US006984628B2
`
`(12) United States Patent
`Bakhit et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,984,628 B2
`Jan. 10, 2006
`
`(54) OPHTHALMIC COMPOSITIONS
`COMPRISING TREFOE FACTOR FAMILY
`PEPTIDES
`
`(75)
`
`Inventors: Peter G. Bakhit, Huntington Beach,
`CA (US); Orest Olejnik, C0t0 De
`Caza, CA (US); Richard Graham,
`Irvine’ CA (US)
`
`2003/0153496 A1 *
`
`8/2003 Thim et al.
`
`................. .. 514/12
`
`FOREIGN PATENT DOCUMENTS
`0473159
`3/1992
`0590655
`4/1994
`W0 O2/46226 A2
`6/2002
`W0 92/985492
`10/2002
`W0 02/102399 A2
`12/2002
`W0 O2/102403
`12/2002
`
`Assignee: Allergan, Inc., Irvine, CA (US)
`
`OTHER PUBLICATIONS
`
`Notice;
`
`Subject to any diseiaimeit the term of this
`patent is extended or adjusted iiiidei 35
`U.S.C. 154(1)) by 0 days.
`
`Appl, No; 10/621,053
`
`Filed:
`
`Jul. 15, 2003
`
`Prior Publication Data
`Us 2005/0014691 A1
`Jan 20) 2005
`
`Int CL
`(2006.01)
`A61K 38/02
`(2006.0i)
`A61K 38/17
`U.S. Cl.
`........................................... .. 514/21; 514/2
`Field ef Classification Search ..................N
`51 4/2
`514/8 12 21
`See application file for complete search history ,
`'
`
`Allen, et al., The mucus barrier, its role in gastroduodenal
`mucosal protection,
`J. Clin Gastroenterol, 1998;
`10
`(5191911): 593-898;.
`Babyatsky, M.W., et al.,Oral trefoil peptides protect against
`ethanol-and indomethacin-induced gastric injury in rats,
`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.bioclieni.ucl.ac.uk,
`(Feb, 13, 2003').
`purification,
`al., Ocular mucins:
`et
`Corfield, A.P.,
`metabolism and functions, Progress in Retinal and Eye
`Research, vol. 16, No. 4, pp 627-656, 1997.
`Danjo,.Y., et al., Alteration of niucin in liiiriiari corijurictival
`epihtelia in dry eye, Invest Ophthalmol \/is .561, 1998, V 39,
`PP 3602'”
`.
`.
`.
`.
`.
`Dignass, A., et al., Trefoil peptides promote epithelial migra-
`tion through a transforming growth factor [3-independent
`pathway’ J. Chin. Invest. 94’ 376-383’ (Jul. 1994).
`Gipson, l.K., et al., Mucin genes expressed by the ocular
`s]i(i)r1fa1c;:, EiEI)C1)I.l'1:l1:;II:l.,8f1’1-’g§:'€.1S'g9I’J71. Retinal and eye research,
`Good, R.J., Surface free energy of solids and liquids:
`lll0[111D(ly11a1I1lC‘S,'IIlOl€C1lla[
`forces, and structures, J. Col-
`laid Interface écz.; 1977, 59:398-419.
`.
`.
`Goke,M., et al., Trefoil peptides promote restitution of
`Woundcd
`corncal
`epithelial
`cells, Experimental Cell
`Research, 2001, V. 264, pp. 337-344.
`Hauser, E, el 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
`~
`_
`NatlAcaa' Sci USA, 1993, V. 90, pp. 6961 6965.
`(Continued)
`
`Primary Examiner—Jeffrey Edwin Russel
`(74) Attorney, Agent, or Firm—Brent A. Johnson; Robert J.
`Baran; Martin A. Voet
`
`ABSTRACT
`(57)
`f .1
`t
`.
`.
`t
`.1.
`1 t
`t.
`.
`Th.
`re 01
`IS IIIVCII 1OI1 I6 3. CS 0 COl'1'lpOS1 101'1S CO]IlpI1S1Hg
`family factor peptides which ‘are useful in preventing. or
`treating dry eye by topical admimstration of the composition
`to eye of the patient. One aspect of this invention relates to
`topical oplitlialniic compositions comprising a trefoil factor
`family peptide, and preferably, a mucoadhesive component,
`as described herein. Another aspect of this invention relates
`to the use of these compositions to treat or prevent drv eye
`in a patient
`'
`
`3 Claims, N0 Drawings
`
`References Cited
`U.S. PATENT DOCUMENTS
`,,
`6/1989
`,aSwan _____________________ N 514/“
`I2/iees Dine et at.
`514/ii
`4/1997 Sullivan ................... N 514/178
`7/1007 Dflugfeldei et 31,
`tttttttttt N 514/2
`11/1997 Sullivan
`514/12
`5/1999
`1
`514/47
`9/1999
`~~ 514/177
`11/1999
`" 514/785
`5/20
`424/78.04
`5/200
`514/2
`8/20
`.. 514/178
`11/20
`.. 514/178
`4/200
`514/12
`8/20
`-- 514/256
`11/20
`. 43.5/69.1
`11/200
`514/51
`
`6,056,9503>3>3>3>>3>3>3>3>3>3>>
`
`4,839,342
`5,474,979
`5,620,921
`5,652,209
`5,688,765
`5,900,407
`5,958,912
`5,981,607
`
`670637755
`6,107,289
`6,153,607
`6,221,840
`5,277,855
`6,316,218
`6,319,908
`
`’
`
`,
`
`’
`
`5
`
`'
`
`6,323,187
`6,331,529
`6,348,508
`6,348,589
`6,432’934
`69436910
`5,455,533
`6,525,018
`6,548,658
`5,555,575
`6585987
`2002/0037842
`2002/0119104
`2002/0151472 A1
`2003/0032585 A1 *
`
`.
`
`.
`
`'
`
`"
`
`'
`
`i
`
`bJt\Jt\Jt\JbJ<.»JbJbJt\JI\Jt\Jt\JI\JHH>—‘HH>—OOOO
`
`. 514/51
`11/20
`514/47
`12/20
`514/772.4
`Deriick, Jr/etual.
`2/200
`' 536/25.6
`)endergeSteta1.
`2/20
`N 514/is-2
`Gflbard ........ N
`8/20
`8/200 Yeixa et a1_
`________________ __ 514/47
`9/20
`Dfiugfcidcr ct a1,
`....... ,. 514/523
`2/20
`’odolsl<.y . . . . . . . .
`. . . .. 514/2
`4/200 Yefxa -------- --
`536/26-22
`4/20
`{M00111 Ct 31-
`- 535/255
`7/20
`Tmnsoni "" "
`" 424/401
`3/205
`Leahy et al.
`514/8
`8/20
`{oscnthal ct al.
`. 424/49
`10/20
`Thim et al.
`.. 514/8
`2/20'
`
`.
`
`~
`
`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 coniunctival goblet cells, Invest Ophthalmol Vis
`Sci, 1999, V. 40, pp 2220-2224.
`Langer, G., Et Al., TFF Peptides, New Mucus-Associated
`Secretory Products Of The Conjunctiva, Opthalmologe,
`2001-982976-979.
`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 human efferent tear
`ducts, Invest Ophthalmol Ws 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, 5822-13.
`Tran, C.P., et al., Trefoil peptide TFF2 (spasmolytic
`polypeptide) potently accelerates healing and reduces
`inflammation in a rat model of colitis, OVID: Tran: Gut, VOl.
`44(5) May 1999, 636-642.
`Uebermuth, C., Mucins of
`l999—96:563-569.
`
`eye, Ophthalmologe,
`
`the
`
`Wong, W.M., et al., Trefoil Peptides, Gut, Vol. 44(6) J11n.
`1999, 890-895.
`Williams, et al., Trefoil factor family domain peptides,
`Wrchows arch, 1997 431:299-304.
`Wright, N.A., Interaction of trefoil family factors with
`mucins: clues to their mechanism of action?, Gut, Vol. 48(3)
`Mar. 2001, pp 293-294.
`Teraing and Dry Eyes, Ocular Times, Eye News and
`Information;
`WWW.ge0cities.com/ocular_ti1nes/tearing.
`html, Feb. 14, 2003, 4 pgs.
`
`* cited by examiner
`
`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 pharmaceutical 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
`eye 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 mucous layer, 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 through the efferent 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 [low [Langer G,
`et al,
`Invest Ophthalmol Vis Sci, 1999, vol. 40, pp.
`2220-2224; Danjo Y, et al, Invest Ophthalmal W5 Sci, 1998,
`vol. 39, pp. 2602-2609; and Paulson F I’, et al., Invest
`Ophthalmal Vis Sci, 2002, vol. 43, pp. 3359-3364].
`Until recently,
`the only methods used to treat dry eye
`disease were topical administration of over-tlie-couiiter
`compositions that serve as artificial 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 shown to be effective in treating many
`cases of dry eye. 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 common stnictiiral
`motif, known as the trefoil domain, as part of their structure.
`The trefoil motif comprises about 20 to about 60 amino acid
`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, known as 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 TFF-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 each
`
`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 ofTFF-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-
`peptides assist healing by both stabilizing mucus membrane
`at 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,
`deReaumont M, Thim I., Podolky D K, Glistruenterulngy,
`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, et al,
`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]
`Although there is 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 TI-'F—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
`occur in the human conjunctival epithelium [Langer G, et al,
`Invest Ophtlwzlmol Vis Sci, 1999, vol. 40, pp. 2220-2224],
`and in vitro studies have shown that TFF2 and TFF3
`peptides promote the migration of wounded corneal epithe-
`lial cells from rabbits [Goke M, et 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 TFF-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 by alterations in mucins as they occur in 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 to the symptoms or cause of dry eye
`disease. In making the above statements,
`the applicants
`make no admission as to whether any of 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 effec-
`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 eye is indicated thereon.
`
`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 the art.
`For example, methods of preparing TEE-peptides are
`included in the following references: U.S. Pat. No. 6,525,
`018; Allen, et. al.,] Clirz Gastraenteral 1998; 10 (Suppl 1):
`S93—S98; Ligumsky,
`et.
`al.,
`Isr J Med Sci
`1986;
`22:801—806; 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 VVO02085402, 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 undue 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 TEE-peptide is preferably from about 0.001% to about
`1%. More preferred 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-
`ment of 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 preferable 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
`Waal forces (Tabor et 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 way by theory, 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 TFF-peptide because of the
`otherwise short contact time between the TFF-peptide and
`the surface of the eye. 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 Tania-
`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 (e .g.
`
`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 copolymers of 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 component is Tamarind seed
`polysaccharide, carboxymethylcellulose, hydroxymethyl-
`cellulose, Carbopol, hyaluronic acid, xanthan gum, or algi-
`nate. The most preferred mucoadhesive component is Tama-
`rind seed polysaccharide, which is a galactoxyloglucan
`that’s extracted from the seed kernel of Tainarindus Imlicu,
`and can be purchased from TC] 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 of its
`underlying causes. In addition, the second therapeutically
`active agent could be any drug which is 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 of this invention, the second therapeu-
`tically active agent could be a drug which is used in topical
`ophthalmic compositions which might cause, contribute to,
`or aggravate dry eye disease as a side effect of its use. In this
`aspect, this invention is useful in reducing or eliminating
`said side effect.
`
`One class 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, P1-(cy-
`tidine 5‘-)-P-(uridine 5‘-)tetraphosphates, P1, P4-di(uridine
`5‘)-tetraphosphates, or their therapeutically effective ana-
`logues or derivatives, which may aifect
`tear secretion,
`particularly the mucous layer of tears, and thus may have
`potential in treating dry eye disease. These compounds are
`described in the following patents, all of which are incor-
`porated herein by reference: US 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; US. Pat. No. 6,331,529; U.S. Pat. No. 6,323,187;
`US. 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 and its 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 compounds are 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 relation to this invention is tetracycline, derivatives
`or analogues of tetracycline, or chemically modified tetra-
`cycline. These compounds are 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-
`ylprednisolone sodium succinate, prednisolone acetate,
`
`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 US. 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 factors or cytokines
`including the transforming growth factor beta (TGFB),
`which are disclosed to be useful in treating dry eye in U.S.
`Pat. No. 5,652,209, incorporated herein by reference.
`Another class useful second therapeutically active agents
`is androgens or androgen analogues such as 17ot—methyl—
`17[3-liydroxy-2-oxa-5ot-androstan-3-one,
`testosterone
`or
`testosterone derivatives, 4,50.-dihydrotestosterone or deriva-
`tives, 17|3-hydroxy-501-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,
`preferably about 7. Buffers used are those 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 by a 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 is preferable for a tonicity agent
`to be used. Tonicity 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 compositions related to the present invention
`which are described herein, it is preferable for a preservative
`to be used when the composition is intended for multiple
`use. There may also be reasons to use a preservative in single
`use compositions depending on the individual circum-
`stances. The term preservative lias 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
`Under certain 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,
`zwitterionic, and nonionic surfactants may all be used in this
`
`6
`invention. For the purposes of this 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 herein is a chelating
`agent. The term chelating agent refers to a compound that is
`capable of complexing a metal, as understood by those of
`ordinary skill in the chemical art. 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
`edetate salts, like edetate disodium, edetate 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 seed
`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 about 8.
`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 amount of a 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 treatment of 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 only to provide direction and guidance in how to make
`and use the invention, and are not intended to limit the scope
`of the invention in any way.
`
`EXAMPLE 1
`
`Compositions related to this invention are prepared by the
`following procedure. Unless otherwise indicated, all proce-
`dural steps are carried o11t at room temperature.
`Part I
`
`TSP is added to purified water at the concentrationindicated
`in the Table 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 micron sterilizing filter.
`Part II
`
`Each component listed in Table 1 is added in amount needed
`to provide the indicated concentration to a fixed volume of
`the solution from part I, in the following order: 'l'FF 1, boric
`acid, sodium borate decahydrate, sodium chloride, and
`BAK. After the addition of each component, the mixture is
`stirred until the solute is completely dissolved before the
`next component is added. When all of the components of the
`formulation have been added and dissolved, the pH is then
`adjusted to 7.0 with NaOH or HCl. The solution is then
`sterile filtered.
`
`FAMY CARE - EXHIBIT 1029-0005
`
`

`
`7
`
`TABLE 1
`
`US 6,984,628 B2
`
`8
`
`TABLE 4-continued
`
`Component
`
`Function
`
`% (W/vi)
`
`Component
`
`Function
`
`TFF-peptide
`"FF1
`"amarind Seed Polysaccharide (TSP) Mucoadhesive
`Boric Acid
`Bulfer
`Sodium Borate Decahydrate
`Butfer
`Sodium Chloride
`Tonicity Agent
`Benzalkonium Chloride (BAK)
`Bulfer
`Purified Water
`HCl or NaOH
`
`Bulfer
`
`0.15
`0.5
`0.6
`0.035
`0.53
`0.005
`Q.s.
`adjust to pH 7.0
`
`Benzalkonium Chloride (BAK)
`Purified Vllater
`HCl or Na0H
`
`Buffer
`
`Buffer
`
`EXAMPLE 5
`
`% (w/vi)
`
`0.005
`Q.s.
`adjust to pH 7.0
`
`EXAMPLE 2
`
`A formulation having the composition of Table 2 is
`prepared according to an analogous procedure to that of
`Example 1.
`
`TABLE 2
`
`Component
`
`Function
`
`% (w/V)
`
`TFF-peptide
`"FF3
`"aniaiind Seed Polysacchaiide (TSP) Mucoadhesive
`Boric Acid
`Bulfer
`Sodium Borate Decahydrate
`Buffer
`Sodium Chloride
`Tonicity Agent
`Benzalkonium Chloride (BAK)
`Buffer
`Purified Water
`HCl or Na0H
`
`Bulfer
`
`0.15
`0.5
`0.6
`0.035
`0.53
`0.005
`Q.s.
`adjust to pH 7.0
`
`EXAMPLE 3
`
`A formulation having the composition of Table 3 is
`prepared according to an analogous procedure to that of
`Example 1.
`
`Component
`
`TABLE 3
`
`Function
`
`TFF-peptide
`TFF 1
`Sodium Carboxymethylcellulose Mucoadhesive
`Boric Acid
`Buffer
`Sodium Borate Deeahydrate
`Buffer
`Sodium Chloride
`Toriicity Agent
`Benzalkoniuni Chloride (BAK)
`Buffer
`Purified Water
`HCl or NaOH
`
`Buffer
`
`% (W/V)
`
`0.15
`0.5
`0.6
`0.035
`0.53
`0.005
`Q.s.
`adjust to pH 7.0
`
`EXAMPLE 4
`
`A formulation having the composition of Table 4 is
`prepared according to an analogous procedure to that of
`Example 1.
`
`TABLE 4
`
`Component
`TFF 3
`Hydroxypropylmethylcellulose
`Boric Acid
`Sodium Borate Decahydrate
`Sodium Chloride
`
`Function
`
`TFF-peptide
`Mucoadhesive
`Buffer
`Buffer
`Tonicity Agent
`
`A forr11ulatior1 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 Abeing added to the Castor oil before introduc-
`ing the oil into the emulsion. An aqueous solution of the
`trefoil factor family peptide is sterile filtered into the emul-
`sion after the emulsion has cooled.
`
`Component
`TFF 3
`Cyclosporin A
`
`Castor oil
`Polysorbate-80
`Pemulen TR-2
`Glyceiin
`Purified Water
`HCl or .\IaOH
`
`TABLE 5
`
`Function
`
`TFF-peptide
`Second
`Therapeutically
`Active Agent
`Oil phase
`Surfactant
`Emulsion stabilizer
`Tonicity agent
`
`Buffer
`
`EXAMPLE 6
`
`1.25
`1.0
`0.05
`2.2
`Q.s.
`adjust to pH 7.4
`
`A drop of a composition prepared according to one of
`Examples 1-5 is added at
`least once a day to a patient
`sulfering from dry eye disease. Relief of symptoms is
`experienced and continues for as long as the patient
`is
`receiving the treatment.
`What is claimed is:
`1. A composition comprising a therapeutically effective
`amount of 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 effective amount
`of trefoil factor family peptide, an effective amount of
`tamarind seed polysaccharide, about 0.5% sodium chloride,
`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
`polysaccharide, about 0.5% sodium chloride, about 0.005%
`benzalkonium chloride, and about