Optimized high-dose mesalazine-containing tablet

Abstract

The present invention relates to an oral enteric high-dose tablet comprising mesalazine as the active substance as well as its use.

Claims

1. An oral enteric high-dose tablet comprising as an active substance 1000 mg of mesalazine or a pharmaceutically acceptable salt thereof and at least one excipient not containing matrix-forming substances, wherein the mass of the oral enteric high-dose tablet is at most 35% higher than the mass of the active substance, wherein the oral enteric high-dose tablet has a resistance to fracture of above 160 N, wherein a release profile in the biodissolution test of mesalazine substantially corresponds to a release profile of two tablets each containing half the amount of mesalazine of the oral enteric high-dose tablet, and wherein the oral enteric high-dose tablet comprises a tablet core, a primer coating on the tablet core wherein the primer coating does not accelerate or otherwise modify the release of the active ingredient, a first enteric coating layer comprising a methacrylic acid methylmethacrylate copolymer having a ratio of free carboxyl groups to ester groups of 1:1 on the primer coating, and a second enteric coating layer comprising a methacrylic acid methylmethacrylate copolymer having a ratio of free carboxyl groups to ester groups of 1:2, or a mixture of a methacrylic acid methylmethacrylate copolymer having a ratio of free carboxyl groups to ester groups of 1:1 and a methacrylic acid methylmethacrylate copolymer having a ratio of free carboxyl groups to ester groups of 1:2, on the first enteric coating layer, the oral enteric high-dose tablet having a release rate of active ingredient in a buffer with a pH of 6.8 of at least 90% within 60 minutes and wherein the first enteric coating layer and the second enteric coating layer makes up less than 10% by weight based on the total weight of the oral enteric high-dose tablet.

2. The oral enteric high-dose tablet according to claim 1, wherein the proportion of the at least one excipient makes up at most 30% by weight based on the total weight of the oral enteric high-dose tablet.

3. The oral enteric high-dose tablet according to claim 1, characterized in that the oral enteric high-dose tablet contains 50 to 100 mg of povidone.

4. The oral enteric high-dose tablet according to claim 1, wherein the oral enteric high-dose tablet has an oblong shape with parallel longitudinal sides and rounded narrow sides and the surfaces are biconvex curved and free from notches or breakage grooves.

5. The oral enteric high-dose tablet according to claim 1 utilized in the treatment of chronic inflammatory bowel diseases.

6. The oral enteric high-dose tablet according to claim 5 utilized in the treatment of ulcerative colitis.

7. The oral enteric high-dose tablet according to claim 6 utilized in the treatment of ulcerative colitis in the remission phase.

8. The oral enteric high-dose tablet according to claim 5 utilized for treatment of chronic inflammatory bowel diseases, wherein three oral enteric high-dose tablets are administered a day.

9. The oral enteric high-dose tablet according to claim 8, wherein one oral enteric high-dose tablet each is administered in the morning, noon and evening.

10. The oral enteric high-dose tablet according to claim 1, wherein the oral enteric high-dose tablet comprises at least one excipient consisting of polyvinyl pyrrolidone.

11. The oral enteric high-dose tablet according to claim 1, wherein said at least one excipient does not contain matrix-forming substances that embed the mesalazine active substance in a skeleton to delay the release of the mesalazine active substance.

12. The oral enteric high-dose tablet according to claim 1, wherein the oral enteric high-dose tablet completely dissolves in artificial intestinal juice comprising 0.3M phosphate buffer having pH 6.8 and a temperature of 37.0° C.±0.5° C. within 60 minutes.

13. The oral enteric high-dose tablet according to claim 11, wherein the oral enteric high-dose tablet completely dissolves in artificial intestinal juice comprising 0.3M phosphate buffer having pH 6.8 and a temperature of 37.0° C.±0.5° C. within 60 minutes.

14. The oral enteric high-dose tablet according to claim 12, wherein no active substance is dissolved in artificial gastric juice having a pH of 1 within 60 minutes.

Description

(1) FIG. 1 shows the release profiles of the three tested batches.

(2) The calculation of the similarity factor (f2) at the final test time yielded the following results: mesalazine enteric 1000 mg high-dose tablet, batch G0605B001, and Salofalk 500 mg enteric tablet, batch 1204966001: f2=66 mesalazine enteric 1000 mg high-dose tablet, batch G0605B002, and Salofalk 500 mg enteric tablet, batch 1204966001: f2=53

EXAMPLE 4: RESULTS OF DURABILITY STUDIES ON MESALAZINE ENTERIC 1000 MG HIGH-DOSE TABLETS

(3) Two batches of mesalazine enteric 1000 mg high-dose tablets were prepared in the preferred embodiment, packed into blisters consisting of PVDC/PVC aluminum foils and stored at 25° C./60% relative humidity and 40° C./75% relative humidity for durability studies. After preparation and in regular intervals during storage both the content and purity of the film coated tablets as well as release of active ingredient were determined. Here, determination of content and purity was performed with a validated HPLC/UV method, while the determination of the active ingredient release from the film coated tablets was spectro-photometrically performed at a wave length of 370 nm. The high-dose tablet according to the invention neither under long-term conditions (36 months at 25° C./60% relative humidity) nor under accelerated conditions (6 months at 40° C./75% relative humidity) shows changes in the tested properties. The two following tables 2 and 3 summarize the results of the durability studies of the two batches

(4) TABLE-US-00004 TABLE 2 Mesalazine enteric 1000 mg high-dose tablet, batch G0605B001 Primary packaging means: PVC/PVDC aluminum blister.sup.1 Storage time (months) at 25° C./60% relative humidity Test parameters 0 6 9 12 18 24 36 Mesalazine content (%) 97.0 96.6 98.5 98.0 100.0 98.9 97.5 Sum of disintegration products (%) 0.07 0.05 0.06 0.11 0.21 <0.05 0.15 Active ingredient release at 37° C. (%) in 0.1M HCl (120 minutes) resistant resistant resistant resistant resistant resistant resistant in buffer pH 6.8 (15 minutes) 0.8 0.1 0.1 0.4 0.3 0.5 0.5 in buffer pH 6.8 (60 minutes) 93.2 94.4 84.4 95.0 91.3 92.5 92.6 Storage time (months) at 40° C./75% relative humidity 0 3 6 Mesalazine content (%) 97.0 97.7 97,0 Sum of disintegration product (%) 0.07 0.07 0.09 Active ingredient release at 37° C. (%) in 0.1M HCl (120 minutes) resistant resistant resistant in buffer pH 6.8 (15 minutes) 0.8 0.5 0.1 in buffer pH 6.8 (60 minutes) 93.2 93.0 90.5 .sup.1PVC/PVDC foil (250 μm, 60 g/m.sup.2, orange), aluminum foil (20 μm)

(5) TABLE-US-00005 TABLE 3 Mesalazine enteric 1000 mg high-dose tablet, batch G0605B002 Primary packaging means: PVC/PVDC aluminum blister.sup.1 Storage time (months) at 25° C./60% relative humidity Test parameters 0 6 9 12 18 24 36 Mesalazine content (%) 98.5 101.6 97.0 100.6 99.6 100.4 98.2 Sum of disintegration products (%) 0.07 0.13 0.21 0.05 0.22 0.06 0.15 Active ingredient release at 37° C. (%) in 0.1M HCl (120 minutes) resistant resistant resistant resistant resistant resistant resistant in buffer pH 6.8 (15 minutes) 3.2 2.9 2.9 4.1 3.8 2.3 3.7 in buffer pH 6.8 (60 minutes) 92.3 91.4 95.2 96.9 96.3 95.4 92.5 Storage time (months) at 40° C./75% relative humidity 0 3 6 Mesalazine (%) 98.5 96.2 102.4 Sum of disintegration products (%) 0.07 0.06 0.07 Active ingredient release at 37° C. (%) in 0.1M HCl (120 minutes) resistant resistant resistant in buffer pH 6.8 (15 minutes) 3.2 2.6 1.3 in buffer pH 6.8 (60 minutes) 92.3 99.5 93.7 .sup.1PVC/PVDC foil (250 μm, 60 g/m.sup.2, orange), aluminum foil (20 μm)

EXAMPLE 5: CLINICAL DATA

(6) The results of the clinical study are summarized in table 4.

(7) TABLE-US-00006 Number (%) of patients in clinical remission at V4-LOCF Analysis M1000 M2x500 Sign. P approach N n % N n % Diff.sup.a 95%-RCI.sup.b level.sup.c value.sup.d PP Interim I.sup.e 103 48 46.6 114 44 38.6 8.0%  [−9.6%, 25.2%] 0.0043 0.0003 FAS Interim I 115 53 46.1 123 46 37.4 8.7%  [−8.1%, 25.0%] 0.0043 <0.0001 PP Final.sup.f 134 64 47.8 144 61 42.4 5.4% [−10.2%, 20.8%] 0.0043 0.0003 FAS Final.sup.f 151 68 45.0 155 65 41.9 3.1% [−11.7%, 17.8%] 0.0043 0.0006 .sup.adifference between proportions (πM100 − πM2x500) .sup.brepeated 95% confidence interval (RCI) .sup.csingle-sided local significance level .sup.dtest of H.sub.0 (πM1000 − πM2x500 ≤ −0.15) by inverse normal test statistics .sup.eprimary analysis .sup.fPP/FAS analysis approaches taking into account 68 overrunning patients taken up into the study during the interim analysis I

(8) In table 4 PP describes the Per Protocol analysis and FAS the analysis in the “Full Analysis Set”, wherein the patients of the PP population have carried out the study according to the protocol and in the FAS population all 306 patients were evaluated who were included in this study.

EXAMPLE 6: “BIO-DISSOLUTION TEST” OF THE HIGH-DOSE TABLET ACCORDING TO THE INVENTION

(9) To objectify and put into perspective the deviations in resolution that necessarily occur in the individual patients a so-called “Biodissolution” test was performed in vitro.

(10) To proof the equivalent active ingredient release profiles of mesalazine enteric 1000 mg high-dose tablet and Salofalk 500 mg enteric tablets under biologically relevant test conditions the following test was performed:

(11) Using the apparatus of the dipping cylinder (apparatus 3 according to chapter 2.9.3 of the European Pharmacopoeia) allows comparing the delayed release of mesalazine from the high-dose tablet according to the invention as well as from Salofalk 500 mg enteric tablets under biologically relevant conditions. Here, one dose of the tablets each is in a vial that is closed upwards and downwards with a wire mesh to hold the dosage form. Said glass cylinder is moved up and down in a dissolving vessel of a volume of ca. 325 ml. In contrast to standard apparatus for determining the active ingredient release with this system a number of test media can be studied. The glass cylinder moves in a vertical moving direction ca, 10 cm in the dissolving vessel containing 200 ml of the test medium. Here, the speed of movement is 10 dipping movements per minute (dips per minute, dpm). The advantages of the system are that by a multiple media exchange in the dissolving vessel the tablets contact different test liquids and thus, gastro intestinal passage can be simulated.

(12) For the tests 1000 mg high-dose tablets according to the invention and Salofalk 500 mg enteric tablets of commercial production batches were used. For comparison of both tablet shapes in total five test media were used that especially simulate the pH conditions of the individual segments of the gastro intestinal tract in fasting state. The retention times in the individual media in combination with the agitation movements correspond to the conditions the dosage form is also subjected to in vivo. The test results impressively show that the active ingredient release of mesalazine from the high-dose tablet according to the invention and from Salofalk 500 mg enteric tablets equally only takes place under the conditions of the distal ileum. Here, the active ingredient is completely released from the tablets and is available for local action. That is, the active ingredient is transported to the desired target site by the formulation. The following explanations summarize the tests in detail:

(13) a) Test Pattern mesalazine enteric 1000 mg high-dose tablet, batch 1501215501 Salofalk 500 mg enteric tablets, batch 1601218801

(14) b) Parameter of the Active Ingredient Release Test release apparatus: apparatus of dipping cylinder (apparatus 3 according to chapter 2.9.3 of the European Pharmacopoeia) mesh size: 840 μm volume of each dissolution vessel: 200 ml temperature: 37.0±0.5° C. dipping movements: 10 dipping movements per minute (dips per minute, dpm) number of samples per test time and batch: N=6 test media and removal and test times, respectively:

(15) TABLE-US-00007 Removal and Segment of the test times gastrointestinal tract pH value Test medium (minutes) stomach 1.2 0.1M HCl 60 proximal jejunum 6.5 phosphate buffer 15 (Ph. Eur. 5.17.1) distal jejunum 6.8 simulated intestinal 15 fluid without pepsins (SIF.sub.sp) (Ph. Eur. 5.17.1) proximal ileum 7.2 phosphate buffer 30 (Ph. Eur. 5.17.1) distal ileum 7.5 simulated intestinal 5, 10, 20, fluid without 30, 40, 50, pepsins (SIF.sub.sp) 60, 90, 120 (Ph. Eur. 5.17.1).sup.1 large intestine not tested .sup.1calculated osmolarity ~0.5 osmol/l

(16) c) Determination of Content for Mesalazine

(17) Determination of the content of the amount of mesalazine released in the test medium was performed by high-performance liquid chromatography with UV/VIS detection (HPLC/UV). Detection wave length was 220 nm.

(18) d) Results

(19) FIG. 2 shows the release profiles of both tested batches.