicity Agent
`Benzalkonium Chloride (BAK)
`Buffer
`Purified Water
`HC! or NaOH
`
`Butter
`
`0.15
`0.5
`0.6
`0.035
`0.53
`9.005
`Qs.
`adjust to pH 7.0
`
`EXAMPLE3
`
`A formulation having the composition of Table 3 is
`prepared according to an analogous procedure to that of
`Example 1.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Component
`
`TABLE 3
`
`Function
`
`% (wiv)
`
`40
`
`A drop of a composition prepared according to one of
`Examples 1-5 is added at
`least once a day to a patient
`suffering from dry eve disease. Relief of symptoms is
`experienced and continues for as long as the patient
`is
`receiving the treatment.
`Whatis claimedis:
`1. A composition comprising a therapeutically effective
`amountof trefoil factor family peptide, an effective amount
`of tamarind seed polysaccharide, about 0.5% sodium chlo-
`ride, about 0.005% benzalkonium chloride, and about 0.6%
`of a borate buffer, and wherein said composition has a pH of
`from about 6 to 8.
`2. Amethod of preventing or treating dry eye in a person
`comprising topically administering to the eye of said person
`a composition comprising a therapeutically cffective amount
`of trefoil factor family peptide, an effective amount of
`tamarind seed polysaccharide, about 0.5% sodiumchloride,
`about 0.005% benzalkonium chloride, and about 0.6% of a
`borate buffer, and wherein said composition has a pH of
`from about 6 to 8.
`3. A pharmaceutical product comprising a composition
`comprising a therapeutically effective amount of trefoil
`factor family peptide, an effective amount of tamarind seed
`% (wiv)
`Function
`Component
`polysaccharide, about 0.5% sadium chloride, about 0.005%
`0.15
`TEE-peptide
`TEF 3
`benzalkonium chloride, and about 0.6% of a borate buffer,
`60
`
`Hydroxypropylmethylcellulose|Mucoadhesive 0.5
`Borie Acid
`Buffer
`0.6
`and wherein said composition has a pH of from about 6 to
`8.
`Sodium Borate Decahydrate
`Buffer
`0.035
`Sodium Chloride
`Tonicity Agent
`0.53
`
`TFF-peptide
`TFF 1
`