Pharmaceutical composition containing escomeprazole magnesium and mosapride citrate and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing escomeprazole magnesium and mosapride citrate and a preparation method of the pharmaceutical composition, the pharmaceutical composition comprises an escomeprazole magnesium layer and a mosapride citrate layer, and optionally, the pharmaceutical composition further comprises an isolating layer arranged between the escomeprazole magnesium layer and the mosapride citrate layer; the esomeprazole magnesium layer comprises esomeprazole magnesium and auxiliary materials, the auxiliary materials comprise a filling agent and an adhesive, and the mass ratio of the filling agent to the adhesive in the esomeprazole magnesium layer is (0.1-20): 1, preferably (0.1-10), preferably (1-5): 1, and more preferably (3-3.5): 1. The pharmaceutical composition containing escomeprazole magnesium and mosapride citrate is designed, so that the pharmaceutical composition has the advantages of good stability, low impurity content, good content uniformity and the like, and the total impurity content is not more than 0.20% within 6 months of acceleration.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition containing esomeprazole magnesium and mosapride citrate and a preparation method thereof. Background Art

[0002] Esomeprazole is a proton pump inhibitor, the S-isomer of omeprazole, which specifically inhibits the H + -K + ATPase inhibits the secretion of gastric acid and is mainly used in the treatment of gastroesophageal reflux disease (GERD) and peptic ulcers. Studies have shown that esomeprazole, as a proton pump inhibitor, has a high cure rate and a low recurrence rate in the treatment of peptic ulcers and is one of the most effective drugs for the treatment of ulcerative reflux esophagitis.

[0003] Mosapride citrate is a selective 5-hydroxytryptamine (5-HT4) receptor agonist. It stimulates 5-HT4 receptors to promote the release of acetylcholine, thereby enhancing the motility of the upper gastrointestinal tract (stomach and small intestine), promoting gastric and duodenal motility and accelerating gastric emptying. At the same time, it can enhance esophageal motility and esophageal sphincter function, inhibit reflux of gastric contents, and improve gastrointestinal dyspepsia. This product does not affect the secretion of gastric acid, and has no affinity with dopamine D2, 5-HT1, and 5-HT2 receptors on the brain synaptic membrane, so there are no extrapyramidal side effects caused by the blockade of these receptors.

[0004] Esomeprazole is weakly alkaline and can be concentrated in the acidic environment of gastric parietal cells and converted into an active form, thereby inhibiting the terminal link of gastric juice forming gastric acid and improving the acidic environment; while mosapride can promote gastrointestinal motility. The combined use of the two has a synergistic effect, relieves the clinical symptoms of reflux esophagitis and improves the treatment effect.

[0005] Patent CN101036787A discloses a novel gastrointestinal composite capsule preparation containing a proton pump inhibitor and a gastrointestinal motility drug, which contains a pharmaceutical dose of a proton pump inhibitor or its stereoisomers and pharmaceutically acceptable salts thereof, a pharmaceutical dose of a gastrointestinal motility drug or its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or excipient, wherein the proton pump inhibitor can be selected from omeprazole, and the gastrointestinal motility drug can be selected from mosapride.

[0006] Patent CN1142792C discloses a compound tablet containing a proton pump inhibitor and a prokinetic agent, wherein the proton pump inhibitor can be selected from esomeprazole magnesium, and the gastrointestinal motility drug can be selected from mosapride. In the compound tablet, the proton pump inhibitor is first made into a pellet coated with an enteric coating, and then tableted with the prokinetic agent. However, when tableting the enteric-coated pellets containing esomeprazole magnesium, the enteric coating layer is easily damaged, resulting in the acid-sensitive esomeprazole magnesium being destroyed by the infiltrated acidic gastric juice after taking the drug. In addition, the damage to the coating layer caused during the tableting process leads to a decrease in drug stability.

[0007] The drug stability of the compound preparation of esomeprazole magnesium and mosapride citrate in the above patent is poor, and further research and development of drugs with better stability is needed. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 The figure is a schematic diagram of the structure of a tablet containing esomeprazole magnesium and mosapride citrate provided in an embodiment of the present invention. Summary of the invention

[0009] The present invention aims to provide a new pharmaceutical composition containing esomeprazole and mosapride citrate and a preparation method thereof. The present invention designs the formula of raw materials and auxiliary materials so that the pharmaceutical composition containing esomeprazole magnesium and mosapride citrate has the advantages of good stability, low impurity content, high content uniformity, etc., and the total impurity content within 6 months is accelerated to not exceed 2.0%. The preparation process provided by the present invention is simple to operate, can save production time, and greatly improve production efficiency.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a pharmaceutical composition containing esomeprazole magnesium and mosapride citrate, comprising an esomeprazole magnesium layer and a mosapride citrate layer, and optionally the pharmaceutical composition further comprises an isolation layer disposed between the esomeprazole magnesium layer and the mosapride citrate layer;

[0012] The esomeprazole magnesium layer comprises esomeprazole magnesium and excipients, wherein the excipients comprise a filler and an adhesive, and the mass ratio of the filler to the adhesive in the esomeprazole magnesium layer is (0.1-20):1, preferably (0.1-10):1, more preferably (1-5):1, and more preferably (3-3.5):1.

[0013] In some embodiments, in the esomeprazole magnesium layer, the mass ratio of the esomeprazole magnesium to the binder is (1-20):1, preferably (1-8):1, more preferably (3-6):1, and more preferably (5.5-6):1.

[0014] In some embodiments, the excipients further include a disintegrant, a stabilizer, a lubricant and a surfactant.

[0015] In the esomeprazole magnesium layer, the mass ratio of the disintegrant to the esomeprazole magnesium is (0.01-5):1, preferably (0.01-2):1, more preferably (0.2-0.25):1;

[0016] And / or, the mass ratio of the stabilizer to the esomeprazole magnesium is (0.01-5):1, preferably (0.01-2):1, more preferably (0.2-0.25):1;

[0017] And / or, the mass ratio of the lubricant to the esomeprazole magnesium is (0.01-3):1, preferably (0.01-2):1, more preferably (0.02-0.025):1;

[0018] And / or, the mass ratio of the surfactant to the esomeprazole magnesium is (0-2):1, preferably (0-1):1, and more preferably 0:1.

[0019] In some embodiments, the esomeprazole magnesium layer comprises the following components in mass percentage: 20%-70% esomeprazole magnesium, 10%-50% filler and 5%-30% binder; preferably, the esomeprazole magnesium layer comprises the following components in mass percentage: 35%-60% esomeprazole magnesium, 15%-45% filler and 5%-20% binder; more preferably, the esomeprazole magnesium layer comprises the following components in mass percentage: 44%-45% esomeprazole magnesium, 26%-27% filler and 7.5-8.5% binder.

[0020] In some embodiments, the esomeprazole magnesium layer further comprises the following components in mass percentage: 5%-20% disintegrant, 5%-15% stabilizer, 1%-5% lubricant and 0-3% surfactant; preferably, the esomeprazole magnesium layer further comprises the following components in mass percentage: 8%-16% disintegrant, 8%-15% stabilizer, 0.8%-2% lubricant and 0-1% surfactant; more preferably, the esomeprazole magnesium layer further comprises the following components in mass percentage: 9.5%-10.5% disintegrant, 9.5%-10.5% stabilizer and 0.5%-1.5% lubricant.

[0021] In some embodiments, the mosapride citrate layer includes mosapride citrate, and the mass ratio of the mosapride citrate to the esomeprazole magnesium is (0.1-10):1, preferably (0.1-5):1, more preferably (0.1-1):1, and more preferably (0.1-0.15):1.

[0022] In some embodiments, the mosapride citrate layer further comprises a filler, a binder, a disintegrant and a lubricant; the mass ratio of the filler to the mosapride citrate in the mosapride citrate layer is (1-40):1, preferably (5-20):1, more preferably (11.5-12.0):1;

[0023] and / or, the mass ratio of the binder to the mosapride citrate in the mosapride citrate layer is (0.01-5):1, preferably (0.1-2):1, more preferably (0.35-0.4):1;

[0024] The mass ratio of the disintegrant to the mosapride citrate in the mosapride citrate layer is (0.01-10):1, preferably (1-3):1, more preferably (1.7-2.2):1;

[0025] The mass ratio of the lubricant to the mosapride citrate in the mosapride citrate layer is (0.01-3):1, preferably (0.1-1):1, and more preferably (0.17-0.22):1.

[0026] In some embodiments, the mosapride citrate layer comprises the following components in mass percentage: 2-20% mosapride citrate, 50-80% filler, 1-10% binder, 1-20% disintegrant and 1-5% lubricant. Preferably, the mosapride citrate layer comprises the following components in mass percentage: 5-10% mosapride citrate, 70-80% filler, 2-3% binder, 10-15% disintegrant and 1-2% lubricant. More preferably, the mosapride citrate layer comprises the following components in mass percentage: 6.3-6.8% mosapride citrate, 77.0-77.5% filler, 2.3-2.8% binder, 12.3-12.8% disintegrant and 1.2-1.3% lubricant.

[0027] In some embodiments, the pharmaceutical composition containing esomeprazole magnesium and mosapride citrate includes an isolation layer, and the mass ratio of the isolation layer to the esomeprazole magnesium in the esomeprazole magnesium layer is (0.1-20):1, preferably (0.1-10):1, more preferably (0.1-5):1, and more preferably (0.4-0.5):1.

[0028] The isolation layer has an isolation function, and the isolation layer can be formed by a filler or other functional auxiliary materials.

[0029] In some embodiments, the filler can be selected from fillers conventionally used in the art, preferably the filler is selected from one or more of mannitol, microcrystalline cellulose, lactose, corn starch and cellulose lactose complex, more preferably the filler is selected from one or more of mannitol, microcrystalline cellulose, lactose and corn starch.

[0030] In some embodiments, the disintegrant can be selected from disintegrants conventionally used in the art, preferably the disintegrant is selected from one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, more preferably the disintegrant is selected from one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose.

[0031] In some embodiments, the binder can be selected from binders conventionally used in the art, preferably the binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone, more preferably the binder is selected from one or more of hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0032] In some embodiments, the stabilizer can be selected from stabilizers conventionally used in the art, preferably the stabilizer is selected from one or more of light magnesium oxide, magnesium carbonate, sodium carbonate and sodium bicarbonate, more preferably the stabilizer is selected from light magnesium oxide.

[0033] In some embodiments, the surfactant can be selected from surfactants conventionally used in the art, preferably the surfactant is selected from one or more of sodium lauryl sulfate, polysorbate 80 and Tween 80, more preferably the surfactant is selected from one or more of polysorbate 80 and Tween 80.

[0034] In some embodiments, the lubricant can be selected from lubricants conventionally used in the art, preferably the lubricant is selected from one or more of magnesium stearate, stearic acid and micro powder silica gel, more preferably the lubricant is selected from magnesium stearate.

[0035] In some embodiments, the pharmaceutical composition further comprises an isolation coating layer and an enteric coating layer, wherein the isolation coating layer is disposed on the plain tablet, and the enteric coating layer is disposed on the isolation coating layer, and the plain tablet comprises the isolation coating layer and the enteric coating layer, and optionally, the plain tablet further comprises the isolation layer. For example, see Figure 1 The plain tablet comprises an esomeprazole magnesium layer 1, an isolation layer 2 and a mosapride citrate layer 3 which are stacked in sequence.

[0036] The mass ratio of the isolation coating layer to the mosapride citrate in the mosapride citrate layer may be (1-10):1, preferably (1-5):1, more preferably (1.6-2.2):1, and more preferably (1.8-2.0):1. The mass ratio of the enteric coating layer to the mosapride citrate may be (1-10):1, preferably (1-5):1, more preferably (3.5-4.0):1, and more preferably (3.7-3.9):1.

[0037] The isolation coating layer is composed of an isolation coating material, which can be selected from coating materials conventionally used in the art. Preferably, the isolation coating material includes hydroxypropyl methylcellulose, triethyl citrate and titanium dioxide.

[0038] The amount of each component in the isolation coating layer can be set as needed. The mass ratio of mosapride citrate, hypromellose, triethyl citrate and titanium dioxide can be 1: (1-6): (0.1-2): (0.1-2); preferably, the mass ratio of mosapride citrate, hypromellose, triethyl citrate and titanium dioxide is 1: (1-3): (0.1-1): (0.1-1); more preferably, the mass ratio of mosapride citrate, hypromellose, triethyl citrate and titanium dioxide is 1: (1.5-1.6): (0.1-0.2): (0.1-0.2).

[0039] The mass percentage of the isolation coating material in the pharmaceutical composition is preferably 1%-10%. Among them, the mass percentage of hydroxypropyl methylcellulose in the pharmaceutical composition can be selected from 1%-8%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.1%-1%, and the mass percentage of titanium dioxide in the pharmaceutical composition can be selected from 0.1%-1%; preferably, the mass percentage of hydroxypropyl methylcellulose in the pharmaceutical composition can be selected from 2-5%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.2%-0.6%, and the mass percentage of titanium dioxide in the pharmaceutical composition can be selected from 0.2%-0.6%; more preferably, the mass percentage of hydroxypropyl methylcellulose in the pharmaceutical composition can be selected from 3.4%-3.5%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.4%-0.5%, and the mass percentage of titanium dioxide in the pharmaceutical composition can be selected from 0.4%-0.5%.

[0040] The enteric coating layer is composed of enteric coating materials, which can be selected from coating materials conventionally used in the art. Preferably, the enteric coating materials include polyacrylic acid resin, triethyl citrate and talc.

[0041] The amount of each component in the enteric coating layer can be set as needed. The mass ratio of mosapride citrate, polyacrylic acid resin, triethyl citrate and talc can be 1: (1-6): (0.1-2): (0.1-2); preferably, the mass ratio of mosapride citrate, polyacrylic acid resin, triethyl citrate and talc is 1: (1-3): (0.1-0.5): (0.1-1.5); more preferably, the mass ratio of mosapride citrate, polyacrylic acid resin, triethyl citrate and talc is 1: (2.2-2.3): (0.2-0.3): (1.2-1.3).

[0042] The mass percentage of the enteric coating material in the pharmaceutical composition is preferably 1%-20%, wherein the mass percentage of the polyacrylic acid resin in the pharmaceutical composition can be selected from 1%-12%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.1%-3%, and the mass percentage of talc in the pharmaceutical composition can be selected from 1%-5%; preferably, the mass percentage of the polyacrylic acid resin in the pharmaceutical composition can be selected from 5%-6%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.3%-0.8%, and the mass percentage of talc in the pharmaceutical composition can be selected from 2.5%-3.5%; more preferably, the mass percentage of the polyacrylic acid resin in the pharmaceutical composition can be selected from 5.2%-5.3%, the mass percentage of triethyl citrate in the pharmaceutical composition can be selected from 0.5%-0.6%, and the mass percentage of talc in the pharmaceutical composition can be selected from 2.9%-3.0%.

[0043] In some embodiments, the particle size of the esomeprazole magnesium is less than 10 μm.

[0044] In some embodiments, the particle size of the mosapride citrate is less than 10 μm.

[0045] In some embodiments, the particle sizes of the esomeprazole magnesium and mosapride citrate are both below 10 μm.

[0046] In some embodiments, the particle size of the stabilizer is below 80 mesh; the particle size of the lubricant is below 60 mesh; and the particle sizes of the esomeprazole magnesium and mosapride citrate are both below 10 μm.

[0047] There are many methods for controlling the particle size of the materials. For example, the particle sizes of esomeprazole magnesium and mosapride citrate can be controlled to be below 10 μm by using a hammer mill.

[0048] The present invention also provides a method for preparing a pharmaceutical composition containing esomeprazole magnesium and mosapride citrate, comprising the following steps:

[0049] Esomeprazole magnesium granules and mosapride citrate granules were prepared by wet granulation;

[0050] Using a tablet press to compress the esomeprazole magnesium granules, the isolation layer material and the mosapride citrate granules to obtain a plain tablet, wherein the plain tablet comprises the stacked esomeprazole magnesium layer, the isolation layer and the mosapride citrate layer;

[0051] The plain tablet is sequentially coated with an isolation layer and an enteric layer to obtain a tablet containing the esomeprazole magnesium and the mosapride citrate.

[0052] The present invention can use a KORSCH three-layer tablet press to perform tableting.

[0053] According to common sense in the art, the liquid solvent used in the wet granulation step can be selected from one or more of water and ethanol. The particle sizes of the stabilizer, lubricant, esomeprazole magnesium and mosapride citrate need to meet the above requirements. Each raw material can be sieved before granulation and mixing, preferably the stabilizer is sieved through an 80-mesh sieve, the lubricant is sieved through a 60-mesh sieve, and the particle sizes of esomeprazole magnesium and mosapride citrate are both below 10 μm, which are generally controlled by hammer crushing.

[0054] There may be various orders for adding the materials during wet granulation. In a preferred embodiment of the present invention, the steps of preparing esomeprazole magnesium granules by wet granulation include:

[0055] S1) mixing the stabilizer, the first filler and esomeprazole magnesium uniformly;

[0056] S2) spraying the first binder and the optional surfactant, mixing the materials and performing wet granulation to obtain esomeprazole magnesium wet granules;

[0057] S3) placing the wet granules of esomeprazole magnesium into a boiling fluidized bed for drying;

[0058] S4) uniformly mixing the dried esomeprazole magnesium granules with the first disintegrant and the first lubricant to obtain esomeprazole magnesium granules.

[0059] The conditions in the above steps can be designed and optimized. Among them, the mixing time in S1) is preferably 2-5 minutes; the granulation time in S2) is preferably 1-3 minutes; the moisture content of the material at the end of drying in S3) is preferably ≤3.0%; the mixing time in S4) is preferably 2-5 minutes.

[0060] In a preferred embodiment of the present invention, the steps of preparing mosapride citrate granules by wet granulation include:

[0061] S5) mixing the second filler and mosapride citrate uniformly;

[0062] S6) spraying a second binder, mixing the materials and performing wet granulation to obtain mosapride citrate wet granules;

[0063] S7) placing the mosapride citrate granules in a boiling fluidized bed for drying;

[0064] S8) uniformly mixing the dried mosapride citrate granules with a second disintegrant and a second lubricant to obtain mosapride citrate granules.

[0065] The conditions in the above steps can be designed and optimized, and suitable equipment can be selected. Among them, the mixing time in S5) is preferably 2-5 minutes; the granulation time in S6) is preferably 1-3 minutes; the moisture content of the material at the end of drying in S7) is preferably ≤3.0%; the mixing time in S8) is preferably 2-5 minutes.

[0066] The preparation process provided by the invention is simple to operate, can save production time, and greatly improve production efficiency.

[0067] The methods and conditions used in the tableting operation are all conventional methods and conditions in the art.

[0068] The methods and conditions used in the above coating operation are all conventional methods and conditions in the art. The solvent used in the coating operation is generally water and / or ethanol.

[0069] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0070] The reagents and raw materials used in the present invention are commercially available.

[0071] The positive and progressive effects of the present invention are:

[0072] By designing a pharmaceutical composition containing esomeprazole magnesium and mosapride citrate, the preparation prepared from the pharmaceutical composition has the advantages of good stability, low impurity content, good content uniformity, etc., and the total impurity content within 6 months is accelerated to not exceed 0.20%. The preparation process provided by the invention is simple to operate, can save production time, and greatly improve production efficiency. DETAILED DESCRIPTION

[0073] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0074] In the following examples, the particle sizes of the esomeprazole magnesium and mosapride citrate used were controlled to be below 10 μm.

[0075] Example 1

[0076] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0077]

[0078] Tablet preparation method:

[0079] Preparation of esomeprazole magnesium granules: esomeprazole magnesium, light magnesium oxide and mannitol are added to a wet granulator for mixing, and the dissolved hydroxypropylcellulose ethanol solution is sprayed in for granulation, and the dried esomeprazole magnesium granules, cross-linked polyvinylpyrrolidone and magnesium stearate are added to a V-type mixer, and mixed for 5 minutes to obtain esomeprazole magnesium granules.

[0080] Preparation of mosapride citrate granules: After passing mosapride citrate and lactose through a 100-mesh sieve, the sieved mosapride citrate, lactose and corn starch are added to a wet granulator for mixing, and the dissolved hydroxypropyl methylcellulose aqueous solution is sprayed into the granulator for granulation and fluidized bed drying. The dried mosapride citrate granules, low-substituted hydroxypropyl cellulose and magnesium stearate are added to a V-type mixer and mixed for 5 minutes to obtain mosapride citrate granules.

[0081] Tableting: A KORSCH three-layer tablet press is used for tableting to obtain plain tablets, which include an esomeprazole magnesium layer, an isolation layer and a mosapride citrate layer stacked on top of each other, wherein the esomeprazole magnesium layer has a tablet weight of 100 mg, the isolation layer has a tablet weight of 20 mg, and the mosapride citrate layer has a tablet weight of 80 mg.

[0082] Coating: First coat the plain tablets with an isolation layer, then with an enteric layer, and control the tablet bed temperature at 33℃±3℃.

[0083] Example 2

[0084] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0085]

[0086]

[0087] The preparation method of the tablets in this Example 2 is similar to the preparation method of the tablets in Example 1.

[0088] Example 3

[0089] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0090]

[0091]

[0092] Tablet preparation method:

[0093] Preparation of esomeprazole magnesium granules: esomeprazole magnesium, light magnesium oxide and mannitol are added to a wet granulator for mixing, and the dissolved polysorbate 80 and hydroxypropylcellulose ethanol solution are sprayed in for granulation, and fluidized bed drying is performed. The dried esomeprazole magnesium granules, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added to a V-type mixer and mixed for a total of 5 minutes to obtain esomeprazole magnesium granules.

[0094] The preparation method of the mosapride citrate granules in this Example 3 is similar to the preparation method of the mosapride citrate granules in Example 1.

[0095] The tableting process in this Example 3 is similar to the tableting process in Example 1.

[0096] The coating process in this Example 3 is similar to the coating process in Example 1.

[0097] Example 4

[0098] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0099]

[0100]

[0101] The preparation method of the tablets in this Example 4 is similar to the preparation method of the tablets in Example 3.

[0102] Example 5

[0103] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0104]

[0105]

[0106] The preparation method of the tablets in this Example 5 is similar to the preparation method of the tablets in Example 1.

[0107] The tablets were pressed using a KORSCH three-layer tablet press, with the tablet weight of the esomeprazole magnesium layer being 90 mg, the tablet weight of the isolation layer being 20 mg, and the tablet weight of the mosapride citrate layer being 70 mg.

[0108] Example 6

[0109] Prescription for tablets containing esomeprazole magnesium and mosapride citrate:

[0110]

[0111]

[0112] The preparation method of the tablets in this Example 6 is similar to the preparation method of the tablets in Example 1.

[0113] The tablets were pressed using a KORSCH three-layer tablet press, with the weight of the esomeprazole magnesium layer being 110 mg, the weight of the isolation layer being 20 mg, and the weight of the mosapride citrate layer being 90 mg.

[0114] Effect Example

[0115] The samples of Examples 1-6 of the present invention were placed in a constant temperature and humidity chamber for stability testing (40±2°C, 75%±5%RH), and samples were taken at 0, 1, 2, 3 and 6 months to detect related substances. The results are shown in Table 1 below.

[0116] Table 1. Sample stability test results

[0117]

[0118]

[0119] Wherein, impurity A: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonyl]-1H-benzimidazole, CAS No.: 88546-55-8, the structure of impurity A is shown in Formula I:

[0120]

[0121] Impurity B: (±)-4-[bis(hydroxymethyl)hydroxyacetyl]-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide, CAS No.: 1215825-20-9, the structure of impurity B is shown in Formula II:

[0122]

[0123] Impurity C: (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide-N-oxide, CAS No.: 1161443-73-7, the structure of impurity C is shown in Formula III:

[0124]

[0125] The stability test results of the products in Examples 1-6 show that in the 6-month sampling test, the limits of impurity A are all within 0.5%, the limits of impurity B and impurity C are all within 0.2%, the limits of other unknown maximum single impurities are all within 0.2%, and the total impurity limit does not exceed 2.0%. Among them, the stability of the product in Example 1 is the best. Because the surfactant is added to the esomeprazole magnesium layer and the dosage relationship of the filler and the binder is adjusted, the stability of the products in Examples 3 and 4 is not as good as that of the product in Example 1.

[0126] In addition, the content uniformity of the samples in Examples 1-6 was measured using the content uniformity detection method in the Appendix to Part II of the Pharmacopoeia 2020 Edition. The content uniformity results of each sample were A+2.2S≤15.0, indicating that the content uniformity of the samples in Examples 1-6 was good.

Claims

1. A pharmaceutical composition containing esomeprazole magnesium and mosapride citrate, characterized in that: The pharmaceutical composition comprises an esomeprazole magnesium layer and a mosapride citrate layer, and optionally the pharmaceutical composition further comprises a separation layer disposed between the esomeprazole magnesium layer and the mosapride citrate layer; The esomeprazole magnesium layer comprises esomeprazole magnesium and excipients, wherein the excipients comprise a filler and an adhesive, and the mass ratio of the filler to the adhesive in the esomeprazole magnesium layer is (0.1-20):1, preferably (0.1-10), more preferably (1-5):1, and more preferably (3-3.5):

1.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the esomeprazole magnesium to the binder in the esomeprazole magnesium layer is (1-20):1, preferably (1-8):1, more preferably (3-6):1, and more preferably (5.5-6):

1.

3. The pharmaceutical composition according to claim 2, characterized in that The excipients also include disintegrants, stabilizers, lubricants and surfactants; The mass ratio of the disintegrant to the esomeprazole magnesium is (0.01-5):1, preferably (0.01-2):1, more preferably (0.2-0.25):1; And / or, the mass ratio of the stabilizer to the esomeprazole magnesium is (0.01-5):1, preferably (0.01-2):1, more preferably (0.2-0.25):1; and / or, the mass ratio of the lubricant to the esomeprazole magnesium is (0.01-3):1, preferably (0.01-2):1, more preferably (0.02-0.025):1; And / or, the mass ratio of the surfactant to the esomeprazole magnesium is (0-2):1, preferably (0-1):1, and more preferably 0:

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The esomeprazole magnesium layer comprises the following components in mass percentage: 20%-70% esomeprazole magnesium, 10%-50% filler and 5%-30% binder; preferably, the esomeprazole magnesium layer comprises the following components in mass percentage: 35%-60% esomeprazole magnesium, 15%-45% filler and 5%-20% binder; more preferably, the esomeprazole magnesium layer comprises the following components in mass percentage: 44%-45% esomeprazole magnesium, 26%-27% filler and 7.5-8.5% binder.

5. The pharmaceutical composition according to claim 4, characterized in that The esomeprazole magnesium layer also includes the following components in mass percentage: 5%-20% disintegrant, 5%-15% stabilizer, 1%-5% lubricant and 0-3% surfactant; preferably, the esomeprazole magnesium layer also includes the following components in mass percentage: 8%-16% disintegrant, 8%-15% stabilizer, 0.8%-2% lubricant and 0-1% surfactant; more preferably, the esomeprazole magnesium layer also includes the following components in mass percentage: 9.5%-10.5% disintegrant, 9.5%-10.5% stabilizer and 0.5%-1.5% lubricant.

6. The pharmaceutical composition according to claim 2, characterized in that The mosapride citrate layer includes mosapride citrate, and the mass ratio of the mosapride citrate to the esomeprazole magnesium is (0.1-10):1, preferably (0.1-5):1, more preferably (0.1-1):1, and more preferably (0.1-0.15):

1.

7. The pharmaceutical composition according to claim 6, characterized in that The mosapride citrate layer also includes a filler, a binder, a disintegrant and a lubricant; The mass ratio of the filler to the mosapride citrate in the mosapride citrate layer is (1-40):1, preferably (5-20):1, more preferably (11.5-12.0):1; and / or, the mass ratio of the binder to the mosapride citrate in the mosapride citrate layer is (0.01-5):1, preferably (0.1-2):1, more preferably (0.35-0.4):1; and / or, the mass ratio of the disintegrant to the mosapride citrate in the mosapride citrate layer is (0.01-10):1, preferably (1-5):1, more preferably (1.7-2.2):1; And / or, the mass ratio of the lubricant to the mosapride citrate in the mosapride citrate layer is (0.01-3):1, preferably (0.1-2):1, and more preferably (0.17-0.22):

1.

8. The pharmaceutical composition according to claim 6 or 7, characterized in that The mosapride citrate layer comprises the following components in mass percentage: 2-20% mosapride citrate, 50-80% filler, 1-10% binder, 1-20% disintegrant and 1-5% lubricant; preferably, the mosapride citrate layer comprises the following components in mass percentage: 5-10% mosapride citrate, 70-80% filler, 2-3% binder, 10-15% disintegrant and 1-2% lubricant; more preferably, the mosapride citrate layer comprises the following components in mass percentage: 6.3-6.8% mosapride citrate, 77.0-77.5% filler, 2.3-2.8% binder, 12.3-12.8% disintegrant and 1.2-1.3% lubricant.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The pharmaceutical composition comprises an isolation layer, and the mass ratio of the isolation layer to the esomeprazole magnesium in the esomeprazole magnesium layer is (0.1-20):1, preferably (0.1-10):1, more preferably (0.1-5):1, and more preferably (0.4-0.5):

1.

10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that The filler is selected from one or more of mannitol, microcrystalline cellulose, lactose, corn starch and cellulose lactose complex; and / or, the disintegrant is selected from one or more of hydroxypropyl cellulose, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose; And / or, the binder is selected from one or more of hydroxypropyl cellulose, hypromellose and povidone; And / or, the stabilizer is selected from one or more of light magnesium oxide, magnesium carbonate, sodium carbonate and sodium bicarbonate; And / or, the surfactant is selected from one or more of sodium lauryl sulfate, polysorbate 80 and Tween 80; And / or, the lubricant is selected from one or more of magnesium stearate, stearic acid and micro powder silica gel.

11. The pharmaceutical composition according to any one of claims 1 to 10, characterized in that The pharmaceutical composition further comprises an isolation coating layer and an enteric coating layer, wherein the isolation coating layer is disposed on a plain tablet, the enteric coating layer is disposed on the isolation coating layer, the plain tablet comprises the isolation coating layer and the enteric coating layer, and optionally, the plain tablet further comprises the isolation layer; The mass ratio of the isolation coating layer to the mosapride citrate in the mosapride citrate layer is (1-10):1, preferably (1-5):1, more preferably (1.6-2.2):1, and more preferably (1.8-2.0); And / or, the mass ratio of the enteric coating layer to the mosapride citrate is (1-10):1, preferably (1-5):1, more preferably (3.5-4.0):1, and more preferably (3.7-3.9):

1.

12. The pharmaceutical composition according to any one of claims 1 to 11, characterized in that The particle size of the esomeprazole magnesium is less than 10 μm; And / or, the particle size of the mosapride citrate is below 10 μm.

13. A method for preparing the pharmaceutical composition according to any one of claims 1 to 12, characterized in that: The method comprises the following steps: Esomeprazole magnesium granules and mosapride citrate granules were prepared by wet granulation; Using a tablet press to compress the esomeprazole magnesium granules, the isolation layer material and the mosapride citrate granules to obtain a plain tablet, wherein the plain tablet comprises the stacked esomeprazole magnesium layer, the isolation layer and the mosapride citrate layer; The plain tablet is sequentially coated with an isolation layer and an enteric layer to obtain a tablet containing the esomeprazole magnesium and the mosapride citrate.

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