PCI‘
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`(51) International Patent Classification 5 :
`
`(1]) International Publication Number:
`
`WO 92/16206
`
`(21) International Application Number:
`
`(22) international Filing Date:
`
`(30) Priority data:
`669,786
`
`5 March 1992 (05.03.92)
`
`15 March 1991 (15.03.91)
`
`US
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`
`A61K 31/40, 31/35, 31/21
`
`
`(43) International Publication Date:
`1 October 1992 (01.10.92)
` PCT/US92/01848
`
`
`
`
`
`
`
`
`
`(81) Designated States: AT, AT (European patent), AU, BB, BE
`(European patent), BF (OAPI patent), BG, BJ (OAPI
`patent), BR, CA, CF (OAPI patent), CG (OAPI patent),
`
`CH, CH (European patent), CI (OAPI patent), CM
`
`(OAPl patent). CS, DE, DE (European patent), DK,
`
`DK (European patent), ES, ES (European patent), FI,
`
`FR (European patent), GA (OAPI patent), GB, GB (Eu-
`
`
`ropean patent), GN (OAPI patent), GR (European pa-
`tent), HU, IT (European patent), JP, KP, KR, LK, LU,
`
`
`LU (European patent), MC (European patent), MG, ML
`
`(OAPI patent), MN, MR (OAPI patent), MW, NL, NL
`
`(European patent), N0, PL, RO, RU, SD, SE, SE (Euro-
`
`
`pean patent), SN (OAPl patent), TD (OAPI patent), TG
`
`
`(OAPI patent).
`
`
`
`Published
`
`147th intemational search report.
`
`
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(71) Applicant: NORWICH EATON PHARMACEUTICALS
`INE. [US/US]; 17 Eaton Avenue, Norwich, NY 13815
`(U ).
`
`
`
`(72) Inventors: CLOYD, George, Gilbert ; Box 566, Lake Road,
`Norwich, NY 13815 (US). FELARCA, Allison, Barretto
`; 22 Newton Avenue, Norwich, NY 13815 (US).
`
`
`
`
`
`(74) Agent: REED, T., David; The Procter & Gamble Com-
`pany,
`Ivorydale Technical Center, 5299 Spring Grove
`
`Avenue, Cincinnati, OH 45217-1087 (US).
`
`
`
`
`
`
`
`
`
`(54) Title: THE USE OF S-AMINOSALICYLIC ACID IN THE TREATMENT OF IRRITABLE BOWEL SYNDROME -
`DIARRHEAL PHASE OR TYPE (IBS-D)
`
`
`(57) Abstract
`
`
`Treatment for a human or other mammal afflicted with iBS-D, comprising the topical delivery to the intestinal tract of said
`human or other mammal, preferably the large intestine, of a safe and effective amount of a pharmaceutical composition consist-
`ing essentially of the 5-ASA aaive ingredient and pharmaceutically-acceptable excipients. Said topical delivery is preferably ac-
`complished 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.
`
`
`
`
`
`
`
`
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`.'1
`
`_
`
`'
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify State: party to the PCI‘ on the hunt pages of pamphlets publishing international
`applications under the PCT.
`
`Madagascar Mali
`
`AT
`
`us
`BE
`BF
`38
`3.}
`
`Austria
`Auurilliu
`Burntdm
`Belgium
`Eurkinu bust:
`Bulgaria
`Benin
`Brazil
`Canada
`('cnlral Airman Republic
`(‘tmgo
`Swillctlulld
`('éu: d'ltmirc
`Cameroon
`chhm'lovatkid
`(icrnumy
`Denmark .
`Spain
`
`l'mland
`l-runuc
`Gabon
`Unilcd Kingdom
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Democratic Peuplc't Republic
`of Korea
`Republic of Korea
`liuuhlcnalcin
`Sri lanka
`luwmhonrg
`Monaco
`
`Mongolia
`Mauritania
`Malawi
`Netherlanda
`Norway
`Poland
`Romania
`Ruaian Federation
`
`Sudan
`
`Sweden
`Senegal
`Soviet Union
`(Thad
`Toto
`United State: of America
`
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`W0 92/ 16206
`
`PCT/US92/01848
`
`THE USE OF 5-AMINOSALICYLIC ACID IN THE TREATMENT OF
`
`IRRITABLE BOWEL SYNDROME - DIARRHEAL PHASE 0R TYPE (IBS-D)
`
`5
`
`BAQKQRQQND QF [HE INIENIIQN
`
`The present
`
`invention relates
`
`to the
`
`novel method of
`
`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
`
`10
`
`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
`
`"S-ASA"),
`
`and
`
`pharmaceutically-acceptable
`
`excipients.
`
`Said
`
`topical delivery is most preferably accomplished by the oral
`
`15
`
`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 "135")
`
`is a poorly understood disorder for which there is presently no
`
`20
`
`adequate treatment.
`
`185 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
`
`25
`
`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 radiological or
`
`histological evidence of organic pathology, i.e.
`
`the presence of
`
`30
`
`an infectious agent or observable inflammation or other pathology
`
`in the intestinal
`
`tract.
`
`185 has been called functional
`
`bowel
`
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`
`PCT/US92/01848
`
`-2-
`
`disorder, mucomembraneous colitis,
`
`nervous diarrhea,
`
`colonic
`
`neurosis, colonic dyspepsia, colonic dysfunction, spastic colon,
`
`mucous
`
`colitis,
`
`irritable
`
`colon
`
`syndrome,
`
`unhappy
`
`colon,
`
`dissynergia of the colon,
`
`and disordered gastrocolonic reflex.
`
`5
`
`It is estimated that about 10% of the adult population suffers
`
`from 185 and that this disorder accounts for from about 40% to
`
`.
`
`_
`
`P
`
`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.
`
`10
`
`As
`
`stated hereinabove,
`
`those
`
`suffering from 185 may
`
`experience diarrhea only, alternating diarrhea and constipation,
`
`or constipation only; accordingly,
`
`there has been a great deal of
`
`effort to categorize 18S patients based upon these symptoms.
`
`Einar Krag,
`
`"Irritable Bowel Syndrome:
`
`Current Concepts
`
`See
`
`and
`
`15
`
`Future Trends,”
`
`cand. J. Gastroenterg), 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, Sgi., Vol. 25, No. 6, pp. 404-13,
`
`June 1980
`
`(hereinafter
`
`20
`
`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 135-0) and that 50% of IBS sufferers
`
`experience constipation only.
`
`0f the population which suffers
`
`from IBS—D, one-fifth experience only diarrhea (IBS-diarrheal
`
`25
`
`type),
`
`and
`
`the
`
`remaining
`
`four-fifths
`
`experience alternating
`
`diarrhea and constipation (IBS-diarrheal phase).
`
`The cause of 185 has been extremely difficult to determine,
`
`and there has been little success
`
`in differentiating possible
`
`causes with regard to symptomatic characterizations.
`
`It has been
`
`30
`
`reported that 183 stems from the ingestion of certain foodstuffs
`
`(often wheat gluten or lactose); other theories as to the cause
`
`of 185 have implicated disorders of gut. motility, while many
`gastroenterologists,
`however,
`have
`attributed
`IBS
`to
`psychological
`factors.
`See generally, V. Alun Jones, et al.,
`
`,
`’
`
`35
`
`“Food
`
`Intolerance:
`
`A Major Factor
`
`in the Pathogenesis of
`
`Irritable
`
`Bowel
`
`Syndrome",
`
`The
`
`Lancet, Vol. 2,
`
`No. 8308,
`
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`W0 92116206
`
`PCI‘/ US92/01848
`
`-3-
`
`pp. 1115-17, November 20, 1982 (hereinafter referred to as I'Jones
`
`et al."); Kumar et al.,
`
`”The
`
`Irritable Bowel
`
`Syndrome:
`
`A
`
`Paroxysmal Motor Disorder",
`
`Ing__L3n§§1, Vol. 2,
`
`No. 8462,
`
`pp. 973-77, November 1985 (hereinafter referred to as "Kumar et
`
`5
`
`al.'); Drossman et al.,
`
`"Psychosocial Factors in the Irritable
`
`Bowel Syndrome," figstxgggtgrglggy, Vol. 95, (3), pp. 701-8, Sept.
`
`1988;
`
`and Drossman et al.,
`
`"The
`
`Irritable Bowel Syndrome,‘
`
`gastroenterglggy, Vol. 73, p. 811-22, Oct. 1977.
`
`In addition to confusion as to the cause of 185-0,
`
`there is
`
`10
`
`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. Kuma: gt al., 92. git., and Cann et al.,
`
`15
`
`"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
`
`20
`
`are two of the most
`
`common Inflammatory Bowel Diseases (herein-
`
`referred to as
`
`"IBD").
`
`In
`
`fact, patients with
`
`IBS-D
`
`after
`
`present with
`
`symptoms which
`
`are markedly
`
`similar
`
`to those
`
`experienced with 180, particularly ulcerative colitis and Crohn’s
`
`disease
`
`and,
`
`therefore,
`
`the
`
`existence of
`
`180
`
`is generally
`
`25
`
`investigated and ruled out before the diagnosis of 185-0 is
`
`given.
`
`It has been reported that
`
`the administration of 5-ASA is
`
`effective in the treatment of ulcerative colitis and Crohn’s
`
`disease.
`
`See U.S. Patent 4,496,552 to Halskov,
`
`issued January
`
`30
`
`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
`
`18$, Crohn’s
`
`disease
`
`(regional
`
`ileitis),
`
`ulcerative
`
`colitis
`
`(proctitis,
`
`distal
`
`35
`
`proctocolitis),
`
`atrophic gastritis,
`
`stump proctitis,
`
`coeliac
`
`disease,
`
`regional
`
`ileitis,
`
`peptic
`
`ulceration,
`
`and
`
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`W0 92/16206
`
`PCT/US92/01848
`
`.
`
`e
`
`-4-
`
`gastrointestinal allergy respond to treatment by a pharmaceutical
`composition comprising a compound having sodium cromoglycate-like
`activity
`as
`the
`active
`ingredient,
`in
`combination with
`sulfasalazine
`or
`an
`ASA.
`See
`U.K.
`Patent
`Publication
`
`5
`
`GB 2,021,409 of Horsley, published December 5, 1979, assigned to
`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.
`
`'
`
`10
`
`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
`
`severe cases. Typically,
`
`the colon, as well as the rectum,
`
`in
`
`is
`
`involved;
`
`it 'is less common
`
`for
`
`the ileum (the most distal
`
`15
`
`The ulcer
`involved.
`to be
`intestine)
`the small
`portion of
`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
`
`20
`
`related to
`being
`characterized as
`is often
`granulomatosa,
`ulcerative colitis, since they are both inflammatory diseases of
`
`25
`
`30
`
`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
`
`the inflammatory reaction of
`considerably difficult. Generally,
`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.
`
`35
`
`557-564.
`
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`W0 92/162116
`
`PCT/US92/01848
`
`-5-
`
`180
`
`is distinguished from 188
`
`by
`
`the presence of
`
`the
`
`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
`
`5
`
`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
`
`180 with 185, see, e.g., Thompson, "Gastrointestinal Symptoms
`
`in
`
`10
`
`the Irritable Bowel Compared with Peptic Ulcer and Inflammatory
`
`Bowel Disease," gut, Vol. 25, No. 10. pp. 1089-92, Oct. 1984;
`
`Hhitehead et al., gn_§it,;
`
`Isgar et al.,
`
`"Symptoms of Irritable
`
`Bowel Syndrome in Ulcerative Colitis in Remission,“ £33, Vol. 24,
`
`pp. 190-2, 1983;
`
`and Ahnfelt-Ronne et al., ”Clinical Evidence
`
`15
`
`Supporting
`
`the
`
`Radical
`
`Scavenger Mechanism
`
`of
`
`S-ASA,”
`
`gastroentgrglggy, 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 188-0 and 180. As
`
`the outline of current research set
`
`20
`
`forth hereinbelow illustrates, there is considerable debate as to
`
`the role of prostaglandins in the etiology of both 188-0 and 180,
`
`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
`
`25
`
`entity than 180,
`
`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 185.
`
`See Wilson,
`
`30
`
`et al.,
`
`'Prostaglandins: Gastrointestinal Effects
`
`and Peptic
`
`Ulcer Disease",
`
`M
`
`l n.
`
`orth.
`
`, Vol.
`
`65,
`
`No.
`
`pp. 773-87,
`
`July
`
`1981,
`
`hereinafter
`
`referred
`
`to
`
`4,
`
`as
`
`"Eggstgglgngins".
`
`It was reported therein that the possible role
`
`of prostaglandins
`
`in
`
`specific
`
`and nonspecific
`
`inflammatory
`
`35
`
`disorders has been suggested by several studies indicating that
`
`the condition of patients with a variety of intestinal disorders
`
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`W0 92/16206
`
`PCT/US92/01848
`
`-5-
`
`radiation enteritis, ulcerative
`in addition to 18$,
`(including,
`improved when
`inhibitors of
`colitis,
`and
`food
`intolerance)
`prostaglandin synthesis,
`such as aspirin or
`indomethacin, were
`administered.
`See Prgstaglangins,
`pp. 781-2.
`Also
`reported
`
`5
`
`10
`
`linking
`information
`that
`fact
`the
`was
`however,
`therein,
`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
`prostaglandin
`levels
`on
`inflammation
`does
`not
`necessarily indicate a pathogenetic role for prostaglandins.“
`
`See Ergstaglandjns at 782.
`It was
`reported that
`
`indomethacin blockade
`
`appeared to
`
`IBS-D.
`implications with
`therapeutic
`important
`exhibit
`J. Rask-Madsen
`et al.,
`"Indomethacin-Responsive Diarrhea
`
`See
`in
`
`15
`
`20
`
`25
`
`Irritable Bowel Syndrome“, gut, Vol. 19, p. 448, 1978.
`
`It was
`
`there were
`92. git., p.1117 that
`reported by Jgngs et al.,
`significant elevations of PGE2
`levels in their patients after
`food challenge and a significant relationship between PGEz 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
`
`See
`exacerbations of colitis.
`cause
`“NSAIDs")
`(hereinafter
`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 135 with prostaglandin inhibitors, see, e.g. Lessof
`
`et al., "Prostaglandins in the Pathogenesis of Food Intolerance",
`
`35
`
`Annals gf 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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`
`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
`
`5
`
`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
`
`10
`
`ulcerative colitis.
`
`In fact, extremely deleterious effects have
`
`been reported with the use of flurbiprofen to treat ulcerative
`
`colitis.
`
`1d 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.
`
`15
`
`Such results with potent prostaglandin inhibitors have led
`
`to
`
`the
`
`alternative
`
`view
`
`that
`
`prostaglandins
`
`may
`
`be
`
`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.
`
`1d.
`
`Hawkey et al. also proposed a third possible theory as to
`
`the mode of
`
`action of
`
`5-ASA in ulcerative colitis.
`
`Weak
`
`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
`
`30
`
`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
`
`35
`
`1g.
`in human colonic mucosa.
`have been shown to exist
`further discussions of
`the possible role of prostaglandins
`
`For
`in
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`PCT/US92/01848
`
`-8-
`
`5
`
`"Enhanced
`Inflammatory Bowel Disease, see e.g. Ligumsky et al.,
`Thromboxane A2
`and Prostacyclin Production by Cultured Rectal
`Mucosa in Ulcerative Colitis and Its Inhibition by Steroids and
`Sulfasalazine,"
`gastroentgrglggy, Vol. 8, No. 3,
`pp.
`144-9,
`September 1981; Pacheco,
`“Inflammatory Bowel Disease:
`The In
`21139 Effect of Sulphasalazine and Other Agents on Prostaglandin
`Synthesis by Human Rectal Mucosa,"
`rag, 9. Med. Biol. Be§., Vol.
`20, No. 3, pp. 221—230, 1987; Campieri et al., "Salicylate Other
`Than 5-Amino Salicylic Acid Ineffective in Ulcerative Colitis,"
`
`10
`
`1978;
`p. 993, Nov. 4,
`Ihe Lancet,
`(letter),
`llArachidonic Acid Metabolites
`and Their Role
`
`and Donowitz,
`in Inflammatory
`
`Bowel Disease:
`
`An Update Requiring Addition of a Pathway,"
`
`Gastrgenterglogy, Vol. 88, No. 2, pp. 580-7, 1985.
`The outline of current research set forth hereinabove serves
`
`15
`
`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 S-ASA inhibits or enhances prostaglandin synthesis and by
`
`20
`
`the fact that there is considerable debate as to whether prosta-
`
`aggravate or alleviate both, or either, ulcerative
`glandins
`colitis and IBS-D.
`Furthermore,
`the relevance of the effect of
`
`S-ASA in inhibiting production of leukotrienes and hydroxyeico-
`
`satetraenoic acids to its therapeutic effects in 185-0 and 180 is
`
`25
`
`yet to be determined.
`In addition,
`as
`
`stated hereinabove,
`
`it
`
`is
`
`a
`
`fact
`
`that
`
`inflammatory
`an
`of
`by-product
`normal
`a
`are
`prostaglandins
`that which would accompany both the topical
`response [such as
`(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 1805,
`as
`compared to those of
`
`30
`
`35
`
`-
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`
`-9-
`
`IBS-D, are markedly distinct and that
`
`the etiology of both 180
`
`and
`
`185-0
`
`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
`
`5
`
`185-0.
`
`Probably largely due to the fact that the etiology of 185-0
`
`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,
`
`l-hyoscyamine,
`
`propantheline
`
`bromide,
`
`and
`
`dicyclomine
`
`hydrochloride);
`
`anticholinergic/barbiturate
`
`combinations
`
`(tryciclamol
`
`and/or
`
`phenobarbital; dicyclomine and/or phenobarbital); antidepressants
`
`15
`
`(desipramine,
`
`trimipramine, amitriptyline); bulking agents (wheat
`
`bran, psyllium (ispaghula)); dopamine antagonists (domperidone);
`
`carminatives
`
`(peppermint oil); opioids
`
`(loperamide);
`
`tranquil-
`
`izers or tranquilizer combinations
`
`(mepiprazol, benzodiazepine,
`
`fluphenazine
`
`and
`
`trimipramine,
`
`phenaglycodol, meprobamate,
`
`20
`
`nortriptylene,
`
`lorazepam and/or hyoscine and/or
`
`ispaghula)
`
`and
`
`miscellaneous actives
`
`such
`
`as phenytoin
`
`(an anticonvulsant),
`
`timolol
`
`(a B-adrenergic
`
`receptor-blocker),
`
`and diltiazem (a
`
`calcium channel blocker).
`
`Said conventional
`
`therapies have been
`
`usually unsatisfactory and are often accompanied by serious and
`
`25
`
`undesirable side effects; accordingly, many symptoms of IBS-D go
`
`untreated.
`
`'§§g, g,g., ang5,
`
`g1 al., 92. 911.,
`
`pp. 1115-7;
`
`Klein,
`
`"Controlled Treatment Trials
`
`in
`
`the
`
`Irritable Bowel
`
`Syndrome:
`
`A Critique", gastrggnterglggy, Vol. 95, pp. 232-41,
`
`1988; Haller et al., "Prognosis in Irritable Bowel Syndrome", Ihg
`
`30
`
`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
`
`35
`
`of S-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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`-10-
`
`active ingredient has been shown to be effective along, 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 S-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 S-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 S-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.
`
`5
`
`10
`
`15
`
`20
`
`UMMA Y OF THE INVENT
`
`N
`
`invention embodies a novel method of treatment
`The present
`for a human or other mammal afflicted with IBS-D, which comprises
`
`25
`
`tract of said human or
`the topical delivery to the intestinal
`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 Inammal
`and is most preferably accomplished by the oral
`
`administration to said human or other mammal of a delayed-release
`
`5-ASA
`said
`of
`essentially
`consisting
`composition
`ingredient and pharmaceutically—acceptable excipients.
`
`active
`
`30
`
`35
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`W0 92/ 16206
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`PCT/US92/01848
`
`-11-
`
`WI!
`
`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
`
`5
`
`other mammal, preferably to the large intestine, of a safe and
`
`effective amount of
`
`a pharmaceutical
`
`composition consisting
`
`essentially of a S-ASA active ingredient and pharmaceutically-
`
`acceptable excipients.
`
`Said topical delivery is most preferably
`
`achieved via the oral‘ administration to said human or other
`
`10
`
`mammal of a delayed-release composition consisting essentially of
`
`the
`
`S-ASA active
`
`ingredient
`
`and
`
`pharmaceutically-acceptable
`
`excipients.
`
`A.
`
`The §-ASA Aetive Ingredient
`
`The present
`
`invention is directed to a method of treatment
`
`15
`
`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
`
`S-ASA
`
`active
`
`ingredient
`
`and
`
`pharmaceutically-acceptable excipients.
`
`20
`
`The term "5-ASA active ingredient”, as used herein, denotes
`
`5-aminosalicylic acid, hereinafter referred to as
`
`"S-ASA" and,
`
`unless
`
`otherwise
`
`specified,
`
`encompasses
`
`the
`
`pure
`
`compound
`
`5-aminosalicylic acid, as well as the pharmaceutically-acceptable
`
`salts or esters thereof, or any mixture thereof.
`
`S-Aminosali-
`
`25
`
`cylic acid (S-ASA)
`
`is often referred to as
`
`"mesalamine"
`
`and
`
`'mesalazine"
`
`and
`
`is more properly referred to as S-amino-Z-
`
`hydroxybenzoic
`
`acid
`
`or
`
`5—amino-Z-hydroxybenzene-1-carboxylic
`
`acid.
`
`Any pharmaceutically-acceptable, non-toxic salt of 5-ASA may
`
`30
`
`be used as the 5-ASA active ingredient
`
`in the composition of the
`
`present
`
`invention.
`
`The salts of S-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
`
`35
`
`acid group may be used,
`
`including, but not
`
`limited to, alkali
`
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`
`-12-
`
`metal salts (K, Na) and alkaline earth metal salts (Ca, Mg),
`
`the
`
`Ca- and Na- salts being preferred.
`
`Any pharmaceutically-acceptable, non-toxic ester of S-ASA
`
`may be used as the 5-ASA active ingredient in the pharmaceutical
`
`5
`
`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,
`reference.
`A
`number
`
`1980,
`of
`
`hereby
`esters
`
`herein
`incorporated
`of
`ortho-, meta-,
`
`by
`and
`
`10
`
`para-salicylic acid are disclosed.
`
`Said esters are effective as
`
`ultraviolet ray screening compounds,
`
`thereby rendering themselves
`
`useful
`
`in preventing solar burning.
`
`Other esters of 5-ASA which are suitable for use as
`
`the
`
`15
`
`active ingredient
`
`in the invention disclosed herein are straight
`
`chain or branched chain Cl-Clg 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-C13 alkenyl
`
`20
`
`esters,
`
`including, but not
`
`limited to, vinyl, alkyl, undecenyl,
`
`and
`
`linolenyl; C3-C3
`
`cycloalkyl
`
`esters,
`
`including,
`
`but not
`
`limited to,
`
`cyclopropyl,
`
`cyclobutyl,
`
`cyclopentyl,
`
`cyclohexyl,
`
`cycloheptyl,
`
`and cyclooctyl;
`
`aryl esters,
`
`including, but not
`
`limited to,
`
`phenyl,
`
`toluyl,
`
`xylyl,
`
`and naphthyl;
`
`alicyclic
`
`25
`
`esters,
`esters,
`
`and aralkyl
`limited to, menthyl;
`including, but not
`including, but not limited to, benzyl, and phenethyl.
`
`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
`
`30
`
`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.
`
`35
`
`In addition to the 5-ASA active ingredients,
`
`the pharma-
`
`ceutical composition and methods of
`
`the present
`
`invention may
`
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`
`.13-
`
`also contain other non-S-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
`
`5
`
`addition to 5-ASA active ingredients, examples of other non-S-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;
`
`10
`
`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;
`
`15
`
`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
`
`limited
`
`to,
`
`20
`
`erythromycin,
`
`chloroquine,
`
`iodochlorhydroxyqu