A stable mesalazine colon-targeted release composition and preparation method thereof

Abstract

The present invention provides a stable mesalazine colon targeted release composition and a preparation method thereof. The mesalazine colon targeted release composition is composed of mesalazine tablets and enteric coating solution; the mesalazine tablets are composed of the following raw materials in parts by mass: 400 parts of mesalazine, 50-100 parts of fillers, 10-15 parts of binders, 20-25 parts of disintegrants, 2-8 parts of anti-adhesive agents, and 1-3 parts of lubricants; the enteric coating solution is composed of the following raw materials in parts by mass: 25-35 parts of Eudragit S100, 6-14 parts of triethanolamine, 1-5 parts of plasticizers, 2-8 parts of anti-adhesive agents, 1-6 parts of pigments, and 450-500 parts of organic solvents. The present invention significantly improves the stability of the mesalazine colon targeted release composition by adding Eudragit S100 and triethanolamine to the enteric coating solution of the mesalazine colon targeted release composition, and making the mass ratio of the two be (25-35): (6-14). The problem of enteric coating film rupture is solved, and the safety of medication is improved.

Description

Technical Field

[0001] The invention relates to a stable mesalazine colon-localized release composition and a preparation method thereof, belonging to the technical field of medicine. Background Art

[0002] Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease that affects the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and bloody stools. It mainly includes Crohn's disease (CD) and ulcerative colitis (UC). The etiology and pathogenesis of IBD have not yet been fully clarified. It is known that the inflammatory response caused by the abnormal response of the intestinal mucosal immune system plays an important role in the onset of IBD. It is generally believed that IBD is caused by the interaction of multiple factors, mainly including environmental, genetic, infectious and immune factors.

[0003] Colon-targeted preparations refer to preparations that are basically not released in the upper gastrointestinal tract, but are mostly or completely released in the colon, that is, they are not released or almost not released in a specified acidic medium and pH 6.8 phosphate buffer within a certain period of time, but are mostly or completely released in a pH 7.5-8.0 phosphate buffer within the required time. It is a synthetic coating material widely used in the market, including methacrylic acid copolymer and methacrylate copolymer, commonly known as acrylic resin in my country, and widely used in gastric coating, enteric coating, sustained-release coating, etc. of pharmaceutical preparations. Among them, Eudragit L and Eudragit S contain carboxyl groups and can dissolve in water by forming salts with alkalis. They are more commonly used enteric coating materials. Eudragit L dissolves in solutions with pH>6, and Eudragit S dissolves in solutions with pH>7. Eudragit S is often used in colon-targeted release preparations.

[0004] Mesalazine (5-ASA) is currently the drug of choice for the treatment of mild to moderate UC. It is the most widely used drug of its kind, with the most dosage forms, and is also the truly effective ingredient of this type of drug. Most of the drugs under development worldwide are biological drugs for moderate to severe UC, and the product has a definite efficacy and good safety. Since mesalazine was launched in 1987, as many as 9 dosage forms have been launched worldwide, among which enteric-coated tablets and suppositories are produced by many manufacturers, which is closely related to the characteristics of the disease. The principle is: after the enteric-coated mesalazine preparation coated with enteric materials such as Eudragit S reaches the colon, the coating dissolves and the drug is released in the colon where the pH is greater than 7, avoiding the release and absorption of ordinary preparations in the stomach or the front part of the intestine, greatly improving the efficacy of the drug.

[0005] Although colon-targeted release can ensure better drug efficacy, enteric coating often has multiple difficulties. Not only is the coating technically difficult, it is also very easy for the coating film to rupture before the drug reaches the colon. In addition, the stability of the coating film after coating is often poor and is easily affected by factors such as temperature and humidity, resulting in changes in the rupture time of the enteric coating, which in turn causes changes in drug release and affects drug efficacy. Therefore, there is an urgent need to develop a stable mesalazine colon-targeted release composition. Summary of the invention

[0006] In view of the deficiencies of the prior art, the present invention provides a stable mesalazine colon targeted release composition and a preparation method thereof. The mesalazine colon targeted release composition provided by the present invention solves the instability problem of mesalazine enteric coating film under high temperature and high humidity conditions, improves the clinical application safety of the drug, avoids the phenomenon of reduced efficacy or even ineffectiveness caused by abnormal coating film rupture time, and also provides a new reference for solving the problem of poor coating film stability of similar enteric products.

[0007] The technical solution of the present invention is as follows:

[0008] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0009] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 parts of mesalazine, 50-100 parts of fillers, 10-15 parts of binders, 20-25 parts of disintegrants, 2-8 parts of anti-adhesive agents, and 1-3 parts of lubricants;

[0010] The enteric coating solution is composed of the following raw materials in parts by mass: 25-35 parts of Eudragit S100, 6-14 parts of triethanolamine, 1-5 parts of plasticizer, 2-8 parts of anti-sticking agent, 1-6 parts of pigment, and 450-500 parts of organic solvent.

[0011] Preferably, according to the present invention, the mesalazine tablets are composed of the following raw materials in parts by weight: 400 parts of mesalazine, 75 parts of filler, 12.5 parts of binder, 23 parts of disintegrant, 5 parts of anti-adhesive agent, and 2 parts of lubricant;

[0012] The enteric coating solution is composed of the following raw materials in parts by mass: 29 parts of Eudragit S100, 10 parts of triethanolamine, 4 parts of plasticizer, 5 parts of anti-sticking agent, 4 parts of pigment, and 480 parts of organic solvent.

[0013] Preferably according to the present invention, the filler is any one of corn starch, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; preferably, the filler is lactose.

[0014] Preferably according to the present invention, the adhesive is any one of corn starch, povidone K30, povidone K90, dextrin, hydroxypropyl methylcellulose and hydroxypropyl cellulose; preferably, the adhesive is povidone K30.

[0015] Preferably according to the present invention, the disintegrant is any one or a combination of two of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose; preferably, the disintegrant is one or a combination of two of sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose.

[0016] Preferably according to the present invention, the anti-sticking agent is talc.

[0017] Preferably according to the present invention, the lubricant is any one of hard sodium fumarate, micro powder silica gel, magnesium stearate, talcum powder, calcium stearate or polyethylene glycol lubricants; preferably, the lubricant is magnesium stearate.

[0018] Preferably according to the present invention, the plasticizer is any one of dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, tributyl citrate, dibutyl phthalate, and dimethyl phthalate; preferably, the plasticizer is dibutyl sebacate.

[0019] Preferably according to the present invention, the pigment is red iron oxide, yellow iron oxide or a mixture of the two.

[0020] Preferably according to the present invention, the organic solvent is any one of isopropanol, ethanol, methanol, phenol, dichloromethane, chloroform, acetone, methyl glycol and n-butanol; preferably, the organic solvent is isopropanol.

[0021] The preparation method of the above-mentioned stable mesalazine colon targeted release composition comprises the following steps:

[0022] (1) dissolving a prescribed amount of adhesive in purified water to obtain an adhesive solution with a mass concentration of 5 to 10%;

[0023] (2) placing the prescribed amount of mesalazine and the filler in a wet mixing granulator and mixing them evenly, spraying the binder solution obtained in step (1) into the granulator by atomization to granulate the granules, and then drying the wet granules by a fluidized bed to obtain mesalazine granules;

[0024] (3) sieving the mesalazine granules obtained in step (2), adding a prescribed amount of a disintegrant to mix, then adding an anti-adhesive agent and a lubricant to mix, and tableting to obtain mesalazine tablets;

[0025] (4) Dissolving the prescribed amount of Eudragit S100 and triethanolamine in 1 / 2 of the prescribed amount of an organic solvent, stirring and mixing at 8000 to 13000 pm for 10 to 20 minutes to obtain a solution; dispersing the prescribed amount of a lubricant, a plasticizer and a pigment in 1 / 2 of the prescribed amount of an organic solvent to obtain a suspension; slowly adding the suspension to the solution, stirring for 1 to 2 hours, to obtain an enteric coating solution;

[0026] (5) coating the mesalazine tablets obtained in step (3) with the enteric coating solution obtained in step (4), and packaging to obtain a stable mesalazine colon-targeted release composition.

[0027] According to the preferred embodiment of the present invention, in step (2), the stirring speed of the wet granulator is 450-550 rpm, the chopping speed is 1200-1800 rpm, the atomization pressure is 0.1-0.2 Mpa, the peristaltic pump speed is 15-25 rpm, and the fluidized bed air volume is 20-40 m 3 / h, inlet air temperature 60±5℃.

[0028] Preferably, according to the present invention, in step (3), the tabletting is performed using a circular punch with a size of 5.5 mm and a hardness of 40 to 65N.

[0029] Preferably, according to the present invention, in step (5), the inlet air temperature of the coating is 35-45°C, the speed of the peristaltic pump is 10-15 rpm, the speed of the coating pan is 15-25 rpm, and the atomization pressure is 0.2-0.4 MPa.

[0030] The technical features of the present invention are as follows:

[0031] The inventor of the present application unexpectedly discovered that when triethanolamine is added to the conventional Eudragit S100 enteric coating solution and a certain ratio is formed, the stability of the enteric coating solution can be greatly increased. When the enteric coating solution is used to coat mesalazine tablets, a stable mesalazine colon-localized release composition is obtained. The combined application of triethanolamine and Eudragit S100 in the enteric coating has not appeared in previous domestic and foreign studies, and the applicant's experiment is also caused by a "wrong" experiment. The composition is characterized in that it not only solves the problem of enteric coating film rupture formed by the enteric coating solution in pH 6.5 and pH 6.8 media of mesalazine enteric preparations. Moreover, when the high temperature and high humidity influencing factor test is carried out, the enteric coating film does not show the phenomenon of significantly prolonged or shortened rupture time, and under the accelerated (40℃±2℃, relative humidity 75%±5%RH) 6-month conditions, the film rupture time is stable, consistent with 0 days, and the stable release of the drug is achieved.

[0032] The specific principle is inferred as follows: triethanolamine replaces three Hs in NH3 with three ethanol groups. The extension of the substituent is similar to forming a "three-claw" structure, which grabs Eudragit S100 and greatly improves its stability. It not only shows stronger stability under acidic conditions, but also avoids the reinforcement of the enteric coating film structure by high temperature, and avoids the phenomenon of prolonged film rupture time under alkaline conditions. Moreover, after the stability is improved, the penetration of water molecules under high humidity conditions into the enteric coating film is slowed down, making the improved enteric coating film have better high humidity stability. The enteric coating film prepared by the combination of triethanolamine and Eudragit S100 is the first discovery.

[0033] The beneficial effects of the present invention are:

[0034] 1. The present invention significantly improves the stability of the mesalazine colon targeted release composition by adding Eudragit S100 and triethanolamine to the enteric coating solution of the mesalazine colon targeted release composition, and making the mass ratio of the two be (25-35): (6-14). The prepared mesalazine colon targeted release composition effectively solves the problem of occasional rupture of the enteric coating film in pH 6.5 and pH 6.8 media, ensures the clinical efficacy of the drug, avoids the problem of reduced clinical efficacy or clinical ineffectiveness, and improves the safety of medication.

[0035] 2. The mesalazine colon targeted release composition provided by the present invention has excellent acid resistance. When the high temperature and high humidity influence factor test is carried out, the enteric coating film does not show the phenomenon of significantly prolonged or shortened rupture time, and under the accelerated condition (40℃±2℃, relative humidity 75%±5%RH) for 6 months, the enteric coating film rupture time is stable and consistent with 0 days, achieving stable release of the drug. It avoids the phenomenon of reduced efficacy or even ineffectiveness caused by abnormal film rupture time during use, and also provides a new reference for solving the problem of poor film stability of similar enteric products.

[0036] 3. The present invention also provides a method for preparing a mesalazine colon targeted release composition, which has few steps, simple operation and is suitable for industrial production. DETAILED DESCRIPTION

[0037] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0038] The raw materials used in the examples are all conventional raw materials, and the equipment used are all conventional equipment, which can be purchased commercially.

[0039] Example 1

[0040] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0041] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0042] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 6g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0043] The preparation method of the above-mentioned mesalazine colon targeted release composition comprises the following steps:

[0044] (1) dissolving the prescribed amount of povidone K30 in 154 mL of purified water to obtain an adhesive solution with a mass concentration of 7.5%;

[0045] (2) placing the prescribed amount of mesalazine and lactose in a wet mixing granulator and mixing them uniformly, spraying the binder solution obtained in step (1) into the granulator by atomization to granulate the granules, and then drying the wet granules by a fluidized bed to obtain mesalazine granules;

[0046] The stirring speed of the wet granulator is 500 rpm, the chopping speed is 1500 rpm, the atomization pressure is 0.15 MPa, the peristaltic pump speed is 15-25 rpm, and the fluidized bed air volume is 30 m 3 / h, the inlet air temperature is 60℃;

[0047] (3) after the mesalazine granules obtained in step (2) are sieved through a 30-mesh sieve, a prescribed amount of sodium carboxymethyl starch is added and mixed, talcum powder and magnesium stearate are added and mixed, and tableting is performed using a circular punch with a size of 5.5 mm (hardness 50N) to obtain mesalazine tablets;

[0048] (4) Dissolve the prescribed amount of Eudragit S100 and triethanolamine in 1 / 2 of the prescribed amount of organic solvent, stir and mix at 10000 pm for 15 min to obtain a solution; disperse the prescribed amount of talc, dibutyl sebacate, red iron oxide and yellow iron oxide in 1 / 2 of the prescribed amount of organic solvent to obtain a suspension; slowly add the suspension to the solution, stir for 1.5 h, and obtain an enteric coating solution;

[0049] (5) coating the mesalazine tablets obtained in step (3) with the enteric coating solution obtained in step (4), placing 4 tablets of the obtained coated tablets into a No. 00 capsule, and packaging them in high-density polyethylene bottles, 30 capsules / bottle, to obtain a stable mesalazine colon-targeted release composition;

[0050] Among them, the inlet air temperature of the coating is 40°C, the peristaltic pump speed is 12rpm, the coating pot speed is 20rpm, and the atomization pressure is 0.3Mpa.

[0051] Example 2

[0052] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0053] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0054] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 8g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0055] The preparation method of the mesalazine colon targeted release composition in this example is the same as that in Example 1.

[0056] Example 3

[0057] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0058] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0059] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 10g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0060] The preparation method of the mesalazine colon targeted release composition in this example is the same as that in Example 1.

[0061] Example 4

[0062] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0063] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0064] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 12g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0065] The preparation method of the mesalazine colon targeted release composition in this example is the same as that in Example 1.

[0066] Example 5

[0067] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0068] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0069] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 14g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0070] The preparation method of the mesalazine colon targeted release composition in this example is the same as that in Example 1.

[0071] Comparative Example 1

[0072] A mesalazine colon-localized release composition, comprising mesalazine tablets and enteric coating solution;

[0073] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0074] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 4g of dibutyl sebacate, 5g of talcum powder, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropyl alcohol.

[0075] The preparation method of the mesalazine colon targeted release composition of this comparative example is the same as that of Example 1.

[0076] Comparative Example 2

[0077] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0078] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0079] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 4g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0080] The preparation method of the mesalazine colon targeted release composition of this comparative example is the same as that of Example 1.

[0081] Comparative Example 3

[0082] A stable mesalazine colon-targeted release composition, comprising mesalazine tablets and enteric coating solution;

[0083] The mesalazine tablets are composed of the following raw materials in parts by weight: 400 g mesalazine, 75 g lactose, 12.5 g povidone K30, 23 g sodium carboxymethyl starch, 5 g talc, and 2 g magnesium stearate;

[0084] The enteric coating solution is composed of the following raw materials in parts by mass: 29g of Eudragit S100, 16g of triethanolamine, 4g of dibutyl sebacate, 5g of talc, 3g of red iron oxide, 1g of yellow iron oxide, and 480g of isopropanol.

[0085] The preparation method of the mesalazine colon targeted release composition of this comparative example is the same as that of Example 1.

[0086] Test example

[0087] According to the prescription compositions of Examples 1 to 5 and Comparative Examples 1 to 3, 1000 tablets of each mesalazine colon targeted release composition sample of Examples 1 to 5 and Comparative Examples 1 to 3 were prepared, and then the samples were subjected to dissolution test, acid resistance test and stability test.

[0088] 1. Dissolution test: According to the "Guidelines for Sustained-Release, Controlled-Release and Delayed-Release Preparations" in the appendix of the 2020 edition (Part IV) of the Pharmacopoeia of the People's Republic of China, mesalazine enteric-coated capsules (specification 400 mg, manufacturer: ABBVIE) were used as the control drug, and pH 7.5 phosphate buffer was used as the release medium. The paddle method was used for 50 revolutions to conduct a comparative study on the release rate. The high performance liquid chromatography method was used to determine and calculate the cumulative percentage of drug release. The similarity factor method in the non-model-dependent method was used to compare the similarity factor f2 (f2 ≥ 50) with the control drug. The time points involved in the calculation of the similarity factor were 15 min, 20 min, 30 min, and 60 min. The measurement results are shown in Table 1.

[0089] Table 1. Drug release of Examples 1 to 5 and Comparative Examples 1 to 3 in pH 7.5 phosphate buffer

[0090]

[0091] As shown in Table 1, in the mesalazine colon targeted release compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3, the ratio of Eudragit S100 to triethanolamine is in the range of 29:(0-16), and in a pH 7.5 buffered salt medium, the similarity factor method in the non-model-dependent method is used to compare similarity with the control drug, and f2 is greater than 50. However, when the ratio of Eudragit S100 to the stabilizer reaches 29:16, the enteric coating film rupture time will be prolonged. This shows that the addition of triethanolamine, a coating stabilizer, within a certain ratio range does not affect the 0-day release behavior of the drug, and can ensure a drug release effect similar to that of the original preparation, thereby ensuring the clinical consistency of the drug.

[0092] 2. Acid resistance test: With reference to the "Guidelines for Sustained-Release, Controlled-Release and Delayed-Release Preparations" in the appendix of the 2020 edition (Part IV) of the Pharmacopoeia of the People's Republic of China and the Review file information of mesalazine enteric-coated tablets and mesalazine enteric-coated capsules published by the FDA, the control drug, Examples 1-5 and Comparative Examples 1-3 were subjected to the following acid resistance experiments: ①: Using 500 mL of 0.1 N hydrochloric acid as the release medium, the paddle method was used for 120 minutes for a release test at 100 revolutions, and no drug release was required; ②: Using 900 mL of pH 4.5 acetate buffer as the release medium, the paddle method was used for 50 revolutions for a release test for 150 minutes, and no drug release was required; ③: Using 900 mL of pH 6.5 phosphate buffer as the release medium, the paddle method was used for 50 revolutions for a release test for 150 minutes, and no drug release or almost no drug release was required. ④: Using 900 mL of pH 6.8 phosphate buffer as the release medium, the release was investigated by paddle method at 50 revolutions for 150 minutes, requiring no or almost no release of the drug; the test results are shown in Tables 2 to 5.

[0093] Table 2. Drug release of Examples 1 to 5 and Comparative Examples 1 to 3 in 0.1N hydrochloric acid

[0094]

[0095] Table 3 Drug release of Examples 1 to 5 and Comparative Examples 1 to 3 in pH 4.5 acetate buffer

[0096]

[0097] Table 4 Drug release of Examples 1 to 5 and Comparative Examples 1 to 3 in pH 6.5 phosphate buffer

[0098]

[0099] Table 5. Drug release of Examples 1 to 5 and Comparative Examples 1 to 3 in pH 6.8 phosphate buffer

[0100]

[0101]

[0102] It can be seen from Tables 2 to 5 that, compared with the control drug, after adding triethanolamine, the acid resistance of the enteric coating film formed by the enteric coating solution can be significantly improved, ensuring that the drug is not released in 0.1N hydrochloric acid, pH 4.5 medium, pH 6.5 medium and pH 6.8 medium, providing a higher guarantee for the colon-localized release of mesalazine. Compared with the control drug, the efficacy of the drug can be guaranteed, the purpose of the invention is achieved, and a drug option with "excellent acid resistance, precise positioning, and better efficacy" is provided for clinical use.

[0103] 3. Stability experiment: According to the “Guidelines for Stability Tests of Raw Materials and Preparations” in the appendix of the 2020 edition (Part IV) of the Pharmacopoeia of the People's Republic of China, the control drug, Examples 1 to 5 and Comparative Examples 1 to 3 were tested for influencing factors for 30 days (① high temperature 60°C condition; ② relative humidity 92.5% condition; ③ light 5000 lux condition), and a 6-month accelerated test (40°C ± 2°C, relative humidity 75% ± 5%) was performed. After sampling at the corresponding time nodes, the coating rupture time of the drug in pH 7.5 phosphate buffer at 0 days was compared; the measurement results are shown in Tables 6 to 7.

[0104] Table 6. Film rupture time under test conditions of Examples 1 to 5 and Comparative Examples 1 to 3 (30-day influencing factor test)

[0105]

[0106] Table 7. Film rupture time under test conditions of Examples 1 to 5 and Comparative Examples 1 to 3 (accelerated test)

[0107]

[0108] As shown in Tables 6 to 7, when no or only a small amount of triethanolamine is added to the control drug, Comparative Example 1 and Comparative Example 2, the enteric coating film formed is extremely sensitive to high temperature and high humidity conditions. The increase in temperature or the increase in humidity will significantly change the stability of the enteric coating film, and this change will cause the drug efficacy to be exerted. After adding an appropriate proportion of triethanolamine in Examples 1 to 5, the "three-claw" structure grasps the "high temperature resistance and high humidity resistance" properties of the enteric coating film, which is better and better, significantly improving the stability of the enteric coating film and ensuring the safety of clinical medication. However, after the triethanolamine ratio in Comparative Example 3 continues to increase, although the stability of the enteric coating film is also good, it can be seen from Table 1 that the release behavior of the drug is reduced compared with the control drug with existing clinical data. In summary, the comparative example cannot achieve excellent stability of the enteric coating film while obtaining a release behavior consistent with the control drug.

[0109] In summary, the mesalazine colon targeted release composition provided by the present invention adopts Eudragit S100 and triethanolamine used for extraordinary purposes, and by adjusting the dosage of the two per 1,000 tablets to 29g:6g-14g, the stability of the coating film can be significantly improved, and the purpose of better acid resistance and better high temperature and humidity resistance is achieved, a new and stable mesalazine colon targeted release composition is provided, and the purpose of the invention is achieved.

Claims

1. A stable mesalazine colon targeted release composition, characterized in that: It consists of mesalazine tablets and enteric coating solution; The mesalazine tablets are composed of the following raw materials in parts by weight: 400 parts of mesalazine, 50-100 parts of fillers, 10-15 parts of binders, 20-25 parts of disintegrants, 2-8 parts of anti-adhesive agents, and 1-3 parts of lubricants; The enteric coating solution is composed of the following raw materials in parts by mass: 29 parts of Eudragit S100, 8-14 parts of triethanolamine, 1-5 parts of plasticizer, 2-8 parts of anti-adhesive agent, 1-6 parts of pigment, and 450-500 parts of organic solvent.

2. The mesalazine colon targeted release composition according to claim 1, characterized in that: The mesalazine tablets are composed of the following raw materials in parts by weight: 400 parts of mesalazine, 75 parts of filler, 12.5 parts of binder, 23 parts of disintegrant, 5 parts of anti-adhesive agent, and 2 parts of lubricant; The enteric coating solution is composed of the following raw materials in parts by mass: 29 parts of Eudragit S100, 10 parts of triethanolamine, 4 parts of plasticizer, 5 parts of anti-sticking agent, 4 parts of pigment, and 480 parts of organic solvent.

3. The mesalazine colon targeted release composition according to claim 1, characterized in that: The filler is any one of corn starch, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; The adhesive is any one of corn starch, povidone K30, povidone K90, dextrin, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

4. The mesalazine colon targeted release composition according to claim 3, characterized in that: The filler is lactose; the binder is povidone K30.

5. The mesalazine colon targeted release composition according to claim 1, characterized in that: The disintegrant is any one or a combination of two of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose.

6. The mesalazine colon targeted release composition according to claim 5, characterized in that: The disintegrant is one or a combination of sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose.

7. The mesalazine colon targeted release composition according to claim 1, characterized in that: The anti-sticking agent is talcum powder; the lubricant is any one of hard sodium fumarate, micro powder silica gel, magnesium stearate, talcum powder, calcium stearate or polyethylene glycol lubricants.

8. The mesalazine colon targeted release composition according to claim 7, characterized in that: The lubricant is magnesium stearate.

9. The mesalazine colon targeted release composition according to claim 1, characterized in that: The plasticizer is any one of dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, tributyl citrate, dibutyl phthalate, and dimethyl phthalate; The organic solvent is any one of isopropanol, ethanol, methanol, phenol, dichloromethane, chloroform, acetone, methyl glycol, and n-butanol.

10. The mesalazine colon targeted release composition according to claim 9, characterized in that: The plasticizer is dibutyl sebacate; and the organic solvent is isopropyl alcohol.

11. The mesalazine colon targeted release composition according to claim 1, characterized in that: The pigment is red iron oxide, yellow iron oxide or a mixture of the two.

12. The method for preparing the mesalazine colon targeted release composition according to any one of claims 1 to 11, characterized in that: The steps include: (1) Dissolve the prescribed amount of adhesive in purified water to obtain an adhesive solution with a mass concentration of 5 to 10%; (2) placing the prescribed amount of mesalazine and the filler in a wet mixing granulator and mixing them evenly, spraying the binder solution obtained in step (1) into the granulator by atomization to granulate the granules, and then drying the wet granules by a fluidized bed to obtain mesalazine granules; (3) After the mesalazine granules obtained in step (2) are sieved and sized, a prescribed amount of disintegrant is added and mixed, and then an anti-adhesive agent and a lubricant are added and mixed, and after tableting, mesalazine tablets are obtained; (4) Dissolve the prescribed amount of Eudragit S100 and triethanolamine in 1 / 2 of the prescribed amount of organic solvent, stir and mix at 8000-13000 pm for 10-20 min to obtain a solution; disperse the prescribed amount of anti-adhesive agent, plasticizer and pigment in 1 / 2 of the prescribed amount of organic solvent to obtain a suspension; Slowly add the suspension into the solution and stir for 1-2 hours to obtain the enteric coating solution; (5) coating the mesalazine tablets obtained in step (3) with the enteric coating solution obtained in step (4), and packaging the obtained tablets to obtain a stable mesalazine colon-targeted release composition.

13. The preparation method according to claim 12, characterized in that: In step (2), the stirring speed of the wet granulator is 450-550 rpm, the chopping speed is 1200-1800 rpm, the atomization pressure is 0.1-0.2 Mpa, the peristaltic pump speed is 15-25 rpm, and the fluidized bed air volume is 20-40 m 3 / h, air inlet temperature 60±5℃; In step (3), the tableting is performed using a circular punch with a size of 5.5 mm and a hardness of 40-65N.

14. The preparation method according to claim 12, characterized in that: In step (5), the inlet air temperature of the coating is 35-45°C, the speed of the peristaltic pump is 10-15 rpm, the speed of the coating pan is 15-25 rpm, and the atomization pressure is 0.2-0.4 MPa.

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