PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(11) International Publication Number:
`
`WO 92/16206
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`(51) International Patent Classification 5 :
`
`
`A61K 31/40, 31/35, 31/21
`
`(43) International Publication Date:
`1 October 1992 (01.10.92)
` (21) International Application Number:
`
`
`PCT/US92/01848|(81) Designated States: AT, AT (Europeanpatent), AU, BB, BE
`% {
`(European patent), BF (OAPI patent), BG, BJ (OAPI
`
`
`«|
`(22) International Filing Date:
`5 March 1992 (05.03.92)
`patent), BR, CA, CF (OAPIpatent), CG (OAPIpatent),
`
`'
`CH, CH (European patent), CI (OAPI patent), CM
`
`
`
`
`4,|(30) Priority data: (OAPI patent), CS, DE, DE (European patent), DK,
`DK (European patent), ES, ES (European patent), FI,
`69,786
`15 March 1991 (15.03.91)
`US
`
`
`
`FR (European patent), GA (OAPI patent), GB, GB (Eu-
`
`
`
`(71) Applicant! NORWICH EATON PHARMACEUTICALS
`ropean patent), GN (OAPIpatent), GR (European pa-
`INC. [US/US]; 17 Eaton Avenue, Norwich, NY 13815
`tent), HU, IT (European patent), JP, KP, KR, LK, LU,
`
`(US).
`LU (European patent), MC (European patent), MG, ML
`.
`(OAPIpatent), MN, MR (OAPIpatent), MW, NL, NL
`
`
`
`(72) Inventors: CLOYD, George, Gilbert ; Box 566, Lake Road,
`(European patent), NO, PL, RO, RU, SD, SE, SE (Euro-
`
`
`pean patent), SN (OAPIpatent), TD (OAPIpatent), TG
`Norwich, NY 13815 (US). FELARCA,Allison, Barretto
`
`
`(OAPI patent).
`; 22 Newton Avenue, Norwich, NY 13815 (US).
`
`
`
`
`
`Published
`(74) Agent: REED, T., David; The Procter & Gamble Com-|
`
`With internationalsearch report.
`pany,
`Ivorydale Technical Center, 5299 Spring Grove
`
`
`Avenue, Cincinnati, OH 45217-1087 (US).
`Before the expiration of the time limit for amending the
`
`
`claims and to be republished in the event of the receipt of
`amendments.
`
`
`
`
`
`
`
`
`
`
`(54) Title: THE USE OF 5-AMINOSALICYLIC ACID IN THE TREATMENTOF IRRITABLE BOWEL SYNDROME-
`DIARRHEAL PHASE ORTYPE(IBS-D)
`
`(57) Abstract
`
`
`
`
`
`Treatmentfor a human or other mammalafflicted with IBS-D, comprising the topical delivery to the intestinaltract of said
`humanor other mammal, preferably thelargeintestine, of a safe and effective amountof a pharmaceutical composition consist-
`
`
`ing essentially of the 5-ASA active ingredient and pharmaceutically-acceptable excipients. Said topical delivery is preferably ac-
`
`complished by the oral administration to said human or other mammalofa delayed-release composition consisting essentially of
`said 5-ASAactive ingredient and a pharmaceutically-acceptable excipient.
`
`*
`
`
`
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`Ne
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`Mauritania
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`Norway
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Madagascar Mali
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`BB
`BE
`BF
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`Bj
`BR
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`Austria
`Australia
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`WO 92/16206
`
`PCT/US92/01848
`
`THE USE OF 5-AMINOSALICYLIC ACID IN THE TREATMENT OF
`
`IRRITABLE BOWEL SYNDROME - DIARRHEAL PHASE OR TYPE (IBS-D)
`
`5
`
`10
`
`BACKGROUND OF THE INVENTION
`novel method of
`invention relates
`to the
`The present
`treating a human or other mammal afflicted with Irritable Bowel
`Syndrome - Diarrheal Phase or Type
`(hereinafter referred to as
`IBS-D) comprising the topical delivery to the intestinal tract of
`said human or other mammal of a safe and effective amount of a
`
`pharmaceutical composition consisting essentially of the active
`ingredient 5-aminosalicylic acid (hereinafter
`referred to as
`"5-ASA"),
`and
`pharmaceutically-acceptable
`excipients.
`Said
`topical delivery is most preferably accomplished by the oral
`administration to said human or other mammal of a delayed-release
`composition
`consisting
`essentially
`of
`said
`5-ASA
`active
`ingredient and a pharmaceutically-acceptable excipient.
`Irritable bowel
`syndrome (hereinafter referred to as "IBS")
`is a poorly understood disorder for which there is presently no
`adequate treatment.
`IBS is usually the diagnosis given when an
`individual suffers from certain characteristic symptoms affecting
`the gastrointestinal
`tract
`and after
`the existence of other
`disorders
`have
`been
`eliminated.
`Accordingly,
`IBS
`sufferers
`exhibit altered bowel habits (characterized either by alternating
`diarrhea
`and
`constipation,
`solely
`constipation,
`or
`solely
`diarrhea), as well as abdominal pain and/or cramping, and various
`other
`symptoms
`including flatulence and
`abdominal distension,
`bloating, and rumbling.
`There is no detectable radiolagical or
`histological evidence of organic pathology, i.e.
`the presence of
`an infectious agent or observable inflammation or other pathology
`in the intestinal
`tract.
`IBS has been called functional
`bowel
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`WO 92/16206
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`
`-2-
`
`colonic
`nervous diarrhea,
`disorder, mucomembraneous colitis,
`neurosis, colonic dyspepsia, colonic dysfunction, spastic colon,
`mucous
`colitis,
`irritable
`colon
`syndrome,
`unhappy
`colon,
`dissynergia of the colon,
`and disordered gastrocolonic reflex.
`It is estimated that about 10% of the adult population suffers
`from IBS and that this disorder accounts for from about 40% to
`about 70% of office visits to gastroenterologists.
`It has also
`been
`suggested that
`IBS
`is
`one of
`the
`leading causes of
`absenteeism from work due to illness.
`suffering from IBS may
`As
`stated hereinabove,
`those
`experience diarrhea only, alternating diarrhea and constipation,
`or constipation only; accordingly,
`there has been a great deal of
`effort to categorize IBS patients based upon these symptoms.
`See
`Einar Krag, “Irritable Bowel Syndrome:
`Current Concepts
`and
`Future Trends,"
`Scand. J. Gastroenteral, Vol. 20
`(Suppl. 109),
`pp. 107-15,
`1985;
`and Whitehead
`et al.,
`“Irritable
`Bowel
`Syndrome - Physiological
`and Psychological Differences Between
`Diarrhea-Predominant and Constipation-Predominant Patients", Dig.
`Dis. Sci., Vol. 25, No. 6, pp. 404-13,
`June 1980
`(hereinafter
`referred to as "Whitehead et al.").
`It has been estimated that
`about 50% of IBS sufferers experience IBS-Diarrheal phase or type
`(hereinafter referred to as IBS-D) and that 50% of IBS sufferers
`experience constipation only.
`Of
`the population which suffers
`from IBS-D, one-fifth experience only diarrhea (IBS-diarrheal
`type),
`and
`the
`remaining
`four-fifths
`experience alternating
`diarrhea and constipation (IBS-diarrheal phase).
`The cause of IBS has been extremely difficult to determine,
`and there has been little success
`in differentiating possible
`causes with regard to symptomatic characterizations.
`It has been
`reported that IBS stems from the ingestion of certain foodstuffs
`(often wheat gluten or lactose); other theories as to the cause
`of
`IBS have implicated disorders of gut motility, while many
`gastroenterologists,
`however,
`have
`attributed
`IBS
`to
`psychological
`factors.
`See generally, V. Alun Jones, et al.,
`"Food
`Intolerance:
`A Major Factor
`in the Pathogenesis of
`Irritable
`Bowel
`Syndrome", TheLancet, Vol. 2,
`No. 8308,
`
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`WO 92/16206
`
`PCT/US92/01848
`
`-3-
`
`pp. 1115-17, November 20, 1982 (hereinafter referred to as "Jones
`et al."); Kumar et al.,
`"The
`Irritable Bowel
`Syndrome:
`A
`Paroxysmal Motor Disorder", TheLancet, Vol. 2,
`No. 8462,
`pp. 973-77, November 1985 (hereinafter referred to as "Kumar et
`al."); Drossman et al., “Psychosocial Factors in the Irritable
`Bowel Syndrome," Gastroenterology, Vol. 95, (3), pp. 701-8, Sept.
`1988;
`and Drossman et al.,
`“The
`Irritable Bowel
`Syndrome,"
`Gastroenterology, Vol. 73, p. 811-22, Oct. 1977.
`there is
`In addition to confusion as to the cause of IBS-D,
`debate as to the precise site of the disorder in the intestinal
`tract; there is confusion as to whether the problematic region is
`the
`small
`intestine,
`the
`colon,
`or both,
`and whether
`the
`problematic site varies amongst
`individuals and/or depending on
`the symptoms.
`See, e.g. Kumar et al., op. cit., and Cann et al.,
`“Irritable Bowel Syndrome:
`Relationship of Disorders
`in the
`Transit of a Single Meal
`to Symptom Patterns", Gut, Vol. 24,
`No. 5, pp. 405-11, May 1983.
`Much of the early work on disorders of the gastrointestinal
`tract has involved ulcerative colitis and Crohn’s disease, which
`are two of the most
`common Inflammatory Bowel Diseases (herein-
`after
`referred to as
`"IBD").
`In
`fact, patients with
`IBS-D
`present with
`symptoms which
`are markedly
`similar
`to those
`experienced with IBD, particularly ulcerative colitis and Crohn’s
`disease
`and,
`therefore,
`the
`existence of
`IBD is generally
`investigated and ruled out before the diagnosis of
`IBS-D is
`given.
`the administration of 5-ASA is
`It has been reported that
`effective in the treatment of ulcerative colitis and Crohn’s
`disease.
`See U.S. Patent 4,496,552 to Halskov,
`issued January
`29,
`1985,
`and assigned to Farmaceutisk Laboratorium Ferring,
`hereby incorporated by reference herein.
`It has
`further been stated that various gastrointestinal
`disorders
`including,
`in
`addition
`to
`IBS, Crohn’s
`disease
`(regional
`ileitis),
`ulcerative
`colitis
`(proctitis,
`distal
`proctocolitis),
`atrophic gastritis,
`stump proctitis,
`coeliac
`disease,
`regional
`ileitis,
`peptic
`ulceration,
`and
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`
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`15
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`
`gastrointestinal allergy respond to treatment by a pharmaceutical
`composition comprising a compound having sodium cromoglycate-1ike
`.
`activity
`as
`the
`active
`ingredient,
`in
`combination with
`
`
`
`sulfasalazine an_ASA.or See U.K. Patent Publication
`
`
`
`GB 2,021,409 of Worsley, published December 5, 1979, assigned to
`5
`;
`Fisons Ltd., hereby incorporated by reference herein, along with
`its U.S. equivalent, U.S. Patent 4,211,777 to Chambers,
`issued
`July 8, 1980, assigned to Fisons Ltd., hereby incorporated by
`reference herein.
`Ulcerative colitis is a chronic inflammatory disease of the
`colon of unknown etiology.
`The disease causes inflammation of
`the mucosa of
`the colon, with extension to the submucosa
`in
`severe cases. Typically,
`the colon, as well as the rectum,
`is
`involved;
`it ‘is
`less common
`for
`the ileum (the most distal
`portion of
`the small
`intestine)
`to be
`involved.
`The ulcer
`formation and its extent may vary amongst individuals and amongst
`different regions of the intestinal tract of the same individual,
`and
`is often detectable via
`sigmoidoscopy or
`colonoscopy.
`Crohn’s disease, also known
`as
`regional enteritis or colitis
`granulomatosa,
`is often
`characterized as
`being
`related to
`ulcerative colitis, since they are both inflammatory diseases of
`the intestine. Crohn’s disease is most frequently located in the
`small
`intestine, especially in the ileum, but also may affect the
`jejunum (the middle part of the small
`intestine,
`just distal
`to
`the duodenum and proximal
`to the ileum)
`and any part of
`the
`colon,
`including the rectum. When
`the colon is involved,
`the
`differentiation of Crohn’s disease from ulcerative colitis is
`considerably difficult. Generally,
`the inflammatory reaction of
`Crohn’s disease differs
`from that of ulcerative colitis by
`progressing to layers deeper than the mucosa and affecting the
`epithelium to a
`lesser degree.
`A
`thorough review of both
`diseases is given by J. B. Kirsner, M.D., Ph.D.,
`in an article
`entitled "Observation on the Medical Treatment of
`Inflammatory
`Bowel Disease," found in JAMA, Feb. 8, 1980, Vol. 243, No. 6, pp.
`557-564.
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`WO 92/16206
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`PCT/US92/01848
`
`-5-
`
`the
`the presence of
`by
`IBD is distinguished from IBS
`inflammation of the mucosa and submucosa layers of the intestine,
`which is detectable usually by visual
`inspection (sigmoidoscopy
`or
`colonoscopy),
`but
`also by
`radiological
`or histological
`examination.
`As stated hereinabove,
`IBS is characterized by the
`lack of any detectable radiological or histological evidence of
`organic pathology,
`such as observable inflammation of
`layers
`deeper
`than the epithelium.
`For further discussions comparing
`IBD with IBS, see, e.g., Thompson, “Gastrointestinal Symptoms
`in
`the Irritable Bowel Compared with Peptic Ulcer and Inflammatory
`Bowel Disease," Gut, Vol. 25, No. 10, pp. 1089-92, Oct. 1984;
`Whitehead et al., opcit,; Isgar et al.,
`“Symptoms of Irritable
`Bowel Syndrome in Ulcerative Colitis in Remission," Gut, Vol. 24,
`pp. 190-2, 1983;
`and Ahnfelt-Ronne et al.,
`"Clinical Evidence
`Supporting
`the
`Radical
`Scavenger Mechanism
`of
`5-ASA,"
`Gastroenterology, Vol. 98, No. 5, pp. 1162-69, May 1990.
`For many years, it has been hypothesized that prostaglandins
`were somehow implicated in various gastrointestinal disorders,
`including IBS-D and IBD. As
`the outline of current research set
`forth hereinbelow illustrates, there is considerable debate as to
`the role of prostaglandins in the etiology of both IBS-D and IBD,
`and whether prostaglandins actually cause, or are merely the
`result of,
`inflammation of the intestinal tract.
`In addition, as
`the discussion hereinabove shows,
`IBS-D is an entirely different
`entity than IBD,
`and conclusions drawn regarding one cannot be
`likewise applied to the other.
`In a symposium on prostaglandins, Donald E. Wilson, M.D. and
`Hulya Kaymakcelan, M.D.
`reviewed the role of prostaglandins in
`various gastrointestinal disorders,
`including IBS.
`See Wilson,
`et al.,
`“Prostaglandins: Gastrointestinal Effects
`and Peptic
`Ulcer Disease", Med. Clin. North.
`Am., Vol.
`65,
`No.
`4,
`pp. 773-87,
`July
`1981,
`hereinafter
`referred
`to
`as
`"Prostaglandins".
`It was reported therein that the possible role
`of prostaglandins
`in
`specific
`and nonspecific
`inflammatory
`disorders has been suggested by several studies indicating that
`the condition of patients with a variety of intestinal disorders
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`radiation enteritis, ulcerative
`in addition to IBS,
`(including,
`improved when
`inhibitors of
`colitis,
`and
`food
`intolerance)
`prostaglandin synthesis,
`such as aspirin or
`indomethacin, were
`administered.
`See Prostaglandins,
`pp. 781-2.
`Also
`reported
`therein,
`however,
`was
`the
`fact
`that
`information
`linking
`prostaglandins to said disorders is in a state of flux and the
`role of prostaglandins in IBS-D is uncertain.
`The confusion is
`exacerbated by
`the
`fact
`that
`"prostaglandins
`are
`a
`normal
`by-product of
`the
`inflammatory response and
`the
`finding of
`elevated
`orostaglandin
`levels
`on
`inflammation
`does
`not
`necessarily indicate a pathogenetic role for prostaglandins."
`See Prostaglandins at 782.
`appeared to
`indomethacin blockade
`It was
`reported that
`IBS-D.
`See
`exhibit
`important
`therapeutic
`implications with
`J. Rask-Madsen
`et al.,
`"Indomethacin-Responsive Diarrhea
`in
`Irritable Bowel Syndrome", Gut, Vol. 19, p. 448, 1978.
`It was
`reported by Jones et _al.,
`op. cit., p.1117 that
`there were
`significant elevations of PGE?
`levels in their patients after
`food challenge and a significant relationship between PGE2 and
`wet fecal weight.
`It was suggested therein that
`these results
`indicate that prostaglandins may be associated with the etiology
`of IBS-D. At the same time, Jones et al. also reported that IBS
`patients who were experiencing pain rather than diarrhea did not
`show pronounced increase in prostaglandin production and further
`hypothesized that other factors may be important
`in the etiology
`of IBS-D.
`There are also reports that
`in a few cases the oral
`administration of various Non-Steroidal Anti-Inflammatory Drugs
`(hereinafter
`"NSAIDs")
`cause
`exacerbations of colitis.
`See
`Clements et al.,
`"Colitis Associated with Ibuprofen", British
`30 Medical Journal, Vol. 301, No. 6758, p. 987, Oct. 22, 1990, and
`references cited therein.
`For an additional discussion of the
`treatment of IBS with prostaglandin inhibitors, see, e.g. Lessof
`et al., "Prostaglandins in the Pathogenesis of Food Intolerance",
`Annals of Allergy, Vol. 51, pp. 249-50, August 1983.
`role of
`Hawkey
`and Truelove
`extensively discussed the
`prostaglandins
`in ulcerative colitis.
`See Hawkey, C.J.,
`and
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`5
`
`Truelove, S. C., "Inhibition of Prostaglandin Synthetase in Human
`Rectal Mucosa", Gut, 1983, 24, pp. 213-7 (hereinafter "Hawkey et
`al.")
`It was
`reported therein that
`there are some
`indications
`that prostaglandin synthesis
`is associated with an excessive
`inflammatory reaction and that
`inhibition of this synthesis is
`therefore desirable.
`However,
`it
`has also been
`shown
`that
`indomethacin and flurbiprofen (which are more potent
`than 5-ASA
`as inhibitors of prostaglandin synthesis by human rectal mucosa)
`do not
`appear
`to be: effective agents
`in the treatment of
`ulcerative colitis.
`In fact, extremely deleterious effects have
`been reported with the use of flurbiprofen to treat ulcerative
`colitis.
`Id at 216. These findings suggest that the inhibition
`of prostaglandin synthesis alone may not be the precise mechanism
`by which 5-ASA works to alleviate ulcerative colitis.
`Such results with potent prostaglandin inhibitors have led
`the
`alternative
`view
`that
`prostaglandins
`may
`be
`to
`cyto-protective in ulcerative colitis. Data have been generated
`which shows that,
`in some circumstances, 5-ASA, although usually
`characterized in a general
`fashion as a prostaglandin inhibitor,
`20 might
`lead to enhanced rather than reduced levels of mucosal
`prostaglandins.
`Id.
`Hawkey et al. also proposed a third possible theory as to
`the mode of
`action of
`5-ASA in ulcerative colitis.
`Weak
`
`10
`
`15
`
`inhibitors of prostaglandin synthetase (such as 5-ASA) have been
`
`25=shown to decrease synthesis of leukotrienes and
`
`
`
`
`
`hydroxyeicosatetraenoic
`acids
`by
`inhibiting the
`lipoxygenase
`pathways which may lead to their production;
`leukotrienes and
`hydroxyeicosatetraenoic acids are non-prostaglandin hydroxy end
`products of
`arachidonic
`acid metabolism associated with
`an
`ability to reduce the accumulation of white cells at sites of
`inflammation.
`By
`contrast,
`potent
`prostaglandin
`synthetase
`inhibitors (such as
`indomethacin and flurbiprofen) have little
`effect on white cell
`accumulation and can,
`therefore, divert
`arachidonic acid metabolism along lipoxygenase pathways which
`have been shown to exist
`in human colonic mucosa.
`Jd.
`For
`further discussions of
`the possible role of prostaglandins
`in
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`WO 92/16206
`
`PCT/US92/01848
`
`-8-
`
`"Enhanced
`Inflammatory Bowel Disease, see e.g. Ligumsky et al.,
`Thromboxane Ag
`and Prostacyclin Production by Cultured Rectal
`Mucosa in Ulcerative Colitis and Its Inhibition by Steroids and
`Sulfasalazine," Gastroenterology, Vol. 8, No. 3,
`pp.
`144-9,
`September 1981; Pacheco,
`“Inflammatory Bowel Disease:
`The In
`Vitro Effect of Sulphasalazine and Other Agents on Prostaglandin
`Synthesis by Human Rectal Mucosa," Braz. J. Med. Biol. Res., Vol.
`20, No. 3, pp. 221-230, 1987; Campieri et al., “Salicylate Other
`Than 5-Amino Salicylic Acid Ineffective in Ulcerative Colitis,"
`(letter), TheLancet,
`p. 993, Nov. 4,
`1978;
`and Donowitz,
`"Arachidonic Acid Metabolites
`and Their Role
`in Inflammatory
`Bowel Disease:
`An Update Requiring Addition of
`a Pathway,"
`Gastroenterology, Vol. 88, No. 2, pp. 580-7, 1985.
`The outline of current research set forth hereinabove serves
`to illustrate the
`state of
`immense
`confusion which exists
`regarding the role of prostaglandins in both ulcerative colitis
`and IBS-D.
`The discussion hereinabove shows
`the confusion is
`further complicated by the fact that there is disagreement as to
`whether 5-ASA inhibits or enhances prostaglandin synthesis and by
`the fact that there is considerable debate as to whether prosta-
`glandins
`aggravate or alleviate both, or either, ulcerative
`colitis and IBS-D.
`Furthermore,
`the relevance of the effect of
`5-ASA in inhibiting production of leukotrienes and hydroxyeico-
`satetraenoic acids to its therapeutic effects in IBS-D and IBD is
`yet to be determined.
`that
`fact
`a
`is
`it
`stated hereinabove,
`In addition,
`as
`inflammatory
`an
`of
`normal
`by-product
`prostaglandins
`are
`a
`response [such as
`that which would accompany both the topical
`(epithelial cells most near
`the intestinal
`lumen)
`irritation
`accompanying diarrhea in IBS-D as well as the deeper irritation
`indicative of mucosal
`and/or
`submucosal
`inflammation of
`IBD];
`accordingly,
`elevated
`prostaglandin
`levels
`in
`disorders
`characterized
`by
`inflammation
`does
`not
`necessarily mean
`prostaglandins caused the inflammation.
`Finally,
`the confusion
`is even further amplified by the facts that the manifestations of
`ulcerative colitis,
`and other
`IBDs,
`as
`compared to those of
`
`an
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`WO92/16206
`
`PCT/US92/01848
`
`-9-
`
`5
`
`15
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`20
`
`the etiology of both IBD
`IBS-D, are markedly distinct and that
`and
`IBS-D
`are
`unknown;
`accordingly,
`data
`generated
`and
`conclusions drawn regarding ulcerative colitis, and other forms
`of IBD, cannot,
`in the current state of knowledge, be applied to
`IBS-D.
`Probably largely due to the fact that the etiology of IBS-D
`is unknown,
`there is no satisfactory treatment for IBS-D at the
`present
`time. Conventional
`treatment has included various types
`of therapies including antispasmodic agents (octilonium bromide,
`10 mebeverine,
`trimebutine, dicyclomine,
`and prifinium bromide);
`anticholinergic
`agents
`(atropine,
`belladonna,
`1-hyoscyamine,
`
`propantheline—bromide, and dicyclomine hydrochloride) ;
`
`
`anticholinergic/barbiturate
`combinations
`(tryciclamol
`and/or
`phenobarbital; dicyclomine and/or phenobarbital); antidepressants
`(desipramine,
`trimipramine, amitriptyline); bulking agents (wheat
`bran, psyllium (ispaghula)); dopamine antagonists (domperidone);
`carminatives
`(peppermint oil); opioids
`(loperamide);
`tranquil-
`izers or tranquilizer combinations
`(mepiprazol, benzodiazepine,
`trimipramine,
`phenaglycodol, meprobamate,
`fluphenazine
`and
`nortriptylene,
`lorazepam and/or hyoscine and/or
`ispaghula)
`and
`miscellaneous actives
`such
`as phenytoin
`(an anticonvulsant),
`timolol
`(a
`f-adrenergic
`receptor-blocker),
`and diltiazem (a
`calcium channel blocker).
`Said conventional
`therapies have been
`usually unsatisfactory and are often accompanied by serious and
`undesirable side effects; accordingly, many symptoms of IBS-D go
`untreated. See, e.g.,
`Jones,
`et _al., op. cit.,
`pp. 1115-7;
`Klein,
`"Controlled Treatment Trials
`in
`the
`Irritable Bowel
`Syndrome:
`A Critique", Gastroenterology, Vol. 95, pp. 232-41,
`1988; Waller et al., "Prognosis in Irritable Bowel Syndrome", The
`Lancet,
`Vol. ii,
`pp.
`753-56,
`1969;
`G.
`Misiewicz,
`"Gastrointestinal Manifestations
`of Stress
`and
`Psychopathic
`Personality", Medicine, Vol. 3, pp. 183-88, 1972.
`Applicants have found that a human or other mammal suffering
`from IBS-D can be successfully treated with the topical delivery
`of 5-ASA or its salts and esters,
`to the intestinal tract of said
`human or mammal, preferably the large intestine.
`The
`5-ASA
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`WO92/16206
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`PCT/US92/01848
`
`-10-
`
`active ingredient has been shown to be effective alone, with no
`sodium cromoglycate-like
`agent,
`and
`to
`be
`generally well
`tolerated, with minimal
`to substantially no side effects.
`It is
`preferred to effect said topical delivery of
`the 5-ASA active
`ingredient by the oral administration of delayed-release tablets.
`Said delayed-release tablets are most preferably formulated in
`such a way that
`the 5-ASA active ingredient
`is substantially
`topically delivered to the large intestine via a release of the
`active ingredient at a pH which is generally present only in the
`large intestine.
`Although the preferred method of treatment described herein
`is the topical delivery of the 5-ASA active ingredient
`to the
`large intestine,
`topical delivery of the active ingredient to the
`small
`intestine may be desirable alone, or in addition to,
`the
`topical delivery to the large intestine. Of course,
`the segment
`of the intestine to which the active ingredient will be topically
`delivered
`can
`be
`varied
`by
`employing
`various
`standard
`pharmaceutical dosage forms as delivery systems. When utilizing
`oral dosage forms,
`it is generally easier,
`and therefore more
`preferable,
`to vary coating methods,
`types, and/or
`thicknesses
`which are readily available to those skilled in the art.
`
`UMMARY_ OF THE INVENTION
`invention embodies a novel method of treatment
`The present
`for a human or other mammal afflicted with IBS-D, which comprises
`the topical delivery to the intestinal
`tract of said human or
`other mammal of a safe and effective amount of a pharmaceutical
`composition consisting essentially of a 5-ASA active ingredient,
`and
`pharmaceutically-acceptable
`excipients.
`Said
`topical
`delivery is preferably to the large intestine of said human or
`other mammal
`and is most preferably accomplished by the oral
`administration to said human or other mammal of a delayed-release
`composition
`consisting
`essentially
`of
`said
`5-ASA
`active
`ingredient and pharmaceutically-acceptable excipients.
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`WO 92/16206
`
`PCT/US92/01848
`
`-j]-
`
`DETAILEDDESCRIPTIONOFTHEPRESENTINVENTION
`
`
`The present invention relates to a novel method of treatment
`for a human or other mammal afflicted with IBS-D which comprises
`the topical delivery to the intestinal
`tract of said human or
`other mammal, preferably to the large intestine, of a safe and
`effective amount of
`a pharmaceutical
`composition consisting
`essentially of a 5-ASA active ingredient and pharmaceutically-
`acceptable excipients.
`Said topical delivery is most preferably
`achieved via the oral administration to said human or other
`
`5
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`10
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`15
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`20
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`25
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`30
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`35
`
`mammal of a delayed-release composition consisting essentially of
`the
`5-ASA active
`ingredient
`and
`pharmaceutically-acceptable
`excipients.
`A.
`The 5-ASA Active Ingredient
`The present
`invention is directed to a method of treatment
`for IBS-D utilizing the topical delivery to the intestinal
`tract
`of a human or other mammal, preferably to the large intestine, of
`a
`safe and effective amount of
`a pharmaceutical
`composition
`consisting
`essentially of
`a
`5-ASA
`active
`ingredient
`and
`pharmaceutically-acceptable excipients.
`The term "5-ASA active ingredient", as used herein, denotes
`5-aminosalicylic acid, hereinafter referred to as
`"5-ASA" and,
`unless
`otherwise
`specified,
`encompasses
`the
`pure
`compound
`5-aminosalicylic acid, as well as the pharmaceutical ly-acceptable
`salts or esters thereof, or any mixture thereof.
`5-Aminosali-
`cylic acid (5-ASA)
`is often referred to as
`"mesalamine"
`and
`"mesalazine"”
`and
`is more properly referred to as 5-amino-2-
`hydroxybenzoic
`acid
`or
`5-amino-2-hydroxybenzene-1-carboxylic
`acid.
`
`Any pharmaceutically-acceptable, non-toxic salt of 5-ASA may
`be used as the 5-ASA active ingredient
`in the composition of the
`present
`invention.
`The salts of
`5-ASA may be acid addition
`salts,
`in
`particular
`the
`hydrochloride,
`but
`any
`pharmaceutically-acceptable, non-toxic organic or inorganic acid
`salt may be used.
`In addition, salts formed with the carboxylic
`acid group may be used,
`including, but not
`limited to, alkali
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`WO 92/16206
`
`PCT/US92/01848
`
`-12-
`
`the
`
`metal salts (K, Na) and alkaline earth metal salts (Ca, Mg),
`Ca- and Na- salts being preferred.
`Any pharmaceutically-acceptable, non-toxic ester of 5-ASA
`may be used as the 5-ASA active ingredient in the pharmaceutical
`composition described herein.
`Particularly suitable esters are
`those meta- (or 5-) aminosalicylic esters and a number of related
`esters disclosed in Great Britain Patent Specification 1,581,444
`of Halpern et al., assigned to Mundipharma A.G. of Switzerland,
`published December 17,
`1980,
`hereby
`incorporated
`herein
`by
`reference.
`A
`number
`of
`esters
`of
`ortho-, meta-,
`and
`para-salicylic acid are disclosed.
`Said esters are effective as
`ultraviolet ray screening compounds,
`thereby rendering themselves
`useful
`in preventing solar burning.
`the
`Other esters of 5-ASA which are suitable for use as
`active ingredient
`in the invention disclosed herein are straight
`chain or branched chain Cj-Cjg alkyl esters,
`including, but not
`limited to, methyl, ethyl, propyl,
`isopropyl, butyl,
`isobutyl,
`amyl, hexyl, heptyl, octyl,
`nonyl, decyl,
`lauryl, myristyl,
`cetyl],
`and stearyl; straight chain or branched C2-Cjg alkenyl
`esters,
`including, but not
`limited to, vinyl, alkyl, undecenyl,
`and
`linolenyl;
`(3-Cg cycloalkyl
`esters,
`including,
`but not
`limited to,
`cyclopropyl,
`cyclobuty],
`cyclopentyl,
`cyclohexyl,
`cycloheptyl,
`and cycloocty];
`aryl esters,
`including, but not
`limited to,
`phenyl,
`toluyl,
`xylyl,
`and naphthyl;
`alicyclic
`esters,
`including, but not
`limited to, menthyl;
`and aralkyl
`esters,
`including, but not limited to, benzyl, and phenethy].
`Generally speaking,
`the proper selection of the 5-ASA active
`ingredient depends
`on
`the selected type of
`formulation,
`the
`disease pattern, especially the site and type of the disease, and
`the desired release of the active ingredient.
`In addition,
`the
`physical
`and chemical characteristics of the active ingredient
`must
`be
`taken into account when
`selecting suitable pharma-
`ceutically-acceptable excipients for use in the pharmaceutical
`composition containing the 5-ASA active ingredient.
`In addition to the 5-ASA active ingredients,
`ceutical composition and methods of
`the present
`
`the pharma-
`invention may
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`WO 92/16206
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`PCT/US92/01848
`
`-13-
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`5
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`also contain other non-5-ASA active agents exhibiting different
`and/or additional
`biological
`activity.
`For
`instance,
`those
`compounds conventionally used in the treatment of diseases or
`disorders of the intestinal tract are of particular interest.
`In
`addition to 5-ASA active ingredients, examples of other non-5-ASA
`active
`agents
`include non-steroidal
`anti-inflammatory drugs
`(i.e., NSAIDs), as described hereinbelow, preferably including,
`but not
`limited to,
`salicylates,
`indomethacin,
`flurbiprofen,
`diclofenac,
`naproxen, piroxicam,
`tebufelone
`and
`ibuprofen;
`steroids,
`including,
`but
`not
`limited
`to,
`hydrocortisone,
`prednisolone,
`prednisolone
`phosphate,
`prednisolone
`metasulpho-benzoate
`sodium,
`prednisolone
`sodium phosphate,
`beclomethasone
`diphosphonate,
`and
`beclomethasone’
`valerate;
`compounds active in the relief of constipation and diarrhea;
`compounds active in the relief of spasm and in the improvement of
`motility, e.g. peppermint oil
`and other carminative essential
`oils;
`compounds
`for
`the
`removal
`of
`excessive bile
`acids,
`including, but not
`limited to cholestyramine; antibacterial or
`antiparasite
`compounds,
`including,
`but
`not
`Jimited
`to,
`
`20=erythromycin, chloroquine, jiodochl orhydroxyquine,
`
`disodohydroxyquine, neomycin and tetracyclines. Non-5-ASA active
`agents do not
`include sodium cromoglycate.
`Other non-5-ASA active agents suitable for use herein are
`5-aminosalicylic acid NSAID conjugates described by Moller et
`al.,
`“Novel 5-Aminosalicylic Acid NSAID Conjugates:
`Synthesis,
`Pharmacological
`and Toxicological Properties,"
`rop.
`J
`Chem., Vol. 24, No. 5, pp. 463-69, 1989, hereby incorporated by
`reference herein.
`The described conjugates are
`produced
`by
`coupling the NSAID carboxyl-group with the 5-amino-group of
`5-ASA.
`The
`5-ASA derivatives
`of
`the
`NSAIDs
`diclofenac,
`ibuprofen,
`indomethacin,
`naproxen,
`and
`salicylic
`acid
`are
`particularly
`described,
`but
`conjugates
`of
`5-ASA_
`active
`ingredients and other NSAIDs are suitable for use as a non-ASA
`active agen