TW201306843A - Oral pharmaceutical tablet for controlled release of mesalazine and process for obtaining it - Google Patents

Abstract

The invention provides an oral pharmaceutical tablet for controlled release of mesalazine or a pharmaceutically acceptable salt thereof as active ingredient with a core and a gastro-resistant outer coating, wherein the core comprises mesalazine and a hydrophilic matrix consisting of a mixture of hydroxypropylmethyl cellulose (HPMC) having a different viscosity and the gastro-resistant outer coating comprises a pH-dependent release polymer, with the pharmaceutically acceptable excipients. The invention also refers to the process for obtaining said oral pharmaceutical tablet and to said oral pharmaceutical tablet of controlled release of mesalazine for treating ulcerative colitis.

Description

Oral pharmaceutical lozenge for controlling the release of Mesala and its obtaining method

The present invention relates to a beauty salad for use as an active ingredient (mesalazine), also known as mesalamine or 5-aminosalicylic acid, a controlled release oral pharmaceutical lozenge.

The invention also relates to a method for obtaining the oral pharmaceutical lozenge and a beauty salad for treating ulcerative colitis Oral medical controlled release lozenges.

Inflammatory bowel disease (IBD) is a range of chronic self-inflammatory inflammatory bowel conditions. Inflammatory bowel disease causes significant gastrointestinal symptoms including diarrhea, abdominal pain, bleeding, anemia, and weight loss. Inflammatory bowel disease is also associated with a range of intestinal dysplasia, including arthritis, ankylosing spondylitis, sclerosing cholangitis, uveitis, iritis, gangrenous pyoderma, and nodular erythema.

Inflammatory bowel disease is divided into two subtypes: ulcerative colitis and Crohn's disease. Ulcerative colitis is characterized by inflamed mucosal inflammation of the colon, which begins at the anal ring and extends proximally to varying degrees (eg, proctitis, left colitis, or pan-colitis). Conversely, Crohn's disease is characterized by penetrating inflammation of any part of the gastrointestinal tract, but is most common in adjacent areas of the ileal ileal valve.

The first line of treatment for mild to moderate ulcerative colitis usually involves mesal (5-Aminosalicylic acid, or 5-ASA). Beauty salad It is an aminosalicylate (5-aminosalicylic acid) having anti-inflammatory properties. Beauty salad It is suitable for the induction of remission in patients with active mild to moderate ulcerative colitis. The chemical name is 5-amino-2-hydroxybenzoic acid and its structural formula is:

When given orally to Mesala At the time, a large amount of the drug is absorbed from the upper gastrointestinal tract, causing systemic side effects. Beauty salad The role of the machine is not fully understood, but it is clearly local.

So use the beauty salad Treatment of ulcerative colitis requires that the drug be specifically delivered to the colon. This particular delivery increases efficiency and allows for a reduction in the minimum effective dose. A variety of systems have been developed for colon-specific drug delivery. Casing systems are commonly used for colon drug delivery because of the pH difference between the small intestine and the colon.

There are several improved release of the beautiful salad Formulations are currently commercially used for the maintenance and treatment of mild to moderate acute exacerbations of ulcerative colitis.

Beauty salad The development of effective modified release compositions is hampered by the fact that compositions of this type generally contain higher concentrations of active ingredients than immediate release compositions containing the same active ingredients. Another problem common to the use of conventional maintenance release dosage forms is the inability to increase the residence time of the absorption window.

Patent application WO 03/011205-A discloses that the controlled release caplet of nifedipine comprises a matrix consisting of a mixture of 1:1 HPMC K15M and HPMC K100M having a viscosity of 13,275-24,780 mPa, respectively. s and 75,000-140000 mPa. s (reference table 1) Providing that the active ingredient is released from the zero-stage release of the active ingredient from the time of administration. Five hours after administration, 50% of the active ingredient was released. The active ingredient was completely released from the formulation 10 hours after administration.

Patent application WO 00/76481-A discloses a beauty salad containing as an active ingredient Controlled release lozenge comprising an internal lipophilic matrix having a melting point below 90 ° C, such as carnauba wax, wherein the active ingredient is spherical in the internal system, and an external hydrophilic matrix such as hydroxypropyl methylcellulose . The resulting lozenge is then coated with a polymethacrylate capsule to provide colonic delivery of the active ingredient.

WO 00/76481-A discloses the preparation of tablets by melt granulating the active ingredient with a lipophilic substance to obtain granules and then mixing the hydrophilic excipient as a hydrophilic matrix and subsequent tableting or compression. The resulting tablet is then coated with a polymethacrylate envelope to obtain colonic delivery of the active ingredient.

However, in order to achieve controlled release or sustained release of the low melting lipophilic material of the active ingredient, blending HPMC can produce different results. Several of these systems have shown that long-term release of the drug is not available, especially when the lipophilic substance is at a high concentration ( 10% w/w) when used. In addition, melt granulation techniques are expensive, time consuming and require special equipment. Melt granulation involves partial or complete melting of the lipid excipient, followed by mixing of the active ingredient with other excipients, and quenching the mixture into granules by quenching or freezing. In this treatment procedure, the active ingredient is heated, so if the temperature is not carefully controlled, the active ingredient may partially decompose. In addition, subsequent cooling may initiate phase changes by solid state or melt machine rotation, which may result in undesired changes in the release of active ingredients.

The present invention provides another oral pharmaceutical lozenge that avoids the disadvantages of the aforementioned formulations.

The authors of the present invention have discovered that a robust matrix system is provided by combining HPMCs of different viscosity grades to achieve desired release characteristics.

Unexpectedly, it was found to have a weight ratio of 10:1 to 1:10 of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. A hydrophilic matrix composed of a mixture of viscosity hydroxypropyl methylcellulose (HPMC) overcomes the shortcomings of prior art formulations.

Excellently, using the novel beauty salad as an active ingredient for controlled release An oral pharmaceutical lozenge that avoids the release of the original active ingredient from the matrix and achieves the beauty salad as an active ingredient. The desired colon release profile.

The present invention also provides an oral pharmaceutical lozenge designed for use as a continuous or controlled release lozenge as an active ingredient. The method.

At least another object of the present invention relates to the use of the oral pharmaceutical lozenge for the treatment of ulcerative colitis.

The present invention provides a beauty salad as an active ingredient Or a controlled release oral pharmaceutical lozenge of a pharmaceutically acceptable salt thereof, wherein the lozenge comprises a core and a gastric acid resistant outer coating.

As used here, "Mesara Controlled release" means immediate release formula, Mesal The release is modified (or sustained) by a long-term dosage form.

According to the invention, the beauty salad It may be either crystalline or amorphous.

Thus, the present invention provides a beauty salad for controlling release as an active ingredient Or a pharmaceutically acceptable salt thereof comprising a core and a gastric acid resistant outer coating, characterized in that the core comprises: i) 40% to 90% by weight of the total salad weight based on the total weight of the tablet Preferably, it is 50% to 90%, more preferably 60% to 80%; and ii) the hydrophilic group system is made up of a weight ratio of 10:1 to 1:10, preferably 1:1 by weight. It has less than 200 mPa in 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. s viscous hydroxypropyl methylcellulose (HPMC), based on the total weight of the tablet, the hydrophilic matrix is present in an amount from 1% up to 20%, preferably from 1% to 15%, more preferably 2 % to 10%, and further preferably 3% to 5% by weight; and the gastric acid-resistant outer coating comprises: iii) the pH-dependent release polymer is present in an amount from 15% to 75% of the outer coating of the tablet % by weight, wherein the outer cover layer is present in an amount of from 5% to 25%, preferably from 10% to 20%, based on the total weight of the tablet.

Unexpectedly, two viscosity grade HPMC polymers having such ratios provide a hydrophilic matrix with improved physical properties that exhibit similar dissolution at different agitation speeds.

Suitable HPMC polymers include those sold under the trade name METHOCEL ^® (Dow Chemical Corporation) or the trade name METOLOSE ^® (Shin-Etsu). See Table 1 for the polymer chemistry and viscosity of different families of HPMC. The number after the respective letter indicates the viscosity of the 2 wt% aqueous solution at 25 °C.

In a preferred embodiment, the hydrophilic basis system has a viscosity of 80-120 mPa. 2% aqueous solution of s (Messo K100 advanced LV) and viscosity 2663-4970 mPa. A 2% aqueous solution of s (Messo K4M Advanced) consisted of a 1:1 weight ratio mixture.

Formulated lozenges can be one or more pH dependent release polymer packs clothes.

As used herein, the term "pH-dependent release polymer" is also termed a casing polymer, meaning that the polymer is insoluble in the highly acidic pH of the stomach but rapidly dissolves in a less acidic (relatively more basic) pH. The pH dependent release polymer according to the present invention does not dissolve in the stomach of acidic gastric acid (pH about 3), but does dissolve in the higher pH environment present in the small intestine such as pH above 5.5 or colon pH above 7.0.

pH-dependent release polymer is selected to make the salad The dosage form is released at the inlet time between the small intestine and the colon, or subsequently released inside the colon. The release is based on the pH of the small intestine and colon. The pH of the small intestine is slowly increased from about 5 to 5.5 in the duodenal bulb to about 7.2 in the small distal part (ileum). The pH at the ileal cecal junction drops significantly to about 6.3 and rises very slowly to about 7 in the left or descending colon.

The authors found that the use of a high viscosity grade of HPMC as a matrix former allows the core to swell as it absorbs gastric juice, gradually eroding over several hours due to increased gel strength. The addition of a low viscosity grade HPMC avoids the initial burst release of the active ingredient from the matrix, thus allowing consistent dissolution. The dissolution process begins simultaneously with the swelling process when the surface of the dosage form contacts the gastric juice. The dissolution reflects the dissolution of the polymer beyond the formation of the gel-solution interface where the polymer becomes sufficiently diluted and the active ingredient can be transported away from the dosage form by diffusion or convection.

The hydrophilic matrix according to the present invention provides the desired colonic release profile, providing sustained release of the active ingredient within the desired absorption window.

Using the oral release lozenge of the present invention to achieve a beauty salad The desired pharmacological activity is obtained in the large intestine in the large intestine with a significant delay in comparing the oral administration time. The oral pharmaceutical lozenges of the present invention provide a suitable colonic release profile in view of the route of the lozenge from oral to the large intestine.

Preferably, the pH dependent release polymer is maintained in a low pH environment in the stomach and small intestine, but the aqueous solution at a pH above 6.3, preferably 6.8 to 7.2, begins to dissolve. Preferably the enteric polymer is selected from poly (methacrylic acid, methyl methacrylate) 1: 2 (preferably Raj (Eudragit ^®) S), and poly (methacrylic acid, methyl methacrylate) 1: 1 (Yuraji L), and poly(methacrylic acid, methyl methacrylate) 1:2 (Yuraji S) from about 1:10 to about 1:1, preferably from about 1:5 to about 1. A mixture of ratios of 3 . It is especially good for yuraji S and yuraji L or a mixture thereof. Tejia is a mixture of yuraji S and yuraji L 1:10 to 10:1.

In a preferred embodiment, the pH-dependent release polymer is present in an amount from 15% to 75% by weight of the outer cover of the tablet.

Preferably, the outer cover layer is present in an amount of from 5% to 25%, preferably from 10% to 20%, based on the total weight of the tablet formulation.

Optionally, the core further comprises a filler, a binding agent, an anti-adherent, a lubricant and a disintegrating agent as pharmaceutically acceptable excipients. Optionally, the outer cover layer of the tablet further comprises an anti-adherent, a plasticizer and a coloring agent as pharmaceutically acceptable excipients.

Preferably, the tablet of the present invention comprises a filler. Materials commonly used as fillers include, but are not limited to, glucose, lactose, lactose monohydrate, fructose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, powdered cellulose, cellulose deuterated, sorbitol , sucrose and talc, or a mixture thereof. A preferred filler is microcrystalline cellulose. The filler may comprise from 0.5% to 10% by weight, preferably from 0.5% to 8% by weight, based on the total weight of the tablet. And preferably in the amount of 1% to 5% by weight.

Preferably, the tablet of the present invention comprises a binding agent or a linker. Materials commonly used as a linker include, but are not limited to, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, Calcium methylcellulose calcium, carboxymethylcellulose calcium and/or mixtures thereof. A preferred binder is polyvinylpyrrolidone. The linker may be present in an amount from 0.1% to 10% by weight, preferably from 0.5% to 9% by weight, and more preferably from 1% to 7.5% by weight, based on the total weight of the tablet.

Preferably, the tablet formulation according to the present invention comprises an anti-adherent agent to the core. The outer cover layer may also include an anti-adhesion agent to eliminate sticking between the coating process.

Materials commonly used as anti-adherents include, but are not limited to, colloidal ceria and talc, preferably colloidal ceria (aerosol) when used in a core and talc when used as an outer cover.

Based on the total weight of the tablet, the anti-adhesive agent is present in the core at a weight ratio of 0.1% to 5% by weight, preferably 0.1% to 3.5% by weight, more preferably 0.1% to 1.5% by weight; The total weight of the layer is present in the amount of up to 30% by weight, preferably from 5% to 30% by weight.

Preferably, the tablet formulation in accordance with the present invention optionally includes a lubricant. Materials commonly used as lubricants include, but are not limited to, stearic acid, and stearates such as magnesium stearate. A preferred lubricant is magnesium stearate. The tablet may be present in an amount of from 0.1% to 5% by weight, preferably from 0.1% to 3% by weight, based on the total weight of the tablet.

Preferably, the tablet formulation according to the invention optionally comprises a collapse Agent. Materials commonly used as disintegrating agents include, but are not limited to, starch, pregelatinized starch, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, cross-linked crospovidone, cross-linked methylcellulose sodium And / or a mixture thereof. Preferably, the disintegrating agent is a pregelatinized starch.

The disintegrating agent is present in the core of the tablet in a weight ratio of from 1% to 10% by weight, preferably from 1% to 8% by weight, more preferably from 2.5% to 7.5% by weight, based on the total weight of the tablet.

Preferably, the outer cover layer selectively comprises a plasticizer to provide a homogeneous film mixture. Preferred plasticizers include triethyl citrate, polyethylene glycol, or dibutyl phthalate, preferably triethyl citrate. The plasticizer may be present in an amount of up to 20%, preferably from 5% to 20% by weight, based on the total weight of the outer cover.

Tablets of the invention comprise one or more pharmaceutically acceptable excipients. All such excipients must be "pharmaceutically acceptable" to indicate compatibility with other ingredients of the pharmaceutical composition and will not harm the patient. Pharmaceutically acceptable excipients may contain coloring agents, flavoring agents such as menthol, sweetening agents such as mannitol, preservatives, stabilizers, antioxidants, and any other excipient known to those skilled in the art.

In a preferred embodiment, the pharmaceutical lozenge according to the present invention comprises a core comprising 40% to 90% by weight of a beauty salad. 1% to 20% by weight of the 1:10 to 10:1 by weight ratio of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in 2% w/w aqueous solution. a mixture of s hydroxypropyl methylcellulose (HPMC), 0.5% to 10% microcrystalline cellulose, 0.1% to 10% by weight of polyvinylpyrrolidone and 1% to 10% by weight Pregelatinized starch; and a cover layer comprising a pH-dependent release polymer and one or more pharmaceutically acceptable excipients.

In a more preferred embodiment, the pharmaceutical lozenge according to the present invention comprises a core comprising 50% to 90% by weight of a beauty salad. 2% to 10% by weight of the 1:10 to 10:1 by weight ratio of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in 2% w/w aqueous solution. a mixture of s hydroxypropyl methylcellulose (HPMC), 0.5% to 8% microcrystalline cellulose, 0.5% to 9% by weight polyvinylpyrrolidone and 2% to 8% by weight Pregelatinized starch; and a cover layer comprising a pH-dependent release polymer and one or more pharmaceutically acceptable excipients.

In a more preferred embodiment, the pharmaceutical tablet according to the present invention comprises a core comprising 60% to 80% by weight of a beauty salad. 3% to 5% by weight of the 1:10 to 10:1 by weight ratio of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in 2% w/w aqueous solution. a mixture of s hydroxypropyl methylcellulose (HPMC), 1% to 5% microcrystalline cellulose, 1% to 7.5% by weight of polyvinylpyrrolidone and 2.5% to 7.5% by weight Pregelatinized starch; and a cover layer comprising a pH-dependent release polymer and one or more pharmaceutically acceptable excipients.

The second aspect of the invention provides a method of obtaining an oral pharmaceutical lozenge according to the first aspect of the invention, the method comprising the steps of: a) blending a beauty salad With less than 200 mPa due to 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. s hydroxypropylmethylcellulose (HPMC) is a hydrophilic matrix composed of a weight ratio of 10:1 to 1:10, and a blending disintegrating agent and a bonding agent are used to obtain a blended mixture. b) the mixed mixture obtained in step a) using water or when the binder is present in step a), granulating using the previously prepared aqueous solution of the linker; c) drying the granulate obtained in step b) d) if a lubricant is present, lubricating the dried granules and compressing to obtain a core; and e) preparing an aqueous dispersion comprising the pH dependent polymer and remaining pharmaceutically acceptable The outer cover is obtained by excipients, and coating the core, and the lozenge is thus obtained.

The method for coating the tablet may be any one known to those skilled in the art.

Excellently, in step b), preparing an aqueous solution of polyvinylpyrrolidone; in step c), drying is carried out in a fluid bed dryer; in step d), adding a lubricant to lubricate the dried particles and then, The blend is compressed to obtain a core; and in step e), an aqueous dispersion of an anti-adhesive agent and an alcohol solution of a pH-dependent polymer and a plasticizer is prepared for coating the core and then obtaining The outer cover.

In another aspect, the invention relates to a lozenge according to the invention for use in the treatment of ulcerative colitis.

The invention is illustrated in a sufficiently complete manner by the following examples.

Example

Example 1

Beauty salad HPMC Messo K4M Advanced, HPMC Messo K100 LV Advanced and pregelatinized starch were mixed and subsequently granulated with polyvinylpyrrolidone in pure aqueous solution (15%).

The granules are dried in a fluid bed dryer. The dried granules are passed through a suitable mesh screen. These particles are mixed with colloidal cerium oxide and microcrystalline cellulose and lubricated with magnesium stearate.

The final blend is then compressed into tablets.

The tablets were coated with a gastric acid resistant coating suspension (talc, yuraji S 100, yuraji L 100, and an alcoholic solution of triethyl citrate).

Examples 2 to 3

Using a procedure similar to that described in Example 1, the preparation of 1000 mg of melissa as shown in Table 1 was prepared. And tablets of unequal amount of HPMC mixture.

The composition of the tablet prepared according to Examples 2 and 3 is shown as follows:

Dissolution method

For all of the examples, the lozenge was tested on the USP Type II device. Solubility. Dissolution medium: 2 hours in hydrochloric acid, 1 hour at pH 6.4 and 9 hours at pH 7.2.

The dissolution profiles obtained for the formulations described in Examples 1 to 3 are disclosed in Figure 1.

Figure 1 shows the use of beauty salad The controlled release core is covered with an outer cover to obtain a different dissolution profile obtained prior to the tablet according to the invention. The symbol ■ is shown to have a weight ratio of 1% by weight based on the total weight of the 2% aqueous solution having less than 200 mPa. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. Hydrophilic hydroxypropyl methylcellulose (HPMC) consisting of a hydrophilic matrix lozenge with 1 gram of mesala The dissolution curve of the core (Example 2). The symbol ◆ is shown to have a total weight of 4.5% by weight due to a 2% aqueous solution having less than 200 mPa. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. Hydrophilic hydroxypropyl methylcellulose (HPMC) consisting of a hydrophilic matrix lozenge with 1 gram of mesala The dissolution curve of the core (Example 1). The symbol ▲ is shown to have a weight ratio of 20% by weight based on the total weight of the 2% aqueous solution having less than 200 mPa. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. Hydrophilic hydroxypropyl methylcellulose (HPMC) consisting of a hydrophilic matrix lozenge with 1 gram of mesala The dissolution curve of the core (Example 3).

Figure 2 shows the use of a beauty salad according to the present invention. The different dissolution profiles obtained by controlled release of the oral pharmaceutical lozenge include the core of Figure 1. The symbol definition is the same as in Fig. 1.

From the two figures, the core and the lozenge can be observed to maintain the beauty salad. The same dissolution curve. In addition, FIG. 1 verifies that the use of a hydrophilic matrix in the core of the tablet according to the present invention can produce a salad having a beauty The desired dissolution of the controlled release profile.

Claims (21)

a beauty salad for controlled release as an active ingredient Oral pharmaceutical lozenge of (mesalazine) or a pharmaceutically acceptable salt thereof, comprising a core and a gastric acid resistant outer coating, characterized in that the core comprises: i) 40% to 90% based on the total weight of the tablet Weight ratio beauty salad And ii) the hydrophilic basis system has a weight ratio of 10:1 to 1:10 of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. s viscous hydroxypropyl methylcellulose (HPMC), based on the total weight of the tablet, the hydrophilic matrix is present in an amount from 1% up to 20%; and the gastric acid resistant outer coating comprises: iii) pH The dependent release polymer is present in an amount from 5% to 25% based on the total weight of the tablet. For example, the oral pharmaceutical lozenge of claim 1 of the patent scope, which is based on the total weight of the lozenge, It is present in a weight ratio of 50% to 90%, preferably 60% to 80%. The oral pharmaceutical lozenge of claim 1, wherein the hydrophilic base system is from 1% to 15%, preferably from 2% to 10%, and more preferably from 3% to 5, based on the total weight of the tablet. % weight ratio exists. The oral pharmaceutical lozenge of claim 1, wherein the outer cover layer is present in a weight ratio of 10% to 20% based on the total weight of the tablet. The oral pharmaceutical lozenge of claim 1, wherein the hydrophilic base system has a weight ratio of 1:1 of less than 200 mPa in a 2% aqueous solution. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. s Viscosity of hydroxypropyl methylcellulose (HPMC). The oral pharmaceutical lozenge of claim 1, wherein the hydrophilic base system is from 1% to 15%, preferably from 2% to 10%, and more preferably from 3% to 5, based on the total weight of the tablet. % weight ratio exists. The oral pharmaceutical lozenge of claim 1, wherein the pH-dependent release polymer is present in an amount of from 15% to 75% by weight of the outer cover layer of the tablet. The oral pharmaceutical lozenge of claim 1, wherein the core further comprises a pharmaceutically acceptable excipient selected from the group consisting of a filler, a binding agent, an anti-adhesive agent, a lubricant, or a disintegrating agent. The oral pharmaceutical lozenge of claim 1, wherein the outer cover layer further comprises a pharmaceutically acceptable excipient selected from the group consisting of an anti-adherent, a plasticizer, or a colorant. The oral pharmaceutical lozenge of claim 8 wherein the filler is from 0.5% to 10%, preferably from 0.5% to 8%, and more preferably from 1% to 5%, based on the total weight of the tablet. The weight ratio exists. The oral pharmaceutical lozenge of claim 8 wherein the linker is from 0.1% to 10%, preferably from 0.5% to 9%, and more preferably from 1% to 7.5%, based on the total weight of the tablet. The weight ratio exists. For example, the oral pharmaceutical lozenges of claims 8 and 9 wherein the hydrophilic base system is 0.1% to 5%, preferably based on the total weight of the tablet. The ground is present in an amount of from 0.1% to 3.5%, and more preferably from 0.1% to 1.5% by weight, based on the total weight of the outer cover, and is present in an amount of up to 30%, preferably from 5% to 30% by weight. The oral pharmaceutical lozenge of claim 8, wherein the lubricant is present in a weight ratio of from 0.1% to 5%, preferably from 0.1% to 3%, based on the total weight of the tablet. The oral pharmaceutical lozenge of claim 8 wherein the disintegrating agent is from 1% to 10%, preferably from 1% to 8%, and more preferably from 2.5% to 7.5%, based on the total weight of the tablet. The weight ratio exists. The oral medicinal controlled release lozenge of claim 9 wherein the plasticizer is present in an amount of up to 20%, preferably from 5% to 20% by weight based on the total weight of the outer cover. A method of obtaining an oral pharmaceutical lozenge according to any one of claims 1 to 15, wherein the method is carried out by the following steps: a) blending a beauty salad And with a weight ratio of 1:10 to 10:1 in a 2% aqueous solution having less than 200 mPa. s hydroxypropyl methylcellulose (HPMC) with a viscosity of more than 200 mPa in a 2% aqueous solution. a hydrophilic matrix composed of s hydroxypropylmethylcellulose (HPMC), and a blending disintegrating agent and a binding agent, if present, to obtain a blended mixture; b) the resulting portion of step a) The blended mixture uses water or when the linker is present in step a), granulated using a previously prepared aqueous solution of the linker; c) dried in the granulate obtained in step b); d) lubricated if lubricant is present Drying the granules and compressing to obtain a core; and e) preparing an aqueous dispersion comprising the pH dependent polymer and the remaining pharmaceutically acceptable excipients, and coating the core The outer cover layer is obtained, and the tablet is obtained in this way. The method of claim 16, wherein in step b), an aqueous solution of polyvinylpyrrolidone is prepared. The method of claim 16, wherein in step c), the drying is carried out in a fluid bed dryer. The method of claim 16, wherein in step d), a lubricant is added to lubricate the dried particles and, subsequently, the blend is compressed to obtain a core. The method of claim 16, wherein in step e), an aqueous dispersion of an anti-adhesive agent and an alcohol solution of a pH-dependent polymer and a plasticizer is prepared for coating the core, and then obtained The outer cover. An oral pharmaceutical lozenge for treating ulcerative colitis, which is a beauty salad as claimed in any one of claims 1 to 15. Or a controlled release oral pharmaceutical lozenge or a pharmaceutically acceptable salt thereof.