EA041224B1 - HIGH DOSE ENTERIC TABLET WITH MESALAZINE ACTIVE SUBSTANCE - Google Patents

Description

Chronic inflammatory bowel diseases are intermittent, destructive inflammations of the intestine. These include the two most common types of Crohn's disease and ulcerative colitis, as well as the rarer collagenous colitis, lymphocytic colitis, and atypical microscopic colitis.

Crohn's disease and ulcerative colitis differ in their distribution as well as their macroscopic and histological features [Dignass et al. (2012) Journal of Crohn's and Colitis 6, 965-990].

Crohn's disease can occur segmentally in all departments from the esophagus to the rectum and affect all layers of the wall. Typical symptoms are painful spasm, diarrhoea, pyrexia, and weight loss. Ulcerative colitis begins in the rectum and from there can spread to all parts of the colon and in a circle affects only the mucous membrane. Patients present with hemorrhagic diarrhea, painful spasm, anorexia, and weight loss. The etiology of chronic inflammatory bowel disease is still unclear, so there is no etiological treatment.

Mesalazine-releasing drugs are used to treat and prevent recurrence of chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Mesalazine is the international non-proprietary name for 5-aminosalicylic acid. Although the exact mechanism of action is not yet known, the therapeutic efficacy of the compound can be attributed to a local anti-inflammatory effect on the intestinal wall. Mesalazine is used orally and/or rectally as a first-line agent. It has been shown that for oral treatment of an acute attack of ulcerative colitis, as well as for the prevention of relapse, treatment with a high dose of mesalazine, with a daily dose of 3 g administered once a day or divided into 3 single doses (morning, afternoon and evening).

To prevent absorption of the active ingredient in the upper small intestine after oral administration, as well as to selectively transport mesalazine to the desired site of action in the intestine, it is necessary to develop specific herbal preparations. To accomplish this task, a single dose of the active ingredient can be prepared in the form of a monolithic compact dosage form, such as, for example, an enteric-coated tablet or a tablet with a modified release of the active ingredients, or in the form of multiparticulate divided dosage forms, such as, for example, granules. /pellets with enteric coating or granules/pellets with modified release of active ingredients. These forms are known to avoid premature release of the active ingredients and instead provide delayed, continuous or intermittent release of the drug dose and delivery of mesalazine to the desired target site. In this case, a monolithic dosage form has the advantage that its volume is usually smaller than that of a multiparticulate dosage form at the same dose and composition. However, for many patients the tablets are easier to swallow than the corresponding multiparticulate form with the same dose.

In addition to such galenic requirements, correct administration of the drug, as well as strict adherence to dosage instructions and the type and duration of administration by patients, is an essential requirement for the effectiveness of mesalazine treatment. Compliance with the treatment regimen itself shows how accurately and for how long the patient adheres to the prescribed dosage regimen. Non-compliance by the patient with the treatment regimen affects the results of treatment up to ineffectiveness.

The World Health Organization (WHO), in addition to social/economic, systemic disease-related factors, describes patient and treatment-related events as reasons for non-adherence. The complexity of the treatment regimen and the duration of treatment, as well as the motivation, expectations and forgetfulness of patients can be noted as a manifestation of patient and treatment-related factors, among others. Thus, an essential measure to improve adherence to treatment is the simplification of drug treatment.

Inappropriate dosing regimens for high-dose oral mesalazine treatment of inflammatory bowel disease may impair daily life and thereby quality of life in affected patients. This applies in particular to patients in whom, after successful treatment, it is necessary to prevent a recurrence of the disease. Treatment adherence can be greatly improved by introducing dosage forms that are convenient for patients, by reducing the amount of drugs taken, and by using a simplified dosage regimen. In this context, daily and accurate intake of high daily doses of mesalazine presents the greatest difficulty for the patient.

The prior art describes various methods of administering oral preparations of mesalazine. The therapeutic use of mesalazine enteric-coated tablets containing relatively small amounts of the active ingredient, such as Salofalk® 250-500 mg enteric tablets (EP0083775), Claversal® 250-500 mg enteric tablets or Azacol enteric tablets, is justified. (Asacol®) 400 mg. These administration forms contain film coatings based on polymeric substances having pH-dependent dissolution characteristics. Depending on the detected pH value, as well as the amount of film-forming agent applied, a specific section of the intestine can be selected,

- 1 041224 in which the release of mesalazine will begin. After complete dissolution of the film coating in the small intestine, mesalazine can be rapidly released from the remainder, and then the tablet core is disintegrated. Thus, drug release is slowed down but not modified.

Current oral administration forms containing mesalazine also include formulations with a high dose of active compound (substance), which, however, have the disadvantage that they require a very complex pharmaceutical technology for their preparation. Thus, multiparticulate preparations in the form of pellets are described (EP 0977557). EP 0977557 describes an oral pellet preparation having a controlled release profile. In this case, controlled release is provided by a complex polymeric matrix in which the active ingredient is contained in the core of the pellet, and enteric film coatings. The use of sachets allows the administration of more than 1000 mg of mesalazine pellets in one sachet. WO 2004/093884 describes the administration of a delayed release preparation of mesalazine in the form of a sachet at a dose of 500 mg to 10 g per sachet. Those. only sophisticated pharmaceutical techniques are known for preparation in tablet form. EP 1198226 also describes an internal matrix in which the active compound is at least partially enclosed. In addition, said oral administration form contains an external hydrophilic matrix and optionally other external carriers.

Another high dose formulation comprises a matrix core of defined viscosity, wherein said hydrophilic matrix is to be contained in an amount equal to 1 to 20% based on the total weight of the tablet (EP2621477).

WO 2011/045775 discloses tablets having a relatively high mesalamine content (1200 mg per tablet). During manufacture, granulated mesalamine is mixed with matrix-forming compounds such as carbopol and then compressed. These tablets are provided with one layer of enteric coating agent.

WO 00/44353 describes pharmaceutical compositions for the slow release of various active ingredients in the gastrointestinal tract. In this case, a number of active ingredient-containing particles are coated with a material that is insoluble in gastric and intestinal juices, where the individual particles are pressed together after application of coating agents such as Eudragit® RS or Eudragit® NE. In this case, the core containing the active ingredient is a homogeneous mixture containing the active ingredient and a polymer that is insoluble in gastric and intestinal juice.

WO 2015/062640 discloses a barrier layer for accelerated release of active ingredients in the intestine for delayed release pharmaceutical preparations. The disclosed tablets contain a core with a pharmaceutically active ingredient, a sealing layer that provides accelerated release of the active ingredient in the intestine and closes the core, and an outer coating, which in turn consists of an inner and outer layers. The outer and inner layers of the outer coating include polymeric materials that dissolve at a pH value greater than 6.

WO 2009/047802 describes pharmaceutical formulations for various active ingredients, in particular 5-aminosalicylic acid or its metabolites. They are administered in a bioadhesive formulation. Delayed release is provided by mixing the active ingredient with a polymer which is insoluble in gastric juice and then compressing. Then, an enteric coating is applied to said matrix tablet.

The object of the present invention is to provide a stable high dose mesalazine tablet which provides administration of 1000 mg of the active ingredient per unit of preparation with an optimized formulation. Due to the chosen design and size, the tablet can be swallowed without any difficulty, so that the same therapeutic efficacy can be achieved, as, for example, when taking twice the number of Salofalk® 500 mg enteric tablets with a simplified dosage regimen. This greatly simplifies the treatment of drugs and ensures regular intake of the drug. Thus, all the features of the present invention improve the acceptability of the administered form for patients, which leads to improved compliance with the therapy regimen.

Another advantage of the present invention is that the mesalazine high dose tablet is well received by patients. In this case, it is essential that the tablet, which itself is relatively large, can be swallowed successfully and without any difficulty. On the other hand, the high dose tablet of the present invention should have a release profile of the active ingredient that matches that of the two smaller tablets. This means that, for example, a mesalazine high dose tablet containing 1000 mg of active ingredient should have a release profile corresponding to the active ingredient profile for two tablets of 500 mg of active ingredient each.

In addition, in order to reduce the burden on patients, the relative content of inert fillers and coating materials must be kept as low as possible. Inert fillers and coating materials may not be well tolerated by at least some patients and thus the content should be kept as low as possible.

Thus, the present invention relates to a high dose oral enteric tablet containing as active substance 1000 mg of mesalazine or a pharmaceutically acceptable salt thereof and at least one excipient which does not contain matrix-forming compounds which comprise the active substance mesalazine in frame, thus delaying the release of the active substance of mesalazine, where the weight of the tablet with a high dose of the active substance is not more than 35% more than the weight of the active substance, where the tablet has a fracture resistance of more than 160 N, where the release profile in the study of the biological dissolution of mesalazine according to essentially corresponds to the release profile of two tablets each containing half the amount of mesalazine in a high dose tablet, and where the high dose tablet contains a protective coating and two film coating layers containing enteric polymers, the content of which is less than 10% by weight, based on the total weight of the high dose tablet.

The preparation of the present invention is not a matrix tablet in which the release of the active ingredient is controlled by a matrix in the tablet core.

In the present case, enteric means that the tablet with a high dose of the active substance meets the requirements for an enteric tablet in accordance with the specifications of the article on injectable forms of the European Pharmacopoeia.

As used in the present invention, a high dose tablet means a high dose tablet of the active substance. In the present invention, a high dose specifically means about 1000 mg of the active substance. About 1000 mg means the range from 980 mg to 1020 mg of the active substance, namely mesalazine. Thus, a daily dose containing 3 g of mesalazine can be used either by a single administration of three high dose tablets or by using one tablet three times (morning, afternoon and evening).

The at least one excipient is selected from conventional pharmaceutically acceptable excipients for granulation and tablet preparation. Said at least one excipient, together with the active ingredient, forms the core of the tablet. It is particularly preferred if at least one excipient consists only of polyvinylpyrrolidone, preferably Povidone K25 (Povidone K25). Thus, for example, the active compound mesalazine is converted into a granule of the active ingredient with a binder solution consisting of water and povidone K25 by wet granulation. Preferably, in this case povidone K25 is contained in a high dose tablet of the active substance in an amount equal to 50 to 100 mg, preferably 50 to 80 mg, and more preferably 66.5 to 73.5 mg per 1000 mg of mesalazine.

In another embodiment, the high dose tablet of the present invention, in addition to the excipient, which is preferably Povidone K25, may contain other excipients selected from the group consisting of dry binders, disintegrating agents, agents for regulating flowability and lubricants. Such other excipients are preferably added in an amount of not more than 180 per 1000 mg of mesalazine.

For example, dry binders are selected from the group consisting of calcium phosphates, lactose, starch, cellulose, hexites, synthetic polymers. In this case, microcrystalline cellulose is particularly preferred. The microcrystalline cellulose is then preferably present in an amount of 95.0 to 105.0 mg per 1000 mg of mesalazine in a high dose tablet.

For example, leavening agents are selected from the group consisting of starch, cellulose, cellulose derivatives, synthetic polymers. In this case, croscarmellose sodium is particularly preferred. Croscarmellose sodium is then preferably present in an amount of 57.0 to 63.0 mg per 1000 mg of mesalazine in a high dose tablet.

For example, flow control agents are selected from the group consisting of starch, metal soaps, anhydrous fumed silica. In this case, anhydrous fumed silica is particularly preferred. The anhydrous fumed silica is then preferably present in an amount of 4.75 to 5.25 mg per 1000 mg of mesalazine in a high dose tablet.

For example, lubricants are selected from the group consisting of metal soaps, fatty alcohols, talc, high molecular weight polyethylene glycols. In this case, calcium stearate is particularly preferred. The calcium stearate is then preferably present in an amount of 12.4 to 13.7 mg per 1000 mg of mesalazine in a high dose tablet.

In addition, at least one inert filler does not contain any matrix-forming compounds. As used in the present invention, matrix-forming compounds means all compounds which include the active substance mesalazine in the framework and thus influence the release of the active substance mesalazine. Examples of matrix compounds are cellulose derivatives such as, for example, ethylcellulose, hydroxypropyl methylcellulose, waxes, polyvinyl acetate, polymers and copolymers of acrylates and methacrylates, such as, for example, without any limitation, Eudragit® types RL, RS or NE. For matrix-forming compounds as used herein, it should be understood that such additives are present in the tablet core and result in delayed release of the active ingredient.

The high-dose film-coated tablet of the present invention is characterized in that the weight of the high-dose film-coated tablet is no more than 40% greater than the weight of the active substance. This means that, for example, a tablet with an active substance weight of 1000 mg has a total weight of at most 1400 mg.

In one embodiment, the weight of the high dose tablet core is no more than 40% more, preferably no more than 35% more, and more preferably no more than 30%, and particularly preferably no more than 25% more than the mass of the active substance.

In another embodiment, the content of at least one inert excipient is not more than 35% by weight, preferably not more than 30% by weight, and more preferably not more than 20% by weight, based on the total weight of the high dose tablet.

In this case, it is only theoretically possible to prepare a 1000 mg tablet with a high dose of active substance based on the Salofalk® 500 mg enteric tablet formulation by simply doubling the mass of the substances, since this procedure does not at all lead to swallowable shaped products with a weight of about 1.7 g In this case, the weight of the tablet is 70% greater than the content of the pure active ingredient.

In contrast, the high dose tablet of the present invention, which has biopharmaceutical and therapeutic characteristics equivalent to Salofalk® 500 mg enteric tablets, contains only about 25% excipient, so that the weight of the tablet is not more than 35% more than pure active ingredient content. As shown in Example 1, the 1000 mg high dose tablet of the present invention has a mass of only 1.3 g. Thus, while maintaining functionality, these molded products have a significantly reduced size and are much more suitable for oral administration. than a tablet made by simply doubling the quantities. This is due to improved acceptability for the patient.

The high dose tablet of the present invention consists of a tablet core with optimized dimensions, shape and size, and in one embodiment, at least one film coating. The tablet core is obtained by pressing a powder mixture. It contains granules of the active ingredient in admixture with at least one excipient. In this case, the total amount of active ingredient per tablet is processed into granules.

In contrast to at least one inert filler, at least one film coating may contain matrix-forming compounds. At least one film coating can be applied in several layers. It is particularly preferred to apply 2, 3 or more layers. These layers may consist of the same or different film-forming substances.

Preferably, the present invention uses such film coatings that do not form a matrix, but dissolve in vivo. At least one film coating is selected from a list of film-forming agents, including hypromellose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl acetate cellulose succinate, polyvinyl acetate phthalate, shellac, anionic copolymers of methacrylic acid and its esters of the Eudragit® type, such as, for example, Eudragit® L, Eudragit® S or mixtures thereof.

In a preferred embodiment, the film coating consists of a protective coating as well as two layers which serve to provide a delayed release of the active ingredient. For example, the protective coating consists of hypromellose and two layers that serve to provide delayed release of the active ingredient, consisting of Eudragit® L and Eudragit® S. For in vivo release of the active ingredient, the protective coating is neutral. The protective coating, either alone or in combination with other coating layers, does not accelerate the release of the active ingredient.

In a particularly preferred embodiment, the high dose tablet of the present invention contains a relatively thin protective coating of hypromellose (hydroxypropyl methylcellulose). One advantage of said protective coating is that the enteric coating attached thereto can be applied better and more evenly, and that thinner layers of one or two layer enteric coating can also be applied in this way. Finally, this results in that although less coating material is applied in terms of active ingredient content, the desired release profile can still be achieved.

- 4 041224

In another preferred embodiment, the film coating consists of two layers which serve to provide a delayed release of the active ingredient. For example, these two layers consist of Eudragit® L or Eudragit® S or mixtures of Eudragit® S and L.

In a preferred embodiment, the active ingredient is granulated by wet granulation of mesalazine with a binder solution consisting of water as solvent and a water-soluble polymer, preferably povidone K25, as binder. In this case, the amount of povidone K25 added is between 66.5 and 73.5 mg per tablet. After wet screening and drying of the granules of the active ingredient, excipients are added to improve disintegration, preferably croscarmellose sodium in an amount equal to 57.0 to 63.0 mg per tablet, a dry binder, preferably microcrystalline cellulose in an amount equal to 95, 0 to 105.0 mg per tablet, flow control agents, preferably anhydrous fumed silica in an amount equal to 4.75 to 5.25 mg per tablet, and a lubricant, preferably calcium stearate in an amount equal to from 12.4 to 13.7 mg per tablet.

The final mixture containing active ingredient granules and other excipients can be deformed very easily. Compression of the mixed granules results in tablet cores which, at a weight of 1248 mg per unit, have an active ingredient content of 80%. According to the invention, it has surprisingly been found that these tablet cores, in spite of the high content of the active ingredient, are characterized by excellent mechanical characteristics, as well as rapid and complete disintegration, which is an important requirement for the release of the drug after dissolution of the film coating. The strength of densified products can be assessed by determining fracture resistance and abrasion resistance. Both characteristics are preferably determined in accordance with the methods 2.9.7 and 2.9.8 of the European Pharmacopoeia. The fracture resistance of mesalazine of the high dose tablet of the present invention is more than 160 N, the abrasion resistance or abrasion wear, respectively, is less than 1%. The disintegration time of the tablet cores in 0.3 M phosphate buffer at pH 6.8 is preferably determined according to the method 2.9.1 of the European Pharmacopoeia and is less than 15 minutes.

The high dose oral enteric tablet of the present invention dissolves completely in artificial intestinal juice containing 0.3M phosphate buffer, pH 6.8, temperature 37.0±0.5°C within 60 minutes.

However, the active compound from the high dose oral enteric tablet according to the present invention does not dissolve in artificial gastric juice with a pH value of 1 within 60 minutes.

According to the invention, it has surprisingly been found that the tablet core administered in accordance with the present invention contains less excipients than the tablet cores in known formulations, such as Salofalk® 500 mg enteric tablet formulation, without changing the characteristics of the molded product. In this case, the granules of the active ingredient of the 1000 mg high dose tablet containing only mesalazine and povidone K25 lead to the same biopharmaceutical and therapeutic characteristics as the significantly more complex granules of the Salofalk® 500 mg enteric tablets, which additionally contain to solubilize the active ingredient inert fillers sodium carbonate and glycine. In the present invention, these two substances can be omitted in the preferred embodiment without substitution. Namely, according to the invention, it has surprisingly been found that for a completely pH-controlled release and availability, sodium carbonate and glycine can be omitted. The omission of sodium carbonate also results in that the granules of the active ingredient in the 1000 mg high dose tablet of the present invention can be prepared using only water and without the use of an organic solvent such as ethanol. The efficacy of the high dose tablet of the present invention has been confirmed by a comparative clinical study.

In addition to the improved granule formulation and product form, another distinct and unexpected feature of the present invention is the qualitatively and quantitatively optimized film coating composition of the 1000 mg mesalazine high dose tablet. Thus, the film coating procedure is greatly simplified and accelerated without compromising the desired release characteristics of the active ingredient. This leads to the fact that when using a simplified dosing regimen, as well as improved patient acceptability, the same therapeutic efficacy is provided as when taking twice the amount of Salofalk® 500 mg enteric tablets.

It is known that for the successful treatment of an acute attack of ulcerative colitis, as well as the prevention of recurrence, using Salofalk® 500 mg enteric tablets, a certain release profile of mesalazine from a dosage form is required. The local availability of the active ingredient begins after the passage of the stomach with an additional delay time of at least 15 minutes,

- 5 041224 in the small intestine. Thus, on the one hand, the film coating must ensure the resistance of the administered form to gastric juice and, on the other hand, it can only completely dissolve after at least 15 minutes after the passage of the stomach in the small intestine to ensure the start of the release of the active ingredient at the desired target site. . When using Salofalk® 500 mg enteric tablets, this release is achieved by successively applying three layers of 90.5 mg of methacrylic acid-methyl methacrylate copolymer (1:1) in total, calculated per tablet, with a surface area of approximately 3.7 cm ² (which corresponds to 25 mg/cm ² and applied to 13% of the surface). It is an anionic copolymer of methacrylic acid and methyl methacrylate with the trade name Eudragit® L. The ratio of free carboxy groups to ester groups is 1:1 and determines the solubility of the polymer starting from a pH value of 6.0. Together with the amount of film applied, this provides resistance to gastric juices and also the beginning of the release of the active ingredient at the target site. In addition, the tablet cores are isolated with a layer of non-functional hypromellose prior to application of the methacrylic acid-methyl methacrylate (1:1) copolymer.

The protective coating that is preferably used in the present invention, and which preferably consists of an enteric coating material such as hydroxypropyl methylcellulose, dissolves in the small intestine regardless of the pH value after dissolution of the enteric outer coating. However, the release of the active ingredient is not accelerated or otherwise modified by said protective coating.

The 1000 mg high dose tablet of the present invention provides the desired small intestinal release characteristics of mesalazine due to the fact that significantly less polymeric material needs to be applied to the tablets. In contrast to Salofalk® 500 mg enteric tablets, the coating contains only 72.0 mg film-forming agent per tablet with a surface area of approximately 5.3 cm ² (corresponding to 14 mg/cm ² and 6% surface coverage). This noticeable film reduction is due to the optimized formulation of the coating material for the delayed release of the active ingredient, which needs to be applied in two coats instead of three. In this case, two copolymers of the Eudragit® type are used as film-forming agent. In addition to Eudragit® L, a mixture of Eudragit® L and Eudragit® S is used. Eudragit® S is the trade name for an anionic polymer of methacrylic acid and methyl methacrylate where the ratio of free carboxy groups to ester groups is 1:2. The solubility of said copolymer is given for pH values of 7.0 or more.

As shown in Example 1, tablet cores isolated with hypromellose are, in a preferred embodiment, first coated with a methacrylic acid-methyl methacrylate (1:1) copolymer layer. In this case, 47.2 mg of polymer is applied to the surface of each tablet core (corresponding to 9 mg/cm ² and 4% surface coverage). Then add a second layer of a mixture containing 60 wt.% copolymer methacrylic acid - methyl methacrylate (1:1) and 40 wt.% copolymer methacrylic acid - methyl methacrylate (1:2). The film formed from said mixture results in the application to the surface of each tablet of an additional polymeric material (corresponding to 5 mg/cm ² and application to about 2% of the surface) consisting of Eudragit® L and Eudragit® S.

By quantitatively and qualitatively optimizing the film coating composition of the 1000 mg mesalazine high dose tablet, gastric resistance as well as desirable upper small bowel release characteristics are achieved by applying markedly less polymeric material. This results in a much simpler scheme for coating the tablet cores. Comparative in vitro release studies of the active ingredient lead to identical release profiles for the high dose tablet of the present invention as well as Salofalk 500 mg enteric tablets in artificial intestinal juice, with a required in vitro delay time of at least 15 minutes. In addition, resistance to gastric juice is provided. Example 3 shows the results of comparative studies on the release of the active ingredient.

Conducting comparative studies of the release of the active ingredient presented in example 3 is an important tool for drug selection, since the results can be used to predict biopharmaceutical and therapeutic characteristics. If two comparable drugs behave similarly in these studies, it is possible to predict the real situation in vivo for the patient.

In vitro release testing apparatus used as a standard, such as a rotary basket and paddle stirrer, are only partially suitable because they cannot adequately simulate the corresponding conditions of passage through the gastrointestinal tract. It has other conditions of passage and residence time, the composition and volume of the gastrointestinal fluid, as well as hydrodynamic conditions. The more gastrointestinal segments stimulated in vitro, the more accurate the prediction of actual dosing behavior.

- 6 041224 bath form in vivo.

A much better technique for predicting a drug after ingestion by a patient is to stimulate the gastrointestinal tract as accurately as possible. An apparatus with an immersion cylinder is particularly suitable for this (apparatus 3 corresponding to chapter 2.9.3 of the European Pharmacopoeia). This system allows you to study and compare dosage forms, taking into account biologically adequate research conditions. They are multiple replacement of media, the use of a smaller test volume, as well as imitation of movements during transfer. Example 6 shows the results of active ingredient release studies of the 1000 mg high dose tablet of the present invention compared to Salofalk 500 mg enteric tablets using a dip cylinder apparatus.

In a particularly preferred embodiment, the 1000 mg mesalazine high dose tablet of the present invention has a biodissolution profile of the active ingredient as shown in Example 6 that substantially corresponds to that of two 500 mg tablets. This means that up to 120 minutes less than 10% of the active ingredient is dissolved and that after 180 minutes 70% or preferably at least 80% or more of the active ingredient is dissolved.

In another preferred embodiment, high dose tablets are oblong with parallel longitudinal sides and rounded narrow sides. Surfaces are biconvex curved and free of notches or break grooves. In this case, the tablet height h is in the range of 6 to 8 mm, preferably in the range of 6.8 to 7.4 mm, more preferably 7.1 mm. The length of tablet 1 is in the range of 19 to 22 mm, preferably in the range of 20 to 21 mm, more preferably in the range of 20.1 to 20.6 mm, for example 20.3 mm. The tablet width b is in the range of 8 to 10 mm, preferably in the range of 9 to 9.8 mm, more preferably in the range of 9.2 to 9.7 mm, for example 9.4 mm.

The radii of curvature (double curvature) of the convex upper and lower sides of the oblong tablet are 4.25 and 60.00 mm in the longitudinal direction and 4.25 and 8.00 mm in the transverse direction and provide optimal coating on tablets, as well as improved swallowing of tablets with coated.

Example 2 describes the dimensions of the 1000 mg mesalazine high dose tablets of the present invention. The surface area of the tablets is about 5 cm ² . The selected tablet size results in stable molded products with optimum mechanical and geometrical characteristics for applying uniform and thin film coatings in the drum coater. At the same time, due to the shape and dimensions, the swallowability and thus the acceptability of the tablets to patients is greatly improved.

The described features of the present invention result in a stable 1000 mg mesalazine high dose tablet. Primary packaging of tablets is preferably carried out in blisters consisting of PVC (polyvinyl chloride) or PVC plastic forming foil, which are coated with PVDC (polyvinylidene chloride) and a solid aluminum closure foil. The qualitative and quantitative composition, as well as the chosen method of preparation and the selected primary packaging materials, lead to the fact that the tablets show changes after storage under conditions of climatic zone II for at least 36 months. In addition, according to studies under load, the tablets are stable. The results of the shelf life studies are shown in example 4.

In addition, the present invention relates to the use of mesalazine tablets with a high dose of the active substance, as described above, for the treatment of chronic inflammatory bowel diseases, preferably for the treatment of ulcerative colitis or ulcerative colitis in remission. In one embodiment, the 1000 mg mesalazine high dose tablet of the present invention, as well as the Salofalk® 500 mg enteric tablet, is used to treat an acute attack of ulcerative colitis as well as to prevent relapse. In another embodiment, three high dose tablets of the active substance of the present invention are administered per day, preferably each one high dose tablet is administered in the morning, afternoon and evening.

In a clinical study conducted to show that the high dose tablet of the present invention can be compared with the 500 mg tablets described in the prior art, both preparations were studied for 8 weeks. A total of 306 patients suffering from active ulcerative colitis were treated in a double blind (double sham) clinical trial in several European countries with 1000 mg mesalazine tablets of the present invention (taken three times a day) or 2x500 mg mesalazine tablets (also taken three times a day). Patients who experienced clinical remission after 8 weeks of treatment (visit 4 patients) were considered successfully cured. Clinical remission was very rigorously defined with a disease activity score <4 (CAI, Colitis Activity Score) with a daily bowel frequency corresponding to a reported score of 0 (defined as <18 bowel movements per week) and a sub-score for rectal bleeding also of 0 (defines

- 7 041224 as 0-1 bloody bowel movements for the specified sub-indicator). Example 5 shows the results of a study of various statistically evaluated groups. The clinical study could have been terminated after the interim analysis due to comparable efficacy. In the group treated with the high dose tablet of the present invention (M1000), 46.6% of patients provided primary evidence of efficacy, while in the group treated with mesalazine 2x500mg (M2x500) daily tablets, there were 38.6% (example 5).

The therapeutic efficacy, safety and tolerability of mesalazine are equally provided by both drugs. In terms of these criteria, there is no difference between the salofalk 500 mg enteric tablet and the 1000 mg mesalazine high dose tablet of the present invention.

However, patients clearly prefer medical treatment with the high-dose mesalazine 1000 mg tablet. A significant majority of patients (47.7%) clearly indicate the preferred intake of only one tablet. Only 10.5% of the patients in the study preferred to take the two smaller mesalazine tablets. This result is robust because all patients in the double-blind clinical trial received both placebo or real formulations during the study. This unexpected decision can be attributed to the chosen form and size of the high dose tablet and therefore a much simpler and more patient-friendly dosage and administration schedule, resulting in easier regular drug administration and improved patient acceptance. Accordingly, in the case of the 1000 mg mesalazine high dose tablet of the present invention, compliance can be improved so that proportionately more successful treatment with mesalazine can be achieved compared to treatment with approved administration forms. Thus, patient treatment-related factors leading to non-compliance can be significantly reduced by using the high dose tablet of the present invention.

Preferred embodiments of the present invention are apparent from the following examples.

Example 1 Qualitative and Quantitative Composition of Preferred Embodiments of a 1000 mg Mesalazine High Dose Enteric Tablet.

Table 1

Compound Tablet weight Mesalazine 1000.00 mg Povidone K25 70.00 mg Microcrystalline cellulose 100.00 mg Anhydrous highly dispersed silica 5.00 mg Croscarmellose sodium salt 60.00 mg calcium stearate 13.00 mg Hypromellose 6.50 mg Macrogol 6000 7.60 mg Copolymer methacrylic acid - methyl methacrylate 1:1 57.10 mg Copolymer methacrylic acid - methyl methacrylate 1:2 14.90 mg Talc 12.05 mg Titanium dioxide 0.60 mg Iron oxide, yellow 0.75 mg Coated tablet weight 1347.50 mg

The composition of the preferred 1000 mg high dose tablet is shown in Table 1. 1.

All of the tablet core compounds described above: mesalazine, povidone K25, microcrystalline cellulose, anhydrous fumed silica, croscarmellose sodium and calcium stearate are added to a weight of 1248 mg. This is 80.1 wt.% of the weight of the finished tablet. Thus, the content of coatings is less than 20.0 wt.% of the weight of the finished tablet.

Example 2 Tablet Shape, Tablet Size, Tablet Geometry, and Dimensions of High Dose 1000 mg Mesalazine Enteric Tablet.

Tablet geometry:

shape, appearance - oblong, rod-shaped;

lateral sides - parallel slightly rounded longitudinal and rounded narrow sides;

surface - biconvex curved surfaces that do not contain risks or grooves for breaking.

Size and dimensions of the tablet (without film coating):

tablet height - 7.1 mm (from 6.8 to 7.4 mm);

tablet length - 20.3 mm (from 20.1 to 20.6 mm);

tablet width - 9.4 mm (from 9.2 mm to 9.7 mm);

- 8 041224 edge height: 3.2 mm (from 2.9 to 3.5 mm);

height of the spherical cap - 1.95 mm;

circumference - 5.1 cm;

the area of the circumferential surface or edge, respectively - 1.64 cm ² ;

area of the designed surface - 1.84 cm ² ;

surface area: 5.32 cm ² (from 5.16 to 5.47 cm ² ).

Curvature of the tablet (radius of curvature of the spherical cap):

radii of curvature, longitudinal:

radius 1 - 4.25 mm;

radius 2 - 60.00 mm;

radii of curvature, transverse:

radius 1: 4.25 mm;

radius 2: 8.00 mm.

Example 3 Evidence of the equivalence of the release profiles of the active ingredient from 1000 mg high dose mesalazine enteric tablets and Salofalk® 500 mg enteric tablets.

The 1000 mg high dose tablet of the present invention has a mesalazine dissolution profile equivalent to that of two Salofalk® 500 mg enteric tablets. In this case, in a preferred embodiment, comparative in vitro release studies of the active ingredient were performed on two different lots of 1000 mg high dose mesalazine enteric tablets and included a study for 2 hours in artificial gastric juice having a pH value of 1 (0.1 M HCl), as well as a subsequent study for 60 min in artificial intestinal juice having a pH value of 6.8 (0.3 M phosphate buffer). After treatment in artificial gastric juice, the film-coated tablets of the reference preparation, i. Salofalk® 500 mg enteric tablets and film-coated tablets of the present invention, i.e. enteric tablets of mesalazine with a high dose of the active substance of 1000 mg, it was found that the profiles of mesalazine in artificial intestinal juice are the same. After the required delay time of at least 15 minutes, the release profiles are almost the same and after 60 minutes mesalazine is completely dissolved. The amounts of mesalazine released after separate studies of different durations in artificial intestinal juice for the reference preparation and the high dose tablet of the present invention differ by less than 10%. In accordance with the European Medicines Agency (EMA) guidelines for biological equivalence studies (CPMP/EWP/QWP/1401/98 Rev. 1/Corr.), a similarity factor (f2) can be calculated from the results of the comparison of the release studies of the active ingredient and it is found to be greater than 50. Thus, the profiles are considered to be the same. Below is a detailed description of the studies.

a) Study Design:

mesalazine high dose enteric tablet 1000 mg, lots G0605B001, G0605B002; enteric tablets Salofalk® 500 mg, batch 1204966001.

b) Active Ingredient Release Test Conditions:

release test apparatus: apparatus with paddle stirrer (apparatus 2 corresponding to chapter 2.9.3 of the European Pharmacopoeia);

research environments:

artificial gastric juice: 0.1 M HCl, volume 500 ml, 120 min;

artificial intestinal juice: 0.3 M phosphate buffer pH 6.8, volume 1000 ml, 60 min;

temperature: 37.0°C±0.5°C;

mixing speed: 100 rpm;

the number of samples used during the study, and the party: N=12; study duration: 0, 5, 10, 15, 20, 25, 30, 35, 45, 60 min.

c) Method for determination of mesalazine content:

the content of mesalazine released in the medium for research, was determined spectrophotometrically at a wave valley equal to 370 nm.

d) Results.

In FIG. 1 shows the release profiles for the three batches tested. Calculations of the similarity coefficient (f2) for the time of the final study gave the following results:

high dose mesalazine enteric tablet 1000 mg lot G0605B001 and salofalk enteric tablet 500 mg lot 1204966001: f2=66.

mesalazine high dose enteric tablet 1000 mg lot G0605B002 and Salofalk 500 mg enteric tablet lot 1204966001:f2=53.

Example 4 Results of studies on the shelf life of mesalazine enteric tablets with high

- 9 041224 with a juice dose of the active substance 1000 mg.

Two batches of 1000 mg high dose mesalazine enteric tablets prepared in the preferred embodiment were packaged in PVDC/PVC aluminum foil blisters and stored at 25°C/60% RH and 40°C/75% RH for expiration studies. relative humidity. After receipt and at regular intervals during storage, the content and purity of the film-coated tablets, as well as the release of the active ingredient, were determined. In this case, determination of content and purity was carried out according to the approved HPLC/UV method, and the determination of the release of the active ingredient from film-coated tablets was carried out spectrophotometrically at a wavelength of 370 nm. The high-dose tablets of the present invention showed no change in the studied characteristics under either long-term storage conditions (36 months at 25°C/60% RH) or accelerated conditions (6 months at 40°C/75% RH). . In the two tables below. 2 and 3 show the results of the shelf life studies for these two batches.

table 2

High dose mesalazine enteric tablet 1000 mg lot G0605B001 Primary packaging materials: PVC/PVDC aluminium, blister ¹ Researched parameters Hra time 0 neniya (month 6 shy) at 25' 9 ^e C/60% rel1 12 ositive 18 humidity 24 36 Mesalazine content (%) 97.0 96.6 98.5 98.0 100.0 98.9 97.5 The sum of the contents of leavening products (%) 0.07 0.05 0.06 oh and 0.21 <0.05 0.15 Release of active ingredient at 37°C (%) in 0.1 MHC1 (120 min) in buffer at pH 6.8 (15 min) in buffer at pH 6.8 (60 min) stable a 0.8 93.2 stable a 0.1 94.4 stable a 0.1 84.4 stable a 0.4 95.0 stable a o z 91.3 stable a 0.5 92.5 stable a 0.5 92.6 Storage time (months) 0 at 40°C/75% relative 3 Noah humidity 6 Mesalazine content (%) 97.0 97.7 97.0 The sum of the contents of leavening products (%) 0.07 0.07 0.09 Release of active ingredient at 37°C (%) in 0.1 MHC1 (120 min) in pH 6.8 buffer (15 min) in pH 6.8 buffer (60 min) stable 0.8 93.2 stable 0.5 93.0 stable 0.1 90.5

1PVC/PVDC foil (250 µm, 60 g/ ^m2 , orange), aluminum foil (20 µm).

Table 3

High dose mesalazine enteric tablet 1000 mg lot G0605B002 Primary packaging materials: PVC/PVDC aluminium, blister ¹ Researched parameters Hra time 0 neniya (month 6 shy) at 25' 9 ^e C/60% οτΗΐ 12 ositive 18 humidity 24 36 Mesalazine content (%) 98.5 101.6 97.0 100.6 99.6 100.4 98.2 The sum of the contents of leavening products (%) 0.07 0.13 0.21 0.05 0.22 0.06 0.15 Release of active ingredient at 37°C (%) in 0.1 MHC1 (120 min) in buffer at pH 6.8 (15 min) in buffer at pH 6.8 (60 min) stable a 3.2 92.3 stable a 2.9 91.4 stable a 2.9 95.2 stable a 4.1 96.9 stable a 3.8 96.3 stable a 2.3 95.4 stable a 3.7 92.5 Storage time (months) 0 at 40°C/75% relative Noah humidity 6 Mesalazine (%) 98.5 96.2 102.4 The sum of the contents of leavening products (%) 0.07 0.06 0.07 Release of active ingredient at 37°C (%) in 0.1 MHC1 (120 min) in pH 6.8 buffer (15 min) in pH 6.8 buffer (60 min) stable 3.2 92.3 stable 2.6 99.5 stable 1.3 93.7

1-1-GT-» -X t /1-GT^ TTL T 1 S T\ ! 2\1X

PVC/PVDC foil (250 µm, 60 g/m2, orange), aluminum foil (20 µm).

Example 5 Clinical Study Data.

The results of the clinical study are given in table. 4.

- 10 041224

Table 4

Analysis Method Number (%) of patients in clinical remission at the V4-LOCF stage Difference ³ 95% FDI ^b Confidence Level ^{3 p} value M1000 М2х500 N P % N P % Interim analysis of PP I ^e 103 48 46.6 114 44 38.6 8.0% [-9.6%, 25.2%] 0.0043 0.0003 Interim analysis of PNA I 115 53 46.1 123 46 37.4 8.7% [-8.1%, 25.0%] 0.0043 <0.0001 PP final ⁷ 134 64 47.8 144 61 42.4 5.4% [-10.2%, 20.8%] 0.0043 0.0003 PNA final ⁷ 151 68 45.0 155 65 41.9 3.1% [-11.7%, 17.8%] 0.0043 0.0006

^a content difference (πμιοοο - Pm2*5oo);

^b repeated 95% confidence interval (CLI);

c _ ____ ^and __ one-sided local confidence level;

^d criterion H0 (π _Μ1000 - π _Μ2 χ ₅₀₀ <-0.15) using inverted normal research statistics;

^e primary analysis.

Methods of analysis of PN/PNA based on 68 excluded patients who participated in the interim analysis I

In table. Table 4 describes the per-protocol analysis (PP) and full set analyzes (FNA) where the PP patients participated in the per-protocol study and the PNA group included all 306 patients that were included in this study.

Example 6 Biodissolution study of a high dose tablet of the present invention.

In order to objectively evaluate dissolution deviations, which are necessarily observed in individual patients, a so-called in vitro biological dissolution study was carried out.

To prove the equivalence of the release profiles of the active ingredient from mesalazine enteric tablet with a high dose of active substance 1000 mg and enteric tablets Salofalk 500 mg under biologically relevant study conditions, the following study was carried out:

The use of an immersion cylinder apparatus (apparatus 3, corresponding to chapter 2.9.3 of the European Pharmacopoeia) makes it possible to compare the delayed release of mesalazine from the high-dose tablet of the present invention, as well as from Salofalk 500 mg enteric tablets under biologically relevant conditions. In this case, one dose of each tablet is placed in a cylinder which is covered at the top and bottom with wire mesh to hold the dosage form. Said glass cylinder moves up and down in a dissolution vessel with a volume of approximately 325 ml. Unlike a standard apparatus for active ingredient release testing, a wide range of test media can be tested with this system. The glass cylinder is moved vertically for about 10 cm in a dissolution vessel containing 200 ml of assay medium. In this case, the frequency of movements is 10 movements with immersion per minute (DPM). The advantage of this system is that by repeatedly changing the media in the dissolution vessel, the tablets are exposed to different test fluids and thus the passage through the gastrointestinal tract can be simulated.

The 1000 mg high dose tablets of the present invention and Salofalk 500 mg enteric tablets from commercially available production lots were used for the studies. A total of five study media were used to compare both tablet forms, which in particular mimic the pH values in specific sections of the gastrointestinal tract in the fasting state. The residence times in the individual media, combined with the stirring movements, correspond to conditions under which the dosage forms are also subjected to in vivo treatments. The results of the studies clearly show that the release of the active ingredient mesalazine from the high dose tablet of the present invention and from the Salofalk 500 mg enteric tablets equally occurs only under the conditions present in the distal ileum. In this case, the active ingredient is completely released from the tablets and is available for local action. This means that the active ingredient is transferred by the formulation to the desired target site. Below is a detailed description of the studies:

a) Study Design:

mesalazine high dose enteric tablet 1000 mg, batch 1501215501;

enteric tablets Salofalk 500 mg, batch 1601218801.

b) Parameters of the active ingredient release study:

-

Claims (9)

apparatus for the study of release - apparatus with an immersion cylinder (apparatus 3, corresponding to chapter 2.9.3 of the European Pharmacopoeia); hole size - 840 microns; the volume of each vessel for dissolution - 200 ml; temperature - 37.0±0.5°C; movements with immersion - 10 movements with immersion per minute (DPM); the number of samples used during the study, and the party: N=6; research environments and extraction and research times, respectively: Gastrointestinal tract pH value Study medium Time of withdrawal and study (min) stomach 1.2 0.1 MHC1 60 proximal jejunum 6.5 phosphate buffer (Ph. Eur. 5.17.1) 15 distal jejunum 6.8 artificial colon pepsin-free juice (SIF _sp ) (Ph. Eur. 5.17.1) 15 proximal ileum 7.2 phosphate buffer (Ph. Eur. 5.17.1) 30 distal ileum 7.5 pepsin-free artificial intestinal juice (SIF _sp ) (Ph. Eur. 5.17.1) 5, 10, 20, 30, 40, 50, 60, 90, 120 colon not examined Calculated osmolality ~ 0.5 osmol/l s). Determination of mesalazine content: Determination of the content of mesalazine released into the test medium was carried out using high performance liquid chromatography with UV/VIS (UV/Visible) detection (HPLC/UV). The detection wavelength was 220 nm. d) Results. In FIG. 2 shows the release profiles for both batches tested. CLAIM 1. An oral high dose enteric tablet containing as active substance 1000 mg of mesalazine or a pharmaceutically acceptable salt thereof and at least one excipient which does not contain matrix-forming compounds which include the active substance mesalazine in a framework, thus delaying release of the active substance of mesalazine, where the weight of the tablet with a high dose of active substance is not more than 35% more than the weight of the active substance, where the tablet has a fracture resistance of more than 160 N, where the release profile in the study of the biological dissolution of mesalazine essentially corresponds to the profile release of two tablets, each containing half the amount of mesalazine in the high dose tablet, and where the high dose tablet contains a protective coating and two film coating layers containing enteric polymers, the content of which is less than 10 wt.% in terms of per full weight of the high dose tablet. 2. The high dose oral enteric tablet according to claim 1, wherein the content of at least one excipient is not more than 30% by weight based on the total weight of the high dose tablet. 3. An oral high dose enteric tablet according to claim 1, characterized in that it contains 50 to 100 mg of povidone (polyvinylpyrrolidone). 4. The high dose oral enteric tablet according to claim 1, wherein the tablet has an oblong shape with parallel longitudinal sides and rounded narrow sides and biconvex curved surfaces and is free from notches or grooves for breaking. 5. Use of the high dose oral enteric tablet according to claim 1 for the treatment of chronic inflammatory bowel diseases. 6. Use of the high dose oral enteric tablet according to claim 5 for the treatment of ulcerative colitis. 7. Use of the high dose oral enteric tablet according to claim 6 for the treatment of ulcerative colitis in remission. 8. Use of the high dose oral enteric tablet according to claim 5 for the treatment of chronic inflammatory bowel disease, wherein three high dose tablets are administered per day. 9. The use of an oral enteric tablet with a high dose of the active substance according to -