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(11) EP 2 361 620 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 31.08.2011 Bulletin 2011/35 A61K 31/166 (2006.01) A61K 31/606 (2006.01) A61P 1/00 (2006.01) A61P 1/06 (2006.01) (2006.01) (2006.01) (21) Application number: 11000447.0 A61P 1/12 A61P 1/14

(22) Date of filing: 04.02.2005

(84) Designated Contracting States: (74) Representative: Keen, Celia Mary AT BE BG CH CY CZ DE DK EE ES FI FR GB GR J.A. Kemp & Co. HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR 14 South Square Gray’s Inn (30) Priority: 06.02.2004 AU 2004900563 London WC1R 5JJ (GB)

(62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: •This application was filed on 20-01-2011 as a 05700172.9 / 1 720 536 divisional application to the application mentioned under INID code 62. (71) Applicant: PHARMATEL (R&D) PTY LIMITED •Claims filed after the date of filing of the application/ as Trustee for the PHARMATEL (R & D) TRUST date of receipt of the divisional application (Rule 68 Hornsby, NSW 2077 (AU) (4) EPC).

(72) Inventor: Shortis, Nicolas Peter Five Dock New South Wales 2046 (AU)

(54) Use of in diarrhoea-predominant

(57) A method for the treatment ofprophylaxis of non- thereof together with a suitable carrier. Use of bal- inflammatory bowel diseases, diarrhoea- predominant ir- salazide, a 4-ASA or 5-ASA compound modified to in- ritable bowel syndrome or other non-specific bowel dis- clude a 4-ABA side chain, or a salt or derivative thereof, order is disclosed comprising administering to a patient for the manufacture of a medicament for the treatment in need of such treatment or prophylaxis an effective of prophylaxis of non-inflammatory bowel disease, diar- amount of , or a 4-ASA or 5-ASA compound rhoea-predominant Irritable Bowel Syndrome or other modified to include a 4-ABA side chain, or a salt or a non-specific bowel disorder is also disclosed. derivative thereof, or a composition comprising bal- salazide the modified compound, or a salt or a derivative EP 2 361 620 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 361 620 A1 2

Description mation is absent and can only be detected by taking a biopsy and finding histological changes of inflammation. Technical Field In this case the pathologist terms the IBD as "microscopic colitis". [0001] This invention relates to the use of balsalazide 5 [0006] Where there are no visible colonoscopic or his- for treatment of Non-Inflammatory Bowel Disease for ex- tological abnormalities in the colon and when the stool ample diverticulosis/diverticulitis, diarrhoea-predomi- tests are negative for any known infection, and yet the nant Irritable Bowel Syndrome (IBS), or other non-spe- patient complains of symptoms referrable to the colon, cific bowel disorders such as Irritable Bowel Syndrome such as urgency, diarrhoea, flatulence, cramping  the (IBS) at times alternating with constipation. 10 diagnosis of Irritable Bowel Syndrome can be made. Be- tween 5% and 25% of the western population in different Background of the Invention age groups may suffer from this disorder which has also been termed spastic colon, unstable colonic neurosis, [0002] Diarrhoea-predominant IBS is a condition spastic colitis or mucous colitis. In a classic case there known to arise from non-obvious causes. In particular, 15 is a triad of symptoms including low abdominal pain re- Irritable Bowel Syndrome which is defined as being a lieved by defecation, alternating constipation/diarrhoea non-inflammatory bowel disease is known not to be and the passage of small calibre stools. In some patients caused by any detectable infection by a pathogenic or- there may be accompanying watery diarrhoea with or ganism or organisms. without pain. Distension, flatulence, wind and at times [0003] Irritable Bowel Syndrome is therefore not a form 20 nausea and headaches may also be accompanying sys- of Inflammatory Bowel Disease. Inflammatory Bowel Dis- temic symptoms. At times diarrhoea alternates with con- eases are characterised by inflammation on histology stipation. and inflammation on colonoscopy whereas Irritable Bow- [0007] The pathogenesis of IBS is unclear. Emotional el Syndrome shows no evidence of inflammation on disturbances, fibre deficiency, purgative abuse and food colonoscopy and the histology shows no increase in in- 25 intolerancehave been some of the implicated aetiological flammatory cells. Irritable Bowel Syndrome is therefore agents but none have been proven nor well demonstrat- referred to as a "non specific" bowel disorder because ed. Evidence is therefore lacking for an infective cause there is no specific diagnostic criterion such as histology or auto-immunity. Conventional treatments for IBS have or a blood test that can diagnose it. Irritable Bowel Syn- been unsatisfactory as exemplified by the large number drome is only diagnosed when one excludes the pres- 30 of therapies that have from time to time been recom- ence of other "specific" diseases or disorders such as mended or trialed. These have included psychotherapy, Salmonella, Gastroenteritis, Campylobacter gastroen- dietary regimens, anti-spasm agents, anti-cholinergics, teritis, Clostridium difficile infection, Giardiasis, Crohn’s anti-depressants, bulking agents, various receptor an- disease or . Irritable Bowel Syndrome tagonists, carminatives, opiates, and tranquillisers - all can be distinguished from infective and inflammatory35 without substantial success. Indeed there is no evidence bowel diseases such as colitis or Crohn’s disease on that cure is possible. Yet IBS is one of the most common culture or histological grounds and endoscopic appear- of all the gastrointestinal illnesses and though not life- ances. threatening, causes great distress especially to those se- [0004] Irritable Bowel Syndrome is therefore a collec- verely affected, and may bring a feeling of frustration and tion of symptoms such as bloating, diarrhoea, cramping, 40 helplessness, being generally lifelong. In particular, di- flatulence, or constipation where there is no specific di- arrhoea-predominant IBS can cause incontinence in agnostic test that turns it into a specific bowel disorder. some patients and, for example, the inability of being Irritable Bowel Syndrome may therefore be diagnosed sure that one can reach ones employment causing some by exclusion of other specific bowel disorders. Another to drive from rest room to rest room on their way to work. example of a non specific gastrointestinal disorder is non 45 In some patients urgency is so severe that they can only ulcer dyspepsia. hold their motions for a few seconds. [0005] The large bowel in man and to a lesser extent [0008] One treatment that has been proposed for the the small bowel, contain large concentrations of various treatment of IBS and for other bowel diseases is the use enteric bacteria. Generally, patients will have no pain, of certain classes of aminosalicylic acids. For example cramping, diarrhoea or constipation if the bacterial con- 50 Borody in US 5,519,014 describes the use of 5- aminosal- tents are not infected with pathogenic strains which may icylic acids (5- ASA compounds) for the treatment of IBS. colonise the bowel and remain there for prolonged peri- Similarly, Lin et al (US Patent 6,326,364) teaches that 5- ods of time. Acute infections and some chronic infections ASA compounds can inhibit clostridia (a pathogen). of the bowel flora however can cause inflammatory [0009] Whilst priorart methods go some way to treating changes in the lining. When inflammation is visible this 55 IBS, there is a need for other treatment regimes and in condition is called Inflammatory Bowel Disease (IBD), particular treatment regimes for non-specific bowel dis- which can be transient or long term  for example ’ul- orders such as diarrhoea-predominant IBS which may cerative colitis’. In some forms of IBD the visible inflam- not be effectively treated by prior art methods.

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Object of the Invention eases, diarrhoea-predominant Irritable Bowel Syndrome or other non-specific bowel disorder. [0010] It is an object of the present invention, at least in preferred embodiments to overcome or substantially Definitions ameliorate at least one of the above disadvantages or at 5 least provide a suitable alternative. [0018] The following definitions are intended as gen- eral definitions and should in no way limit the scope of Summary of the Invention the present invention to those terms alone, but are put forth for a better understanding of the following descrip- [0011] According to a first aspect, there is provided a 10 tion. method for the treatment or prophylaxis of non-inflam- [0019] Unless the context requires otherwise or spe- matory bowel diseases, diarrhoea-predominant irritable cifically stated to the contrary, integers, steps, or ele- bowel syndrome or other non-specific bowel disorder ments of the invention recited herein as singular integers, comprising administering to a patient in need of such steps or elements clearly encompass both singular and treatment or prophylaxis an effective amount of bal-15 plural forms of the recited integers, steps or elements. salazide or a salt or a derivative thereof or a composition [0020] Throughout this specification, unless the con- comprising balsalazide or a salt or a derivative thereof text requires otherwise, the word "comprise", or varia- together with a suitable carrier. tions such as "comprises" or "comprising", will be under- [0012] In one embodiment, in a sub-group of patients stood to imply the inclusion of a stated step or element the method alleviates symptoms of alternating diarrhoea 20 or integer or group of steps or elements or integers, but and constipation type Irritable Bowel Syndrome or con- not the exclusion of any other step or element or integer stipation-predominant Irritable Bowel Syndrome. or group of elements or integers. Thus, in the context of [0013] According to a second aspect, there is provided this specification, the term "comprising" means "including a method for the treatment or prophylaxis of non-inflam- principally, but not necessarily solely". matory bowel diseases, diarrhoea-predominant irritable 25 [0021] Those skilled in the art will appreciate that the bowel syndrome or other non-specific bowel disorder invention described herein is susceptible to variations comprising administering to a patient in need of such and modifications other than those specifically de- treatment or prophylaxis an effective amount of a 4-ASA scribed. It is to be understood that the invention includes or 5-ASA compound modified to include a 4-ABA side all such variations and modifications. The invention also chain, or a salt or a derivative thereof or a composition 30 includes all of the steps, features, compositions and com- comprising the modified compound or a salt or a deriva- pounds referred to or indicated in this specification, indi- tive thereof together with a suitable carrier. vidually or collectively, and any and all combinations or [0014] According to a third aspect, there is provided any two or more of said steps or features. use of balsalazide or a salt or derivative thereof for the [0022] All the references cited in this application are manufacture of a medicament for the treatment or proph- 35 specifically incorporated by reference are incorporated ylaxis of non-inflammatory bowel diseases, diarrhoea- herein in their entirety. However, inclusion of a specific predominant Irritable Bowel Syndrome or other non- spe- reference herein is not intended to indicate that the ref- cific bowel disorder. erence is generally known in Australia or elsewhere. [0015] According to a fourth aspect, there is provided use of a 4-ASA or 5-ASA compound modified to include 40 Detailed Description of Preferred Embodiments a 4-ABA side chain, or a salt or derivative thereof for the manufacture of a medicament for the treatment or proph- [0023] There is provided a method for the treatment or ylaxis of non-inflammatory bowel diseases, diarrhoea- prophylaxis of non-inflammatory bowel diseases includ- predominant Irritable Bowel Syndrome or other non- spe- ing diverticulosis/diverticulitis, diarrhoea-predominant ir- cific bowel disorder. 45 ritable bowel syndrome or other non-specific bowel dis- [0016] According to a fifth aspect, there is provided order including constipation, bloating, diarrhoea-consti- balsalazide or a salt or a derivative thereof or a compo- pation IBS or constipation IBS. The method comprises sition comprising balsalazide or a salt or a derivative administering to a patient in need of such treatment or thereof together with a suitable carrier when used for the prophylaxis an effective amount of balsalazide or a salt treatment or prophylaxis of non-inflammatory bowel dis- 50 or a derivative thereof or a composition comprising bal- eases, diarrhoea-predominant Irritable Bowel Syndrome salazide or a salt or a derivative thereof together with a or other non-specific bowel disorder. suitable carrier. The patient may be a mammal including [0017] According to a sixth aspect, there is provided a a human. 4-ASA or 5-ASA compound modified to include a 4- ABA [0024] Balsalazide corresponds to the formula side chain, or a salt or a derivative thereof or a compo- 55 sition comprising balsalazide or a salt or a derivative thereof together with a suitable carrier when used for the treatment or prophylaxis of non-inflammatory bowel dis-

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pounds may also be used to treat other non- specific dis- orders such as non-ulcer dyspepsia. [0027] Hence, the invention provides a methodof treat- ment or prophylaxis ofnon-inflammatory bowel diseases, 5 diarrhoea-predominant Irritable Bowel Syndrome and other non-specific bowel disorders and their associated symptoms comprising a step of dosing a patient suffering therefrom with balsalazide or a derivative or salt thereof. Other non-specific bowel disorders includes any disorder and is 5[(1E)-[4-[[(2-carboxyethyl)amino]carbonyl]phe- 10 diagnosed by exclusion of other specific bowel disorders nyl]azo]-2-hydroxybenzoic acid. such as non-ulcer dyspepsia, alternating diarrhoea and [0025] The present invention arose from the discovery constipation type Irritable Bowel Syndrome, Constipa- by the inventors that treatment of patients with non in- tion-predominant Irritable Bowel Syndrome, constipation fectious bowel disorders with 5ASA compounds such as or bloating. Non-inflammatory bowel diseases includes and olsalazine or with 4ASA compounds15 diverticulosis or diverticulitis. such as 4-aminosalicylic acid, whether alone or in com- [0028] In one embodiment, the invention provides a bination with 5ASA compounds, whilst capable of sup- method for the treatment or prophylaxis of one or more pressing symptoms in most patients with diarrhoea-pre- of Non-inflammatory Bowel Disease, diverticulosis, di- dominant IBS symptoms may be even more effective verticulitis, diarrhoea-predominant Irritable Bowel Syn- when balsalazide is administered alone or in combina- 20 drome, Irritable Bowel Syndrome, bloating, diarrhoea, tion. From clinical experience, it has been found by the cramping, pain, low abdominal pain, distension, wind, inventor that balsalazide is much more powerful at sup- flatulence, gas production, fluid secretion, mucus pro- pressing the symptoms of diarrhoea-predominant Irrita- duction, constipation, urgency, non ulcer dyspepsia, ble Bowel Syndrome than the conventional 4ASA and spastic colon, unstable colonic neurosis, spastic colitis, 5ASA compounds. Balsalazide is better than mesalazine 25 mucous colitis, alternating constipation/ diarrhoea, incon- (5-ASA) in controlling and may inhibit even more power- tinence, alternating diarrhoea and constipation type IBS fully the symptoms of diarrhoea-predominant IBS and or constipation IBS. associated conditions enumerated below. This is unex- [0029] There is also provided balsalazide or a deriva- pected. It was not expected that balsalazide would be tive or salt thereof used for treatment or prophylaxis of capable of treating diarrhoea-predominant IBS as it is a 30 non-specific bowel disorders, particularly diarrhoea- pre- very different molecule to the conventional 4ASA and dominant IBS. 5ASA compounds. Balsalazide (5-[(1E)-[4-[[(2-carbox- [0030] There is also provided use of balsalazide or a yethyl) amino] carbonyl] phenyl] azo- 2- hydroxybenzoic derivative or salt thereof in the manufacture of medica- acid and its sodium salt, molecular weight 437.32 (for- ment with said balsalazide, derivative or salt thereof as 35 mula C17H13N3O6Na2.2H2O), is composed of a 5-amino the base product with or without accompanying support- salicylic acid joined to an unusually long chain, 4-amino ive or combination active and inactive agents. The sup- benzoyl-β-alanine (4-ABA). It is therefore a much larger portive or combination active and inactive agents may molecule and does not belong to the same molecular be administered together with balsalazide. Such admin- shape as mesalazine or olsalazine. The inventors noted istration may or may not be coincidental administration. that balsalazide can substantially inhibit the symptoms 40 For example, the active agents may be administered as of diarrhoea in patients with diarrhoea- predominant IBS. a single combined composition or may be administered It is thought that this is due to a large extent to the prop- as separate entities in such a manner as to have over- erties of the unique ’inactive carrier’ side chain (4- ABA). lapping therapeutic profiles. When administered as sep- It is noted that the side chain together with the ASA5- arate entities, the active agents may be administered in potentiates inhibition of gas production, cramping, fluid 45 any order as determined by the treating physician. secretion, and mucus production. It appears the large [0031] The supportive or combination agents may con- side chain apart from the salicylate component is effec- tain, amongst others, separate 5-ASA or 4-ASA com- tive in treating diarrhoea. In addition, in a subgroup of pounds, such as mesalazine (5-amino salicyclic acid), patients the constipation component of IBS may respond olsalazine, , ipsalazide, benzalazine, para- to the same treatment. 50 amino salicylic acid (4- amino salicylic acid) and pharma- [0026] Although it is reported that balsalazide is an an- ceutical acceptable salts thereof. A combination of bal- alogue of 5-aminosalicylic acid, while not wishing to be salazide and olsalazine, for example together in a single bound to any theory, in the present method it would ap- capsule or separately administered, may be used to treat pear that it is not the 5-ASA group that is functioning in both diarrhoea and constipation predominant IBS since diarrhoea control but the large side chain 4- ABA appears 55 olsalazine does secrete water into the bowel. Mesalazine to be the active component. Other 5- ASA or 4- ASA com- together with balsalazide may also be combined for di- pounds modified to include the 4-ABA side chain may arrhoea predominant IBS. Such a combination is syner- also be effective in the inventive methods. The com- gistic with amplification of the combined individual activ-

4 7 EP 2 361 620 A1 8 ities. In this regard it appears that the side chain of bal- tablet or capsule, the balsalazide may be combined in salazide may have antimicrobial activity. When com- powdered or granulated form, for example by compres- bined with mesalazine, which has specific activity against sion into a tablet or as a filling for a capsule. Alternatively, Clostridium difficile in patients with IBS/diarrhoea who the balsalazide may be provided in the form of a tablet/ have mixed infections, balsalazide and mesalazine pro- 5 capsule containing the balsalazide in a microencapsu- vide a synergistic combination in the control of diarrhoea. lated form. [0032] Other supportive or combination ingredients in- [0036] Liquid forms for oral administration may con- clude anti-cholinergics, probiotics (eg., lactobacilli, bifo- tain, in addition to the above agents, a liquid carrier. Suit- dobacteria, clostridia such as Clostridium butyricum, able liquid carriers include water, oils such as olive oil, bacteroides, E coli and others), acceptable 10 peanut oil, sesame oil, sunflower oil, safflower oil, arachis (eg., rifamycins such as rifabutin, rifampicin, refalazil, ri- oil, coconut oil, liquid paraffin, ethylene glycol, propylene faximin and others; , , tetracy- glycol, polyethylene glycol, ethanol, propanol, isopropa- clines), anti-spasm (e.g. dicyclomine), as nol, glycerol, fatty alcohols, triglycerides or mixtures well as various excipients. thereof. [0033] The medicament/composition for use in the in- 15 [0037] Suspensions for oral administration may further vention may be prepared by means known in the art for include dispersing agents and/or suspending agents. the preparation of pharmaceutical compositions includ- Suitable suspending agents include sodium car- ing blending, grinding, homogenising, suspending, dis- boxymethylcellulose, methylcellulose, hydroxypropyl- solving, emulsifying, dispersing and, where appropriate, methyl-cellulose, poly-vinyl-pyrrolidone, sodium alginate mixing of the balsalazide and where present other amino- 20 or cetyl alcohol. Suitable dispersing agents include leci- salicylic acid derivative(s), optionally together with one thin, polyoxyethylene esters of fatty acids such as stearic or more selected excipients, diluents, carriers and adju- acid, polyoxyethylene sorbitol mono- or di- oleate, -stea- vants and optionally together with one or more supportive rate or - laurate, polyoxyethylene sorbitan mono- or di- combination ingredients. oleate, -stearate or -laurate and the like. [0034] The medicament/composition of the invention 25 [0038] Emulsions for oral administration may further may be in the form of a tablet, lozenge, pill, troche, cap- include one or more emulsifying agents. Suitable emul- sule, soft-gel capsule, sachet or other vehicle, elixir, pow- sifying agents include dispersing agents as exemplified der, including lyophilised powder, solution, granule, sus- above or natural gums such as gum acacia or gum tra- pension, emulsion, syrup or tincture including any form gacanth. suitable for preparation as a rectal enema. Slow- release, 30 [0039] Typically the disodium salt of balsalazide will or delayed-release forms may also be prepared, for ex- be used. However any other salt or derivative or prodrug ample in the form of coated particles, multilayer tablets can be used. Accordingly where reference herein is made or microgranules. The composition may also be present- to balsalazide, the salt, prodrug or derivative thereof is ed in a compliance-enhancing blister pack. likewise referenced. [0035] Solid forms for oral administration may contain 35 [0040] The active ingredient may be incorporated with pharmaceutically acceptable binders, sweeteners, disin- the pharmaceutically acceptable excipient/s in any suit- tegrating agents, diluents, flavourings, coating agents, able form, including but not limited to tablets, lozenges, preservatives, lubricants and/or time delay agents. Suit- pills, troche, capsules, soft-gel capsules or as powder in able binders include gum acacia, gelatin, corn starch, sachets. It may also be presented as granulated medi- gum tragacanth, sodium alginate, carboxymethylcellu- 40 cation in larger volumes in sachets. The capsules, tablets lose or polyethylene glycol. Suitable sweeteners include or sachets may be taken one or more times per day in sucrose, lactose, glucose, aspartame or saccharine. balsalazide doses ranging from 100mg to 30grams per Suitable disintegrating agents include corn starch, meth- day, for example 100mg, 200mg, 300mg, 400mg, ylcellulose, , xanthan gum, betonite, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 2g, alginic acid or agar. Suitable diluents include lactose, 45 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 12g, 13g, 14g, 15g, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium 16g, 17g, 18g, 19g, 20g, 21g, 22g, 23g, 24g, 25g, 26g, carbonate, calcium silicate or dicalcium phosphate. Suit- 27g, 28g, 29g or 30g per day or any selected amounts able flavouring agents include peppermint oil, oil of win- within this range. Agents may be enteric coated, and may tergreen, cherry, orange or raspberry flavouring. Suitable take the form of slow-release format to reach both the coating agents include polymers or copolymers of acrylic 50 upper and lower bowel. In one embodiment, the bal- acid and/or methacrylic acid and/or their esters, waxes, salazide is presented in a form which facilitates its release fatty alcohols, zein, shellac or gluten. Suitable preserv- in the distal small bowel. For example, in a composition atives include sodium benzoate, vitamin E, alpha-toco- of the invention, the balsalazide may be provided with an pherol, ascorbic acid, methyl paraben, propyl paraben or enteric coating or provided in an enteric coated release sodium bisulphite. Suitable lubricants include magnesi- 55 capsule, or enteric coated microencapsulated particles um stearate, stearic acid, sodium oleate, sodium chloride can be carried within a capsule of a distally-releasing or talc. Suitable time delay agents include glyceryl mon- amino-salicylic acid, for example olsalazine. Suitable ostearate or glyceryl distearate. For administration as a materials for enteric coating are known in the art and

5 9 EP 2 361 620 A1 10 include various synthetic resins bearing carboxyl groups, EXAMPLE 1. phenyl salicylate, and shellac. Examples of such enteric coating materials are polymethacrylic acid and meth- [0045] A 34 year old female presented with a 7 year acrylic acid copolymers such as methacrylic acid- acrylic history of worsening diarrhoea (watery 6-12/day), urgen- acid ester copolymers; modified cellulose esters such as 5 cy, cramping lower abdominal pain and at times faecal hydroxypropyl cellulose phthalate, hydroxypropyl meth- incontinence. There was no clear preceding illness nor ylcellulose phthalate; ethyl cellulose phthalate, methyl usage. She underwent numerous investiga- cellulose phthalate and mixtures thereof, cellulose ace- tions, beginning with general practitioners ordering stool tate phthalate, hydroxypropyl methylcellulose succinate, cultures, blood tests, ultrasound and CT scan examina- ethyl cellulose succinate, methyl cellulose succinate and 10 tions. With the passage of time she noticed that some mixtures thereof, cellulose acetate trimellitate, cellulose foods caused worsening of symptoms, and was told by ether phthalates; and polyvinyl acetate phthalate, succi- a naturopath that she suffered from a ’food allergy’. The nate or trimellitate. Inone embodiment the enteric coating patient restricted her diet and this gave her some benefit is Opadry OY-P 22920, available from Colorcon, 415 in reducing the symptoms but resulted in progressive Moyer Blvd, West Point, Pa. 19486, United States of15 weight loss. She consulted a gastroenterologist and un- America. Enteric film-forming compositions are de- derwent endoscopic small bowel biopsy - where coeliac scribed, for example, in U.S. Pat. Nos. 4,556,552 and disease was excluded histologically  and colonoscopy 4,704,295, the disclosures of which are incorporated with biopsy and further stool cultures. All tests being non- herein by reference. diagnostic, she was told she had severe, diarrhoea- pre- [0041] Generally for long term therapy dosage may 20 dominant IBS. She continued on the restricted diet, and typically commence at a lower level, such as daily and was referred for counselling and hypnotherapy. Over the build up to the desired full amount over several weeks, next 6-12 months she progressively lost weight with only such as twice or three times daily if required. The inven- modest control of her symptoms by the diet. Within 2 tion also extends in one embodiment to multiple packag- weeks of commencing increasing doses of balsalazide es of individual dosages to be taken in sequence to pro- 25 from 1.5 gram to 3 grams per day, the stools progres- vide such a gradual build up. The balsalazide may there- sively formed up, with frequency reducing to 1-2 formed fore be taken once, twice, three times a day or more stools per day. Pain was completely abolished, urgency frequently. In one embodiment, balsalazide is adminis- disappaeared and she broadened her diet. By 6 weeks tered twice daily. Administration may be over a period of of treatment she regained 7 kg in weight. She continues 1 to 60 days or more, including indefinitely for the lifetime 30 to be virtually completely symptom-free on balsalazide of the patient. For example the balsalazide may be ad- at 26 weeks. ministered over 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months or more. After relief EXAMPLE 2 of symptoms is achieved, administration of balsalazide may be ceased, tapered, or continued for an indefinite 35 [0046] A 67 year old female complained of greater than period, for example including reduction to lower mainte- 20 years of diarrhoea with intervening constipation, ab- nance dosages. dominal bloating, pains, flatulence, and nausea with acid [0042] Any suitable dosage and method of administra- reflux. She had undergone several complete medical in- tion may be utilized, as determined by the treating phy- vestigations including stool tests, blood tests, X-ray im- sician. Typically this may be orally or as a rectal enema. 40 agingand colonoscopic examinations, with negative find- In one embodiment, the medicament/composition may ings apart from the presence of diverticulosis. Diagnosed be administered orally at a dose generally of about 3 as chronic IBS she tried increasing fibre intake, control- grams balsalazide per day, this dose being the ideal ling stress, and changing her diet, all to no avail. On com- dose. In another embodiment for clinical use, a bal- mencing balsalazide 1.5g/day and pushing the dose up- salazide dose of between about 1 gram and 4 grams may 45 wards to 4.5g/d her diarrhoea, pains, flatulence and nau- be used by patients either as a twice daily or three times sea abated. At the higher dose the constipation also dis- daily dosage. appeared. The improvements remain sustained at 26 [0043] With the foregoing it will be appreciated that a weeks. new use has been discovered for balsalazide where pre- viously no such effect has been described, and that ac- 50 EXAMPLE 3 tions of balsalazide can be further potentiated, even syn- ergistically, by the addition of further agents. [0047] A 28 year old male was referred because of long standing diarrhoea predominant Irritable Bowel Syn- Examples drome. This was described as being "porridgy" and 55 sometimes watery or explosive and associated with [0044] The present invention will now be described by cramping abdominal pain which passed through to his way of example. The examples should not be construed back. There was no bloating but there was marked flat- as in any way limiting the scope of the invention. ulence, no nausea and some acid reflux. The man had

6 11 EP 2 361 620 A1 12 previously been extensively investigated with tests such spastic colitis or mucous colitis, or in suppressing at as stool tests and colonoscopic examinations finding no least one symptom of diarrhea- predominant irritable cause for his symptoms. Having tried a number of stand- bowel syndrome. ard therapies the man presented for further investiga- tions. Because ongoing trials with patients with diar-5 2. A compound for use according to claim 1, wherein rhoea-predominant IBS was being carried out, the male the symptom of diarrhea-predominant irritable bow- patient commenced with a trial product (Salofalk™ oral el-system is gas production, cramping, fluid secre- granules, 1 gram, twice daily). Salofalk™ is a particular tion, mucus production or diarrhea. form of 5 Aminosalicylic acid (mesalazine) which has been found to be useful in patients with the condition. 10 3. A compound for use according to claim 1 or 2, where- The symptoms however continued. Even after progres- in the compound is balsalazide. sively raising the dose to 2 grams twice daily, and then to3 grams twice daily, the symptoms still continued, albeit 4. A compound for use according to any one of claims slightly reduced in severity. The male patient was not 1 to 3, wherein the use further comprises adminis- prepared to go to a higher dose (such a dose is also not 15 tering a 5-ASA or 4-ASA compound. used clinically). [0048] The male patient was offered treatment with 5. A compound for use according to claim 4, wherein balsalazide inaccordance with the present invention. The the 5-ASA or 4-ASA compound is mesalazine, ol- balsalazide was not immediately available and after sev- salazine, sulfasalazine, ipsalazide, benzalazine, eral weeks, the patients symptoms returned to a severe 20 para-amino salicylic acid or a salt thereof. level. Balsalazide was commenced at a dose of 750mg twice daily and slowly raised to 1.5 grams twice daily. 6. A compound for use according to any one of claims Improvement in symptoms was dramatic and far out- 1 to 5, wherein the use further comprises adminis- weighed the slight improvement with the higher doses of tering anti-cholinergics, probiotics, antibioticsor anti- Salofalk™ granules. To attempt to completely control the 25 spasm medications. mans symptoms, the patient was treated with a dose of 3 grams balsalazide twice daily (gram equivalent to Salo- 7. A pharmaceutical composition comprising a 4-ASA falk™). The patients symptoms largely disappeared. The or 5-ASA compound modified to include a 4-ABA patient had two formed stools per day without any urgen- side chain, or a salt thereof, for use in the treatment cy or flatulence and was able to eat foods he previously 30 orprevention of diarrhea- predominantirritable bowel would not have considered ingesting. The improvements syndrome, diverticulosis, diverticulitis, bloating, di- were sustained at four months follow up. arrhea, cramping, pain, low abdominal pain, disten- [0049] This example shows clinically the difference be- sion, wind, ulcer dyspepsia, spastic colon, unstable tween the use of standard mesalazine and the use of colonic neurosis, spastic colitis or mucous colitis, or balsalazide in accordance the invention in diarrhoea- pre- 35 in suppressing at least one symptom of diarrhea- dominant IBS. predominant irritable bowel syndrome.

Industrial Applicability 8. A composition for use according to claim 9, wherein the symptom of diarrhea- predominant irritable bowel [0050] The present invention relates to a method of 40 syndrome is gas production, cramping, fluid secre- treating or preventing non- inflammatory bowel diseases, tion, mucus production or diarrhea. diarrhoea-predominant irritable bowel syndrome or other non-specific bowel disorders. 9. A composition for use according to claim 7 or 8, [0051] Other embodiments of the invention will be ap- wherein the compound is balsalazide. parent to those skilled in the art from consideration of the 45 specification and practice of the invention disclosed here- in.

Claims 50

1. A compound which is a 4- ASA or 5-ASA compound modified to include a 4-ABA side chain, or a salt thereof, for use in the treatment or prevention of di- arrhea-predominant irritable bowel syndrome, diver- 55 ticulosis, diverticulitis, bloating, diarrhea, cramping, pain, low abdominal pain, distension, wind, ulcer dyspepsia, spastic colon, unstable colonic neurosis,

7 EP 2 361 620 A1

8 EP 2 361 620 A1

9 EP 2 361 620 A1

10 EP 2 361 620 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 5519014 A [0008] • US 4556552 A [0040] • US 6326364 B, Lin [0008] • US 4704295 A [0040]

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