GB2300807A - Oral dosage forms of omega-3 polyunsaturated acids for the treatment of inflammatory bowel disease - Google Patents

Abstract

Inflammatory bowel disease, especially Crohn's disease and ulcerative colitis, is treated by administration of an oral dosage form, containing as an active principle an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof, which releases the acid in the ileum. Preferably the oral dosage form is a gelatine capsule coated with a poly(ethylacrylate-methylmethacrylate).

Description

ORAL DOSAGE FORMS OF OMEGA-3 POLYUNSATURATED ACIDS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE The present invention relates to the oral administration of omega-3 polyunsaturated acids especially, but not exclusively, eicosapenta-5,8,11,14,17-enoic acid ("EPA") and/or docosahexa-4,7,10,13,16,19-enioc acid ("DHA"). In particular, it provides enteric dosage forms of omega-3 polyunsaturated acids for the treatment of inflammatory bowel disease especially, but not exclusively, Crohn's disease and ulcerative colitis.

It is known that DHA, EPA and other omega-3 polyunsaturated acids are of use in the treatment of inflammatory bowel disease (see, for example, EP-A-0244832, EP-A-0289204, EP-A-0311091 & WO-A-93/21912).

EP-A-0244832 discloses pharmaceutical compositions containing certain unsaturated fatty acids with certain specified stimulators. The compositions are of use for treating disorders associated with prostaglandin deficiency, especially gastro-intestinal ulcers. The unsaturated fatty acids are those which have 3 to 5 isolated double bonds and 18 to 22 carbon atoms arranged in a straight chain and are capable of being methylated or ethylated at one or two carbon atoms in positions 2, 3, 4, 16, 17, 18, 19 or 20. EPA is amongst the exemplified acids. Reference is made to pH dependent delayed release formulations containing polystyrene or polyacrylic derivatives and to enteric coated products.

EP-A-0289204 discloses disinfectant and pharmaceutical compositions comprising the lithium salt of a Cl8-C22 polyunsaturated fatty acid. Specified polyunsaturated fatty acids include DHA and EPA. The pharmaceutical compositions can be for enteral, parenteral and topical administration and are for use in the treatment of conditions responsive to lithium and/or polyunsaturated fatty acid therapy. Specified conditions responsive to polyunsaturated fatty acid therapy include Crohn's disease and ulcerative colitis. Reference is made to providing an enteric coat of, for example, an acrylate or cellulose acetate phthalate to delay release of the salt until the intestine.

EP-A-0311091 discloses physiologically acceptable isotonic fat emulsions containing an omega-3-fatty acid or ester, a medium-chain length triglyceride, and an emulsifier. The fatty acid or ester component can be present as a pure compound or in the form of a fish oil and preferably is EPA. The emulsion is administered parenterally for, inter alia, treatment of chronic inflammatory bowel disease.

WO-A-93/21912 discloses the use of emulsions containing a polyunsaturated long-chain omega-3-fatty acid or ester for parenterally administration to treat inflammatory disorders including inflammatory bowel disease. The fatty acid or ester can be present as fish oil and preferred fatty acids include DHA and EPA.

Enteric coated products containing DHA or EPA have been reported for use in the treatment of other conditions (see GB-A-2090529, JP-A-62201823, & WO-A-90/04391) GB-A-2090529 discloses the prophylaxis and treatment of thrombosis using DHA or esters or amides thereof.

Reference is made in general terms to intestine soluble coated tablets and to film coated tablets.

JP-A-62201823 discloses enterically coated capsules for treating enteral abnormal fermentation or diarrhoea which contain bacteria in an oils . The oil can be EPA and a number of enteric materials are specified including shellac, carboxymethyl cellulose, cellulose acetate phthalate, hydroxymethyl propylcellulose phthalate, and polyvinyl alcohol phthalate.

WO-A-90/04391 discloses that enteric dosage forms of EPA, DHA and other omega-3 polyunsaturated fatty acids overcome the problem of belching and flatulence associated with oral administration of these acids. The exemplified coating is cellulose acetate phthalate/ethyl phthalate but reference is made to the use of polymethacrylate as the coating material.

When administered in uncoated products, omega-3 polyunsaturated fatty acids are well adsorbed but, as mentioned above, there are unpleasant side-effects, particularly belching, flatulence and pyrosis. Coating the product with conventional enteric coatings, which release the polyunsaturated fatty acid at about pH 5.5 and has about 2 hours gastric resistance (using the test set forth in the British Pharmacopoeia ("BP") 1988), reduces these side effects but produces a laxative effect causing diarrhoea in a significant number of patients. An attempt to overcome this problem by using a coating which does not dissolve until about pH 6.8 so as to delay release of the polyunsaturated fatty acid until the small intestine was unsuccessful and substantially reduced absorption of the acid.However, it was surprisingly found that use of a retard coating releasing the polyunsaturated fatty acid in the ileum, especially mid-ileum, not only solved the laxative problem but also permitted good absorption.

Thus, the present invention provides an oral dosage form, containing as an active principle an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof, which releases the acid in the ileum.

The present invention also provides the use of an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof in the manufacture of a medicament releasing the acid in the ileum for the treatment of inflammatory bowel disease.

Further, the present invention provides the use of said oral dosage forms in the treatment inflammatory bowel disease.

It is preferred that the omega-3 polyunsaturated acid is DHA, EPA or a mixture thereof. It is present in free acid form or as a pharmaceutically acceptable salt thereof and can be present as the sole active principle or with other active principles. Suitably, a fish oil concentrate containing at least 60% by weight DHA and EPA is used.

Omega-3 polyunsaturated acids are readily oxidised and hence an antioxidant usually will be present. The presently preferred antioxidant is gamma-tocopherol but other pharmacologically acceptable antioxidants can be used, for example butylated hydroxy anisole, butylated hydroxy toluene, propyl gallate or a quinone.

The oral dosage form may also contain one or more pharmaceutically acceptable excipients depending upon the precise nature of the dosage form. Suitably, the oral dosage form can be a coated tablet containing the omega-3 polyunsaturated acid in a microencapsulated form or loaded on a suitable absorbent. However, it is preferred that the oral dosage form is a coated capsule, especially a soft or, more especially, hard gelatine capsule.

The coating must be such as to release the acid in the ileum, preferably in the mid-ileum. Usually, dissolution of the coating will be entirely time dependent but a coating relying on a combination of time and pH dependence can be used. Suitably, the coating is resistant for a period of 30 to 60 minutes at pH 5.5. The presently preferred coating is a neutral polyacrylate such as a poly (ethylacrylate-methylmethacrylate), especially Eudragit# NE 30-D (Röhm Pharma GmbH) which has an average molecular weight of about 800,000. Other suitable coatings include cellulose acetate trimellate (dissolves at pH 5.5) at a thickness providing only 15 to 60 minutes gastric resistance.

Usually, the omega-3 polyunsaturated acid will be administered in a daily dosage of 20 to 50 mg/kg, especially 30-40 mg/kg. The actual dose will vary depending inter alia on the identity of the omega-3 polyunsaturated acid and the nature and degree of the disorder being treated. Usually, each unit dose will contain 250 to 1000 mg, especially 400 to 800 mg.

The following is a description, by way of example only, of a presently preferred embodiment of the invention.

Example 1 Transparent hard gelatine capsules (Elanco Qualicaps size 0; Lilly France SA) were each filled with 500 mg of a fish oil concentrate containing at least 60t by weight DHA and EPA (Incromega 3F60; Croda Universal Ltd, UK). The filled gelatine capsules were film coated in a pan coater (Erweka DKE/UG) using an airborne spray system at an application rate of 5 to 15 ml/min and an air inlet temperature of 400C. The film formulation consisted of a 7% w/w methylene chloride/ethanol solution of the polymer containing diethylphthalate (25% w/w based on polymer) as plasticizer.The polymer was cellulose acetate phthalate ("CAP") or cellulose acetate trimellate ("CAT") and the capsules were coated to the following specifications: Type 11 - > 20 mg CAP coating, gastric resistant2 for 2 hours; Type 21 - > 20 mg CAT coating, gastric resistant2 for 2 hours; and Type 3 - 10-15 mg CAT coating, gastric resistant2 for 15 to 60 minutes.

not according to the present invention 2 according to BP 1988 CAP dissolves at pH 6.8 and CAT dissolves at pH 5.5. All capsules disintegrate within 15 minutes at the relevant pH.

Example 2 Transparent hard gelatine capsules (Elanco Qualicaps size 0; Lilly France SA) were each filled with 500 mg of a fish oil concentrate containing at least 60% by weight DHA and EPA (Incromega 3F60; Croda Universal Ltd, UK). The filled gelatine capsules were film coated with Eudragit NE 30-D to provide resistance for 30 to 60 minutes at pH 5.5 by spraying with a film coating composition (see below) at 35 ml/min using 0.8 bar pressure at 250C and air drying for at least 30 mins at 250C.

The film coating composition (for 50,000 capsules) was prepared by slowly adding silicon anti-foam emulsion (0.36 mg), brown iron oxide (E 172; 3.00 mg), titanium dioxide (2.35 mg) and talc (10 mg) in succession to water (75 mg) and agitating for 1 to 2 hours to form a very fine dispersion. A 30% aqueous dispersion of a poly(ethylacrylate-methylmethacrylate) having an average molecular weight of about 800,000 (Eudragit NE 30D; 60 mg) and added to polysorbate 80 (MO 55 F; 0.2 mg) in a little water and the resultant mixture agitated. Silicon anti-foam emulsion (2 or 3 drops) was added to destroy the resultant foam and the aforementioned dispersion was slowly added. The vessel was washed with water (25 mg) and the dispersion stirred for 30 minutes before being filtered (150 sum).

Example 3 A clinical trial was conducted with a group of 50 patients with Crohn's disease (see Table 1). All the patients were in clinical and laboratory remission, in accordance with Crohn's Disease Activity Index (CDAI < 150; 19) and Laboratory Index (L1 < 100; 20). No patient was taking any other drugs and none had intestinal resection of greater than 60 cm. The weight of the patients was not less than 80 percentile ideal body weight, sex- and agerelated. No patient had a serum transferrin greater than 200 mcg/dL and serum albumin less than 3.5 g/dl. The patients were asked not to change their dietary habits During the study. Patient clinical characteristics are reported in Table 1.

The patients were randomized in five groups of 10 patients each and treated with the following: Group A - uncoated gelatine capsules containing 500 mg "Purepa" fish oil concentrate (containing EPA 40% and DHA 20%); Group B - gelatine capsule containing 500 mg "Purepa" fish oil concentrate and coated with a pH 5.5/120 minutes CAT coating (Type 1 of Example 1); Group C - gelatine capsule containing 500 mg "Purepa" fish oil concentrate and coated with a pH 5.5/60 minutes CAT coating (Type 3 of Example 1); Group D - gelatine capsule containing 500 mg "Purepa" fish oil concentrate and coated with a pH 6.9/120 minutes CAP coating (Type 1 of Example 1); and Group E - uncoated gelatine capsule containing 1000 mg "Max-EPA" triglyceride fish oil (EPA 18% and DHA 10k).

The compositions of "Purepa" and "Max-EPA" are set forth in Table 2.

The four groups taking Capsule Types A to D took 9 capsules (2.7 g of omega-3 polyunsaturated acid) during meals 3 times daily for 6 weeks and those taking Type E capsules received 12 capsules (3.4 g of omega-3 polyunsaturated acid) daily in divided doses during meals over the 6 week period. The amount of omega-3 polyunsaturated acid administered using the Type E capsules had previously been used in several clinical studies involving patients with inflammatory bowel disease.

Table 1 PATIENT CLINICAL CHARACTERISTICS (n=50) MALE 21 FEMALE 29 SMOKERS: yes 18 no 32 AGE 39 # 15 (years; mean :: SD) DURATION OF DISEASE 68 # 36 (months; mean + SD) PREVIOUS OPERATIONS 19 (Resection < 60 cm) no 31 SITE OF INVOLVEMENT Ileum 31 Ileum + Cecum 19 Table 2 COMPOSITION OF CAPSULES Purepa (fish-oil) Max-EPA Lipid profile free fatty acids triglycerides C 14:0 - 7% C 16:0 0.4% 19 C161 3.2 7 C 16:2 2.1 C 16:3 2.4 C 16:4 5.2 C 18:0 - 4 C 18:1 0.8 21 C 18:2 1.5 1 C 18:3 1.3 0.9 C 18:4 6.9 1.9 C 20:1 - 1 C 20:3 1.5 C 20:4 (AA) 1.7 2.0 C 20:5 (EPA) 42.4 18.2 C 21:5 1.6 C 22:5 0.5 1.2 C 22::6 (DHA) 19.9 10.8 Plasma and red cell phospholipid fatty acid analyses were performed using plasma and red blood cell membranes before and after treatment and compared using the students t-test for paired data (2-tailed). The results are set forth in Tables 3 and 4. Table 3 shows the percentage of omega-3 polyunsaturated acid incorporated in red blood cell phospholipid membranes before and after the six week treatment period. Table 4 shows the percentage of omega-3 polyunsaturated acid incorporated in plasma phospholipid membranes before and after the six week treatment period.

The patients were asked to register all the side effects which occurred during the treatment and the result is set forth in Table 5. No patient left the study because of side effects, but 3 patients in Group E, 2 patients in Group D and 1 patient in Group A admitted that they had reduced the daily intake of capsules and so were not included in the statistical data reported in Table 3 and 4.

As shown in Tables 3 and 4, all of the five regimens modified the phospholipid-fatty acid by increasing the incorporation of the omega-3 polyunsaturated acid both in plasma and red blood cell phospholipid membranes. This incorporation of omega-3 polyunsaturated fatty acids occurred by displacing arachidonic acid, linoleic acid, and to a lesser extent oleic acid. Patient clinical characteristics, such as previous operations, smoking and the site of involvement did not affect the incorporation of the omega-3 polyunsaturated fatty acids.

Table 3 PERCENTAGE OF FATTY ACIDS INCORPORATION (SUM 100%) IN RED BLOOD CELL PHOSPHOLIPID-MEMBRANES, BEFORE AND AFTER THE 6 WEEKS OF TREATMENT, IN THE 5 DIFFERENT GROUPS OF CROHN'S DISEASE PATIENTS.

Group A Group B Group C Group D Group E B A B A B A B A B A 20:3 0.4 0.51 0.45 0.5 0.38 0.4 0.5 0 48 0 4 0 4 n-9 #0.1 #0.13 #0.1 #0.15 #0.09 #0.1 #0.2 #0.2 #0 1 #0 2 20::4 175'' 15.5 18** 16 178'' 132 181 177 18.1 ' 17 n-6 #12 #1.1 #0.9 #0.8 #1.2 #1 #0.9 #0.8 #1.4 #1 2 20::5 0.2** 2.4 0.3** 2.8 0.2** 4.4 0.4** 1.1 0 4** 1 4 n-3 #0.1 #0.4 #0.1 #0 5 #0.09 #0.6 #0.1 #0.2 #0 06 #0 1 22::5 0.8 0.87 0.9 1 1 1 1.1 1 09 1 n-6 #0 2 #0.18 #0.1 #0.09 #0.3 #0.4 #0.3 #0.4 #0 2 #0 1 22::6 3.5** 5 3.4** 4.9 3.7** 6.3 3.2* 4.0 3.2* 4 2 n-3 #0.6 #0.9 #1.1 #0.7 #0.8 #0.9 #0.5 #0.9 #0 3 #0 6 t-statistic for paired data *p < 0 01 " p < 0.001 Mean j SD Table 4 PERCENTAGE OF FATTY ACID INCORPORATION (SUM 100%) IN PLASMA PHOSPHOLIPID-MEMBRANES, BEFORE AND AFTER THE 6 WEEKS OF TREATMENT, IN THE 5 DIFFERENT GROUPS OF CROHN'S DISEASE PATIENTS

Group A Group B Group C Group D Group E B A B A B A B A B 4 A 20:3 0.5 0.7 0.67 0.5 0.6 0.57 0.85 1.1 0.71 08 n-9 #0.09 #0.1 #0.1 #0.15 #0.13 #0.2 #0 1 #0.2 #0.2 #0 1 20::4 7.9* 6.1 9.1** 7.8 8.5** 6.1 8.8** 6.5 8.4** 6.8 n-6 #1.1 #0.8 #0.6 #0.5 #0.8 #0.8 #0.9 #1 #1.1 #0 6 20::5 0.4'* 4.8 0.5** 4.2 0.5" 8.5 0.6** 2.8 0.55' 3 2 n-3 #0.08 #0.8 #0.05 #0.6 #0.08 #0.5 #0.1 #0.3 #0 1 #0 1 22::5 48 5.1 5 4.6 4.5 5.1 4.1 4.7 4.2 3.6 n-6 #1.2 #1.1 #2 #1.8 #1.9 #2 #1.4 #1 #1.7 #2 1 22: :6 2.3** 4.1 1.9** 4.0 2.4** 5.3 2.8* 3.6 2** 3 7 n-3 #0.2 #1 #0.9 #0.8 #0.4 #0.6 #0.8 #0.8 #0.1 #0 5 t-statistic for paired data *p < 0.01 **p < 0.001 Mean # SD Table 5 SIDE EFFECTS REGISTERED IN 50 PATIENTS WITH CROHN'S DISEASE TREATED WITH 5 DIFFERENT TYPES OF FISH OIL PREPARATIONS PATIENT'S SIDE EFFECTS

Groups A B C D E Patients n=10 n=10 n=10 n=10 n=10 Upper GI (Belching, flatulence 5 0 0 0 6 Halitosis, etc Lower GI (increased bowel 0 5 0 0 6 motions) No side effects 5 5 10 3 2 Much more of the free omega-3 polyunsaturated fatty acid mixture was absorbed using the capsules containing the fish oil concentrate ("Purepa") than when using the triglyceride mixture "Max-EPA). After 6 weeks of treatment in Group C, the incorporation was 4.4k and an increase of 4.2 compared with 1.4% incorporation and 1 k increase in Group E.The incorporation was coating dependent and is believed to be related to the site of capsuledisintegration. The Group C capsules (having the pH 5.5/60 minutes coating) gave the best incorporation of the omega-3 polyunsaturated fatty acids in the plasma and red blood cell phospholipid membranes. The Group D capsules (having the pH 6.9 coating) gave very poor incorporation, suggesting low absorption of their content and 7 patients in this Group had increased daily bowel motion possibly due to capsule disintegration in the lower colon. Slightly better incorporation was registered with the Group B capsules (having the pH 5.5/120 minutes coating), but again 5 patients in the Group reported diarrhoea.

In connection with the above, the variability of the intestinal motility can substantially modify the time of transit of the capsules in the gastrointestinal tract and complete disintegration of the 120 minutes coating may be delayed causing release of the capsule content at lower bowel sites. In contrast, the uncoated Group A capsules release their content in the upper part of the gastrointestinal tract (stomach-duodenum), and hence the main side effect registered in this group is belching and no diarrhoea was observed. The uncoated Group E capsules produced side effects on both the upper (7 patients) and lower (2 patients) gastrointestinal tract, suggesting that this amount of fish oil is difficult to tolerate.

Moreover, the incorporation of omega-3 polyunsaturated fatty acid in Group A was much higher than in Group E, confirming the ease of absorption of free fatty acids compared with triglycerides, which must first be broken down by the pancreatic enzyme lipase.

In both Groups A and E taking uncoated capsules, the incorporation of omega-3 polyunsaturated fatty acid was smaller due to poorer patient compliance and the reduced daily intake of the capsules. The Group C capsules, combining both pH and time-dependent release mechanisms, made it possible to avoid capsule-breakdown (pH 5.5) in the stomach-duodenum, and consequently to avoid the upper gastrointestinal side-effects, whilst, since only gastric resistant for 60 minutes, they allowed quick release of the fish oil concentrate in the small intestine and its complete absorption.

Example 4 A double-blind placebo-controlled randomised study was conducted using 78 patients with well established diagnosis of Crohn's disease in clinical remission according to the Crohn's disease activity index (CDAI) and satisfying all the following criteria: (a) CDAI < 150 for at least 3 months but less than 2 years; (b) at least one abnormal value of alpha-l acid glycoprotein ( > 130 mg/d]), erythrocyte sedimentation rate (ESR); (c) ( > 40mm/h), or alpha-2 globulin ( > 0,9 g/dl); (d) no treatment with 5-aminosalicylate, suiphasalazine or corticosteroids in the previous 3 months, or with immunosuppressive therapy in the previous 6 months; (e) no previous bowel resection > 1 m; and (f) age 18-75 years.

The patients were blindly randomised into two groups of 39 patients to receive daily either 9 entericcoated hard gelatine capsules containing 500 mg of a fish oil concentrate ("Purepa"; see Table 6) or 9 enteric-coated capsules of identical appearance containing 500 mg of a placebo (Miglyol 812). The fish oil concentrate contained 40k EPA and 20% DHA. Both sets of capsule were coated with Eudragit NE 3OD to resist gastric acid for at least 30 min and to disintegrate within 60 min at pH 5.5, allowing release of the fish oil in the small intestine. During the treatment the patients did not take any other medication.

The clinical characteristics of both groups of patient are set forth in Table 7.

Each patient in the fish oil group received 1.8 g of EPA and 0.9g of DHA daily for 12 months. They were examined on entry to the study and at 3, 6 and 12 months or before if symptoms worsened with an increase of CDAI of at least 100 points from baseline value and above 150 for more than 2 weeks. During each visit, laboratory tests were made of blood, kidney, liver, ESR, alpha-l acid glycoprotein, alpha-2 globulin and CRP (c-AMP-Receptor Protein). At time 0, 6 months and at the end of the study, 2 ml of packed red cells and polymorphonuclear leucocytes were obtained following the procedure described by Popp Snijders et al (Scan. J. Clin. Lab. Invest 44 (1984) 39-46) and their membrane lipids were extracted as described by Dodge and Phillips (J.Lipid Res. 8 (1967) 667-675) using a 2:1 mixture of chloroform and methanol containing 0.01% butylated hydroxytoluene (2,6 di-tert-butyl-p-cresol) as antioxidant. Samples were stored under nitrogen at -200C for less than 2 weeks prior to separation of the phospholipids and analysis of the omega-3 polyunsaturated fatty acids. Phospholipid fractions were obtained from the extracted lipids using 1-dimensional thin layer chromatography. The samples were spotted in one corner of a silica plate and developed with chloroform/methanol/ acetic acid/water (25:14:4:2). The separated phospholipids were transmethylated using 1 N potassium hydroxide in methanol and boron trifluoride in 14t methanol for 10 min at 800C.Fatty acid methyl esters were then extracted in hexane, resuspended in 100 y1 of benzene and analyzed by gas-chromatography equipped with a capillary column (0.32 mm i.d. x 25 m), using helium as the carrier gas (flow rate 3ml/min) and flame ionisation detection. The column temperature was programmed between 1700C and 2100C at 50/min with the injector and detector temperatures at 22O0C and 2500C, respectively. Individual fatty acid methyl esters were identified by comparison with commercial standards. Heptadecanoic acid (17:0) was used as the internal standard (1 mg/ml in benzene) and the results expressed as relative percentages.

The difference in the relapse rate in the fish oil and placebo groups was analyzed using the chi-squared test on a 'compliance only' and 'intention to treat' basis.

Differences between features of patients in the active and the placebo group were analyzed using the Mann-Whitney Utest, and the laboratory results were analyzed with Student's t-test for paired data (both tests 2-tailed).

Kaplan-Maier life-table curves for patients remaining in remission were calculated according to the assigned treatment. Differences in the curves were tested by log rank analysis. Multiple regression analysis was performed between some variables (trial treatment, gender, age, previous surgery, length of disease) and clinical relapses; the forward procedure was used for selecting a more representative model.

Table 6 COMPOSITION OF CAPSULE CONTENTS Purepa (fish oil) Miglyol (placebo) Lipid profile Free fatty acids Neutral oil C 14:0 C 16:0 0.4 C 16:1 3.2 C 16:2 2.1 C 16:3 2.4 C 16:4 5.2 C 18:0 C 18:1 0.8 C 18:2 1.5 C 18:3 1.3 C 18:4 6.9 C 20:1 C 20:3 1.5 C 20:4 (AA) 1.7 C 20:5 (EPA) 42.4 C 21:5 1.6 C 22:5 0.5 C 22:6 (DHA) 19.9 Table 7 CLINICAL CHARACTERISTICS OF PATIENTS PUREPA PLACEBO MALE 20 19 FEMALE 19 20 AGE (years; median (range) 34 (18-67) 39 (20-65) SMOKERS 14/39 13/39 DURATION OF DISEASE 68 (24-94) 66 (20-88) (months; median (range) PREVIOUS OPERATION < im 14/39 13/39 SITE OF INVOLVEMENT ileum 25 24 ileum + colon 14 15 CDAI median (range) 78 (28-120) 82 (30-112) ESR 36.9 35.7 (mmlh) (SD 27 - min 6; max 122) (SD 24 - min 12; max 90) ALPHA-2 9.6 9.2 globulins (SD 1.8 - min 6.1; max 13.2) (SD 1.3 - min 6.5; max 11.9) (sn) ALPHA- i 136.8 137.1 GLYCOPROTEIN (SD 52 - min 53; max 257) (SD 58 - min 60; max 263) (mg/dl) In the fish oil group, 1 patient withdrew (moved away) and 4 dropped out because of diarrhoea. In the placebo group, 1 patient withdrew (did not attend the outpatient clinic) and 1 dropped out because of diarrhoea. Diarrhoea started in all 5 cases within the first month of treatment and symptoms did not improve when the daily capsule intake was reduced. This diarrhoea might have been due to the delivery of the capsule contents into the distal part of the gut. The coating is time-dependent (30-60 min at pH 5.5) so if the transit time is short, the capsules would remain intact further along the intestine.

The relapse rate was significantly reduced by the fish oil compared to the placebo group: chi squared 11.75; p=0.0004 (difference 41%, 95% confidence interval (Cl) 1666). This difference was significant too on an intention to treat analysis: chi squared 9.05; p=0.0026 (difference 32%, 95% (Cl) 12-52).

Table 8 summarises the clinical results and Table 9 summarises the laboratory variables of inflammation at entry and at 12 months in the patients who received the fish oil and were still in remission at the end of the study. No significant decrease in any of the laboratory findings of disease activity occurred in the placebo group.

Table 10 shows the incorporation of the main fatty acids into phospholipid membranes (AA = arachidonic acid and LA = linoleic acid). Multiple regression analysis indicated that only the fish oil capsules significantly affected clinical relapse (t=3,16; p=0,002;F ratio=l0; p=0,002).

Tables CLINICAL RESULTS AFTER 12 MONTHS OF TREATMENT fish oil (n=39) placebo (n=39) Withdrew 1 1 REMISSIONS 23/38 10/38 drop-out 4 1 RELAPSES 15138 (39,5%)* 28/38 (73,7%) (intention to treat) with drop-out * chi square 9.05; p= 0.0026 excluding drop-outs 11/34 = 32,4% 27/37 = 73,0% *chi square 11,75; p=0,0004 Table 9 23 PATIENTS GIVEN PUREPA IN REMISSION AFTER 12 MONTHS TIME 0 12 MONTHS

ESR 37.8 (6-122) SD25 19.5 (340) SD 11.2 (mm/h) p= 0.0002 CRP 3.6 (0.2-9.9) SD 3.4 1.0 (0.2-3.5) SD 0.9 (mg/dl) p= 0.001 ALFA-2 0.91 (0.64-1.32) SD 0.15 0.74 (0.56-0.91) SD 0.1 globulin (g/dl) p= 0.001 ALFA - 1 137 (57-248) SD 49 111 (69-180) SD 33 GLYCOPROTEIN (mgidl) p= 0.002 ALBUMIN 3.7 (3.04.4) SD 0.4 4.0 (3.14.7) SD 0.35 (g/dl) p= 0.004 WBC 8780 (4000-11700) SD 2093 7400 (3310-11550) SD 2634 p= 0.01 Table 10 PERCENTAGE OF MAIN FATTY ACIDS INCORPORATED INTO RBCs PUREPA MIGLYOL TIME 0 6 MONTH TIME 0 6 MONTH 18:2n-6 LA 10.2#1 7.0#0.8 6.4#0.4 10.6#1.5 9.8#2 11.1#1.5 20:4n-6 AA 13.9#1.5 8.4#1.2 7.1#1.2 13.5#1.3 12.3#1.8 14.1#1.2 20::5n-3 EPA 0.2#0.1 4.1#0.3 5.8#0.6 0.3#0.1 0.1#0.1 0.2#0.1 22:6n-3 DHA 2.9#0.6 7.4#1.2 11.4#1.2 3.2#0.5 2.8#0.7 3.0#0.6 Over a period of 12 months the fish oil capsules used in the study reduced the clinical relapse of Crohn's disease in comparison with placebo by 50%. It is important to note that the patients in the study were in clinical remission for less than 24 months prior to entry, and presented laboratory evidence of inflammation. Patients of this type have about 75% greater risk of relapse in comparison with patients with long previous remission with normal laboratory tests.

The results indicate that the fish oil capsules are the most effective and safe available treatment for preventing clinical relapses in Crohn's disease, with relatively few side effects.

Claims (40)

1. An oral dosage form containing as an active principle an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof, characterized in that it releases the acid in the ileum.

2. An oral dosage form as claimed in Claim 1, wherein the omega-3 polyunsaturated acid is released in the mid-ileum.

3. An oral dosage form as claimed in Claim 1 or Claim 2, wherein release of the omega-3 polyunsaturated acid is controlled by an exterior coating.

4. An oral dosage form as claimed in Claim 3 which is a coated capsule.

5. An oral dosage form as claimed in Claim 3 or Claim 4, wherein delay in dissolution of the coating is timedependant but not pH dependent.

6. An oral dosage form as claimed in Claim 5, wherein the coating is resistant for a period of 30 to 60 minutes at pH 5.5.

7. An oral dosage form as claimed in Claim 5 or Claim 6, wherein the coating is a neutral polyacrylate.

8. An oral dosage form as claimed in Claim 7, wherein the coating is a poly(ethylacrylate-methylmethacrylate).

9. An oral dosage form as claimed in Claim 3 or Claim 4, wherein delay in dissolution of the coating is both timeand ph'- dependant.

10. An oral dosage form as claimed in Claim 9, wherein the coating is cellulose acetate trimellate.

11. An oral dosage form as claimed in any one of the preceding claims, wherein said acid is DHA, EPA or a mixture thereof.

12. An oral dosage form as claimed in any one of the preceding claims, wherein said acid is present in free acid form.

13. An oral dosage form as claimed in any one of the preceding claims, wherein said acid is present as the sole active principle.

14. An oral dosage form as claimed in Claim 1 and substantially as hereinbefore described in the Examples.

15. The use of an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof in the manufacture of a medicament releasing the acid in the ileum for the treatment of inflammatory bowel disease.

16. A use as claimed in Claim 15, wherein the medicament releases the omega-3 polyunsaturated acid in the mid-ileum.

17. A use as claimed in Claim 15 or Claim 16, wherein release of the omega-3 polyunsaturated acid is controlled by an exterior coating.

18. A use as claimed in Claim 17, wherein the medicament is a coated capsule.

19. A use as claimed in Claim 17 or Claim 18, wherein delay in dissolution of the coating is time-dependant but not pH dependent.

20. A use as claimed in Claim 19, wherein the coating is resistant for a period of 30 to 60 minutes at pH 5.5.

21. A use as claimed in Claim 19 or Claim 20, wherein the coating is a neutral polyacrylate.

22. A use as claimed in Claim 21, wherein the coating is a poly(ethylacrylate-methylmethacrylate).

23. A use as claimed in Claim 17 or Claim 18, wherein delay in dissolution of the coating is both time- and pHdependant.

24. A use as claimed in Claim 23, wherein the coating is cellulose acetate trimellate.

25. A use as claimed in any one of Claims 15 to 24, wherein said acid is DHA, EPA or a mixture thereof.

26. A use as claimed in any one of Claims 15 to 25, wherein said acid is present in free acid form.

27. A use as claimed in any one of Claims 15 to 26, wherein said acid or salt is present as the sole active principle.

28. A use as claimed in Claim 15 and substantially as hereinbefore described in the Examples.

29. The use of an oral dosage form as claimed in any one of Claims 1 to 14 in the treatment of inflammatory bowel disease.

30. A use as claimed in Claim 29, wherein the inflammatory bowel disease is Crohn's disease.

31. A use as claimed in Claim 29, wherein the inflammatory bowel disease is ulcerative colitis.

32. A method of treating inflammatory bowel disease, which comprises administering to a patient an effective amount of an oral dosage form as claimed in any one of Claims 1 to 14.

33. A method as claimed in Claim 32, wherein the inflammatory bowel disease is Crohn's disease.

34. A method as claimed in Claim 33, wherein the inflammatory bowel disease is ulcerative colitis.

35. A method of treating inflammatory bowel disease, which comprises releasing in the ileum of a patient an effective amount of an omega-3 polyunsaturated acid in free acid form or as a pharmaceutically acceptable salt thereof.

36. A method as claimed in Claim 35, wherein said acid or salt is released in the mid-ileum.

37. A method as claimed in Claim 35 or Claim 36, wherein the inflammatory bowel disease is Crohn's disease.

38. A method as claimed in Claim 35 or Claim 36, wherein the inflammatory bowel disease is ulcerative colitis.

39. A method as claimed in any one of Claims 35 to 38, wherein said acid is DHA, EPA or a mixture thereof.

40. A method as claimed in any one of Claims 35 to 39, wherein said acid is present in free acid form.