PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE AND IRRITABLE BOWEL SYNDROME

Abstract: Inflammatory bowel disease and irritable bowel syndrome are treated by oral or rectal administration to a patient of an effective amount of a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof. Preferably, the active compound is glyceryl trinitrate.

Description: PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE AND IRRITABLE BOWEL SYNDROME This invention relates to use of a nitric oxide donor for the treatment of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and to post- gastrically delayed release oral (DRO) and rectally administrable compositions containing a nitric oxide or a nitric oxide donor. IBS is a functional bowel disorder of abdominal pain and altered bowel habit. Pain is characteristically relieved by defecation and may be associated with increase or decrease in stool frequency, alterations in stool consistency, straining or urgency, a sensation of incomplete evacuation, passage of mucus, or abdominal distension. The pathophysiology is poorly understood despite the fact that about a quarter of the population in the UK may exhibit the symptoms. IBD covers chronic non-specific inflammatory conditions of the gastro-intestinal tract, of which the two major forms are Crohn's disease and ulcerative colitis including protococolitis, ileocolitis, protitis and pouchitis. The aetiology of these diseases is uncertain. Many inflammatory mediators have been proposed including prostanoids, leu otrienes, platelet activating factor, cytokines, and free oxygen radicals. Although specific inhibitors of most of these have been tried in experimental models, the most effective drugs currently available for these diseases have a broad activity against inflammatory processes. Crohn's disease is characterised by thickened areas of the gastro-intestinal wall, with inflammation extending through all layers, deep ulceration and fissuring of the mucosa, and the presence of granulomas. Affected areas may occur in any part of the gastro- intestinal tract, although the terminal ileum is frequently involved, and they may be interspersed with areas of relatively normal tissue. Symptoms depend on the site of disease but may include abdominal pain, diarrhoea, fever, weight loss and rectal bleeding. In ulcerative colitis, the disease is limited to the colon and rectum. Inflammation is superficial but continuous over the affected area and granulomas are rare. In mild disease, the rectum alone may be affected (proctitis) . In severe disease ulceration is extensive and much of the mucosa may be lost, with an increased risk of toxic dilatation of the colon, a potentially life-threatening complication. Numerous compounds have been examined in the last twenty years to find effective measures for the treatment of IBD. Such compounds include azathioprine, arsenicals, disodium cromoglycate, metronidazole, lignocaine, 5- aminosalicyclic acid (5-ASA) , fish oils, thalidomide and cyclosporin. The wide diversity of treatments is an indication of the complexity and intransigence of this condition. There have been a number of different theories of how Crohn's disease is initiated. Surgically resected specimens from patients with Crohn's disease when perfused with resin, show substantial damage to the normal blood supply - particularly in the areas which are macroscopically abnormal (Lancet 1989, ii : 1057-1062) . This was coined λ multifocal gastrointestinal infarction' . Similar pathological changes are seen in animal models when the blood supply is obstructed (Gastroenterology 1992; 102 (5) :1591-1596) . Granulomas, the pathological hallmark of Crohn's, appear to form mainly within the walls of blood vessels (Gastroenterology 1991; 100 (5) :1279-1287) . Vascular damage with rupture of capillaries occurs early on in the damage process, even before the wall is infiltrated by inflammatory cells (Gut 1993; 34:375-381) . Glyceryl trinitrate and other organic nitrates have been the mainstays of therapy in cardiovascular disease for many years. In recent years, it has been found that these compounds are actually prodrugs for nitric oxide. This in turn has been found to have two main roles: as a vasodilator and as an antiplatelet agent (The American Journal of Cardiology Volume 70, Sept. 24, 1992: A Symposium Nitroglycerin Therapy) . Glyceryl trinitrate and other nitric oxide donors were also found to be useful in the treatment of anal fissures (WO-A-9532715) . In Nature Medicine, Jan. 1997; (3)1: 30-31, it is reported that nitric oxide levels in the intestines were more than 100 times higher in ulcerative colitis patients and 30 times higher in patients with Crohn's as compared to normal patients. In Pharmacol. Rev. 1991; 43:109-142 nitric oxide was suggested as an inhibitory nonadrenergic noncholinergic (NANC) neurotransmitter which could play an important role in the autonomic innervation of smooth muscle, in the gastrointestinal tract, the pelvic viscera and the airways. In US-A-5574068 , use of S-nitrosothiols (nitric oxide donors) were proposed for disorders which involve non-vascular smooth muscle such as respiratory disorders, gastrointestinal disorders, urological dysfunctions, impotence, uterine dysfunction and premature labour. The inventors have now discovered that nitric oxide and physiological derivatives thereof can treat both IBD and IBS. The nitric oxide is delivered in vivo classically by a nitric oxide donor such as is used to treat angina pectoris. However nitric oxide could also be introduced directly to the intestine, such as in the form of a gas or dissolved gas. In a first aspect of the invention, there is provided a post-gastric delayed release oral (DRO) or a rectally administrable pharmaceutical composition for the treatment or prophylaxis of IBD or IBS, said composition comprising nitric oxide or a nitric oxide donor or pharmacologically acceptable derivative thereof and a pharmaceutically acceptable carrier or vehicle. In a second aspect of the invention, there is provided use of nitric oxide or a nitric oxide donor or pharmacologically acceptable derivative thereof, in the preparation of a medicament for the treatment or prophylaxis of IBD or IBS. A further aspect of the invention is a method for the treatment of IBD or IBS comprising administering to the patient a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof. The nitric oxide donor can be selected from the group of compounds known as nitrovasodilators and is preferably an organic nitrate or nitrite such as glyceryl trinitrate, amyl nitrate, octyl nitrate, propatylnitrate, sorbide nitrate, trolnitrate (phosphate), ethylene glycol dinitrate, glyceryl 1, 2-dinitrate, glyceryl 1,3-di- nitrate, glyceryl 1-mononitrate, butane 1,2,4-triol nitrate, mannitol hexanitrate, pentaerythrityl tetra- nitrate, pentaerythrityl trinitrate, isosorbide dinitrate, isosorbide mononitrate, erythrityl tetra- nitrate, or other organic esters of nitric acid of the formula R- [C-0-N0 2 ] x , where R is an alkyl, cycloalkyl, or alkenyl group having from 1 to 18 carbon atoms or an aromatic group having from 6 to 18 carbon atoms and where x is an integer of from 1 to 5, or a combination of two or more of the foregoing. Other preferred nitric oxide donors are the S-nitrosothiols such as S-nitroso-N- acetylpenicillamine (SNAP) , S-nitrosoglutathione (GSNO) (described in more detail in Analytical Biochemistry 249, 1-9 (1997)), S-nitroso-N-acetylcysteine, S-nitroso- cysteine, S-nitroso-homocysteine, S-nitrosopantathoeine derivatives and S-nitraso-captopril . It is not known how the nitric oxide or its derivatives improve the disease state, but the inflammation is decreased. Although it is thought that nitric oxide acts either directly or indirectly to help resolve the disease, a derivative of nitric oxide such as the S-nitrosothiols may be involved in the mechanistic pathway. Therefore physiological derivatives of nitric oxide which are metabolised from or as a result of nitric oxide are also within the scope of the invention. The term nitric oxide donor also encompasses pharmaceutically acceptable salts thereof . The nitric oxide donor is preferably delivered to the small or large intestine, rectally or via a post- gastric DRO composition. In this way the active agent can be delivered to the disease site and is believed to exhibit a beneficial topical action against both IBD and irritable bowel system. Furthermore since systemic absorption from the intestine of glyceryl trinitrate and other nitric oxide donors is limited by a high first pass hepatic metabolism, the side effects such as headaches and nausea classically present with nitric oxide is minimised. Thus high doses of nitric oxide donor can be delivered to treat the disease without the normal concomitant side effects. In this respect glyceryl trinitrate is particularly preferred. A preferred form of the invention provides a delayed and sustained-release pharmaceutical composition for oral administration. By delayed release we mean that release is substantially post-gastric, and by sustained release we mean that the total release of the nitric oxide donor is slow and sustained over a period of time, as opposed to being released as a bolus. The sustained release of the nitric oxide donor will preferably be over a 2 to 12 hour period, preferably a 4 to 8 hour period, such as a 4 to 6 hour period. According to one embodiment of the present invention, the pharmaceutical composition takes the form of an enema formulation such as a liquid or foam enema which is rectally administered to the lower colon. Useful enema formulations comprise an effective amount of nitric oxide donor dissolved or dispersed in a suitable flowable carrier vehicle, such as deionised and/or distilled water. The formulation can be thickened with one or more thickeners, such as xanthan gum or carbomer, can contain a buffer, and can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g. a tris-fatty acid glycerate or lectithin. Non-toxic non-ionic surfactants can also be included as wetting agents and dispersants. Unit doses of enema formulations can be administered from pre-filled bags or syringes. In the case of a pressurised enema formulation the carrier vehicle may also comprise an effective amount of a foaming agent such as n-butane, propane or i-butane. Such formulations can be delivered from a preloaded syringe or pressurised container, so that the vehicle is delivered to the colon as a foam, which inhibits its escape from the target site. Enema foams may also comprise expanding agents and foam-stabilisers. The viscosity of the enema is preferably 3 to 5 milliNewton metres (mNm) as measured using a Rheomat™ 108 rotary viscometer (50 to 85 Pa.s) and the pH is preferably 3.5 to 5.5. The DRO composition of the invention are ideally coated so as to release the unit dosage form in the lower intestinal tract, e.g. in the mid to distal small bowel and/or in the colon of the patient. Enteric coatings such as acrylic or methacrylic acid resins remain intact in the stomach, but dissolve and release the contents of the dosage form once it reaches the region of the intestine where the pH is optimal for dissolution for the coating used. The majority of the release will be targeted to the part of the small intestine or colon where the active disease is prevalent and this varies for Crohn's disease and ulcerative colitis. Thus typically for an enteric coated capsule, the enteric coating should dissolve in the pH of the jejunum, ileum or colon. Thereafter preferably sustained release, of the nitric oxide donor will take place. The dosage of nitric oxide donor such as glyceryl trinitrate in a rectally administrable composition typically an enema or foam enema would be 1 to 50 mg, preferably 1 to 15 mg. Aqueous film-coating technology is advantageously employed for the enteric coating of pharmaceutical dosage forms. A useful enteric coating is one that remains intact in the low pH of the stomach, but readily dissolves when the optimum dissolution pH of the particular coating is reached. This can vary between pH 3 to 7.5 depending on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material and the site to be treated. Preferably the unit dosage of nitric oxide donor, such as isosorbide dinitrate or glyceryl trinitrate, in a rectally administrable (e.g. enema) or DRO composition is 1 to 50 mg, more preferably 1 to 30 mg, more preferably still 1 to 15 mg. The inventors are presently using 3 mg glyceryl trinitrate in their trial. The total daily dose for a 70 kg patient for any composition would be from 3 to 100 mg, preferably up to 30 mg. In one embodiment of the invention, a delayed release oral formulation is provided in which an enteric coated capsule containing a nitric oxide donor of the invention has a coating, thickness of coating and dissolution profile as described in EP-A-0097651 (the contents of which are incorporated herein by reference) . A delayed-release formulation can also be achieved by coating a powder or microgranular formulation of a nitric oxide donor of the invention with, for example, ethylcellulose or an acrylic resin based on acrylic and methacrylic acid esters containing a low content of quaternary ammonium groups at a predetermined molar ratio. Suitable resins include EUDRAGIT™ L, S, RL and RS . The coated microgranules or material may then be compressed into tablets or packed into hard gelatin capsules suitable for oral administration. Suitable coatings are thicknesses to achieve this sustained release are disclosed in EP-A-0572486 (incorporated herein by reference) . A sustained release of the nitric oxide donor can also be achieved by incorporating it into a saturated polyglycolized glyceride excipient comprising a mono-, di- and triglycerides and of mono- di-fatty acid esters of polyethylene glycol (PEG) hydrophobic matrix. The polyglycolized glyceride can be adapted to have a different melting point and hypophilic-lipophilic balance (HLB) depending on the type and proportion of triglyceride and fatty acid esters of PEG used. For example, for a more lipophilic nitric oxide donor the melting point/HLB could suitably be 42/12, 44/14 or 50/13. On the other hand, for more hydrophilic nitric oxide donor such as various water soluble salts, the melting point/HLB could suitably be 46/07, 48/09, 53/10 or 50/13. A particularly preferred melting point/HLB, particularly for use with isosorbide dinitrate and glyceryl trinitrate is a mixture of 42/12 and 50/13, or 50/13 alone. An example of a commercially available polyglycolized excipient for use with the invention is Gelucire™ (available from Gattefosse, France) . A polyacrylic acid derivative can also be used to achieve sustained release of the nitric oxide donor by, for example, forming a nitric oxide donor - polyacrylate complex. A preferred polyacrylate is a carbomer, such as Carbopol (available from B.F. Goodrich) . Carbomers are synthetic, high molecular weight, non-linear, polymers of acrylic acid, cross-linked with polyalkenyl polyether. A sustained release nicotine-carbomer complex in an enteric coated capsule is described in O-A-9728301 (incorporated herein by reference) and the same technology would be applicable to the present invention. As acidic material for the coating of oral compositions of the invention for delayed-release, anionic polymers, particularly anionic acrylate polymers and especially anionic polymers synthesised from methacrylic acid and methyl methacrylate, may be used. Carboxyl groups in such polymers render the material capable of forming salts in alkaline environments in which they are sparingly soluble while in the acid to neutral pH range the coatings are substantially insoluble and substantially impermeable thus protecting the active ingredient contained within from gastric acids. The coatings may be applied conventionally, typically as a lacquer or solution containing the acidic material from which the solvent or carrier is then evaporated. A particularly suitable acidic material for coating the compositions of the invention for lower bowel treatment is the anionic methacrylate polymer sold under the registered Trade Mark EUDRAGIT S by Rohm Pharma GmbH of Darmstadt, Germany. Capsules coated with EUDRAGIT™ S100 disintegrate in the ascending colon of the patients. EUDRAGIT™ S is a copolymer of methacrylic acid and methyl methacrylate in which the ratio of free carboxyl groups to ester groups is approximately 1:2 and having a mean molecular weight of 135,000. Coatings of acidic materials, such as that sold as EUDRAGIT L (composition as EUDRAGIT S but having a carboxyl/ester ratio of 1:1), may be used in the coating of tablets or capsules to release active agents in the small intestine, although they may be applied in much greater thicknesses than was hitherto conventional thereby delaying release of the active agent until the tablet or capsule reaches the large intestine. It will be apparent to the skilled person that mixtures of substances, such as EUDRAGIT™ S and EUDRAGIT L, may be used as coating materials. In general coating thicknesses of 25 to 200 μm, and especially 75 to 150 μm, are preferred using 3 to 25 mg, preferably 8 to 15 mg, of acidic coating material per cm 2 of tablet or capsule surface. The precise coating thickness will however depend upon the solubility characteristics of the acidic material used and site to be treated. Together with the acidic material, the coating material may contain additives such as colouring agents, plasticisers, opaque film coatings, gloss producers and auxiliary materials (e.g. talc). The provision of the coating to the compositions of the invention may be achieved in conventional manner, e.g. by the use of spraying, fluidized bed, immersion tube and immersion blade techniques. (See for example D. Dreher "Film coatings on acrylic resin basis for dosage forms with controlled drug release" Pharma International 1/2 (1975) 3 ) . Preferably, the coating is applied from aqueous suspension. The coating can, and usually will, contain plasticiser and possibly other coating additives such as colouring agents, gloss producers, talc and/or magnesium stearate as well known in the coating art. In particular, anionic carboxylic acrylic polymers usually contain 10 to 25% by weight of a plasticiser especially diethyl phthalate, although the presence of such a plasticiser may not be necessary when using an aqueous suspension for coating. Usually, the capsule into which the coated material is loaded will be a soft or, preferably, hard gelatin capsule although other capsules which will dissolve in the small intestine can be used. The capsule is coated with an enteric coating which will protect it during passage through the stomach. Any conventional enteric coating material which is soluble in the small intestine can be used, e.g. cellulose acetate phthalate, hydroxy propylmethyl cellulose phthalate or initially ethyl cellulose followed by polyvinyl acetate phthalate, but it is preferred to use an anionic polymer having an appropriate dissolution profile. The presently preferred polymers are anionic carboxylic polymers, e.g. EUDRAGIT™ L. In addition to the nitric oxide donor ingredient, the tablet or capsule cores (e.g. in the form of microgranules) for the compositions of the present invention may also contain additives such as fillers (e.g. lactose or dicalcium phosphate), binders (e.g. starch or polyvinylpyrrolidone) , lubricants (e.g. magnesium stearate, stearic acid or talc) and disintegrants (e.g. alginic acid or sodium starch glycolate) . The tablet or capsule cores may be prepared in a conventional manner. It is preferable to include a suitable disintegrant , such as Explotab™ (a brand of sodium starch glycollate made by K&K Greef) , or Primojel™ (from AVEBE, Netherlands) in the orally administered compositions according to the invention. In a particularly preferred DRO form of the invention, a capsule containing a nitric oxide donor, such as glyceryl trinitrate, in a polyglycolized excipient such as Gelucire™, is enteric coated, such as by Eudragit™ L (dissolving at pH6.8) or Eudragit™ S for release in the mid to distal small bowel and/or colon. The invention will now be described by way of example only in which the attached figure is a graph of the release profiles of isosorbide dinitrate from various capsules containing Gelucire™ of different melting points/HLB. Example 1 2% w/w isosorbide dinitrate in lactose powder (120 mg = 30 mg isosorbide dinitrate) was incorporated into the melted Gelucire™ and dispersed into size 1 opaque hard gelatin capsules. Initially six formulations were prepared using Gelucire™ (G) 42/12, 44/14, 53/10, 53/13, 46/07 and 48/09 so that each capsule contained 120 mg of the isosorbide powder dispersed in 440 mg of Gelucire™. Subsequently additional formulations were prepared using mixtures of two Gelucires™. These were G42/12 1 part plus G50/13 2 parts (33%) , G42/12 1 part plus G50/13 6 parts (15%) , and G42/12 1 part plus G50/13 9 parts (10%) . The dissolution profile of these capsules were tested using a Erweka™ Tablet dissolution tester model DT80. Peak investigation was determined from which the amount (in mg) of isosorbide dinitrate present in the sample was calculated. The results are shown in the attached figure. A good release pattern over a 4-6 hour time period, (and released 30 mg of isosorbide dinitrate from the Gelucire™) was achieved by the mixture of Gelucire™ 42/12 plus Gelucire™ 50/13, 10% and 15%. These are indicated on the attached figure as G42/50 (10%) and G42/50 (15%) . The capsule containing Gelucire™ 50/13 also gave a good sustained release of isosorbide dinitrate . Example 2 Gelatin capsules containing 30 mg isosorbide dinitrite and Gelucire™ 42/12 plus Gelucire™ 50/13 (10% and 15%) were prepared as outlined above and coated using Eudragit™-L. Example 3 Example 2 was repeated, but using 3 mg glyceryl trinitrite in place of the 30 mg isosorbide dinitrate. Example 4 A preliminary clinical trial was conducted to assess the effect of oral glycerol trinitrate (GTN) in active Crohn's disease. 14 patients were treated for 6 weeks with 2 capsules of Example 3 (6 mg GTN) twice daily and the CDAI assessed at commencement of the trial and after 3 and 6 weeks. The treatment was withdrawn over the subsequent 4 weeks to enable the patients to assess the effect upon their symptoms. Five of the patients had ileal Crohn's disease, two patients had large bowel Crohn's disease and seven patients had Crohn's disease at both sites. The CDAI was greater than 1 50 in only 7 of the patients at commencement of the trial. Nine of the patients were receiving steroids. There was some change in the steroid dose in three of them during the course of the trial (one was on a reducing dose before entry; two had an increase in steroids during the trial) . One patient had intra-articular steroids for an arthritis and two patients discontinued their steroids on commencement of the trial. These variations in treatment about the time of and during the trial made it a little difficult to draw firm conclusions. The GTN was very well tolerated. One patient had vague headaches for a couple of days, and a second patient had a fainting episode but both were able to continue with the treatment. The CDAI was lower at 6 weeks than on commencement in ten patients and the reduction in CDAI appeared clinically significant in 6 of these patients, About half of the patients had a reduction in stool frequency but there was little effect on the pain score . Five patients requested to continue with the treatment at the end of the trial. All were women with ileal Crohn's disease; two also had small bowel involvement proximal to the terminal ileum; two had recurrent ileal Crohn's disease after surgical resection; and two had colonic involvement. Four of these 5 patients increased the daily dose to 6 capsules (18 mg GTN) without side effects. All 5 patients reported that their symptoms had improved whilst taking GTN over this period and noticed a reduction in episodes of pain.

Claims: CLAIMS 1. A post-gastric delayed release oral (DRO) or a rectally administrable pharmaceutical composition for the treatment or prophylaxis of inflammatory bowel disease or irritable bowel syndrome, said composition comprising nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof and a pharmaceutically acceptable carrier or vehicle. 2. A composition as claimed in Claim 1, wherein the nitric oxide donor is selected from glyceryl trinitrate, amyl nitrate, octyl nitrate, propatylnitrate, sorbide nitrate, trolnitrate (phosphate) , ethylene glycol dinitrate, glyceryl 1, 2 -dinitrate, glyceryl 1,3- dinitrate, glyceryl 1-mononitrate, butane 1,2,4-triol nitrate, mannitol hexanitrate, pentaerythrityl tetranitrate, pentaerythrityl trinitrate, isosorbide dinitrate, isosorbide mononitrate, erythrityl tetranitrate, or other organic esters of nitric acid of the formula R- [C-0-N02] X, where R is an alkyl, cycloalkyl, or alkenyl group having from 1 to 18 carbon atoms or an aromatic group having from 6 to 18 carbon atoms and where X is an integer of from 1 to 5; and an S- nitrosothiol or a combination of two or more of the foregoing. 3. A composition as claimed in Claim 2, wherein the nitric oxide donor is glyceryl trinitrate. 4. A composition as claimed in any one of the preceding claims, wherein the medicament is a DRO composition. 5. A composition as claimed in Claim 4, wherein the DRO composition is an enteric coated tablet, capsule or granules . 6. A composition as claimed in any one of Claims 1 to 3 , wherein the medicament is a rectally administrable composition. 7. A composition as claimed in Claim 6, wherein the rectally administrable composition is a liquid or foam enema . 8. A composition as claimed in any one of the preceding claims wherein the amount of nitric oxide donor per unit dosage form is from 1 to 50 mg. 9. A composition as claimed in Claim 8, wherein said amount is from 1 to 15 mg. 10. A composition as claimed in any one of the preceding claims, wherein the nitric oxide donor is in the form of a complex with a polyacrylate. 11. A composition as claimed in any one of Claims 1 to 9. wherein the nitric oxide donor is incorporated in matrix of a polyglycolized glyceride comprising mono-, di- and triglycerides and mono-, di-fatty acid esters of polyethylene glycol . 12. A composition as claimed in Claim 11 which is an enteric coated capsule comprising 1 to 15 mg glyceryl trinitrate in said matrix, the capsule being coated with an anionic copolymer of methacrylic acid and methylmethacrylate . 13. Use of nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof in the preparation of a medicament for the treatment or prophylaxis of inflammatory bowel disease or irritable bowel syndrome. 14. A use as claimed in Claim 13 , wherein the disease state is Crohn's disease or ulcerative colitis. 15. A use as claimed in Claim 13 or Claim 14, wherein the nitric oxide donor and dosage are as defined in any one of Claims 1 to 12. 16. A method for the treatment of inflammatory bowel disease or irritable bowel syndrome comprising administering to a patient an effective amount of a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof.

Inventors: EVANS BRIAN KENNETH, RHODES JOHN, EVANS, BRIAN, KENNETH, RHODES, JOHN
Applicants: EVANS BRIAN KENNETH, RHODES JOHN, EVANS, BRIAN, KENNETH, RHODES, JOHN
Application year: 1998
Main classification: A61K31
IPC codes: A61K9, A61K31, A61P1