Omeprazole Enteric-coated Capsules and Their Preparation Method

Abstract

The present invention discloses an omeprazole enteric-coated capsule and a preparation method thereof. First, sodium citrate, soybean phospholipid and omeprazole are mixed to obtain a functional liquid. Then, mannitol, lactose, corn starch, antioxidant, chelating agent and hydroxypropyl methylcellulose are mixed to form a granulation mixture. The granulation mixture and the functional liquid are mixed, made into wet pellets and then dried, and the medicated pellets are collected. Then, an isolation layer coating and an enteric layer coating are carried out, and finally they are filled into capsules to obtain the omeprazole enteric-coated capsule. Compared with the prior art, the enteric-coated capsule prepared by this method has good solubility and stability, can protect the drug under the influence of gastric acid, and improve the bioavailability of the drug.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly to an omeprazole enteric-coated capsule and a preparation method thereof. Background Art

[0002] Omeprazole enteric-coated capsule is a commonly used pharmaceutical preparation for treating peptic ulcers and gastroesophageal reflux disease caused by excessive gastric acid.

[0003] Traditional omeprazole enteric-coated capsule preparations usually adopt conventional preparation techniques such as dry mixing method, impregnation method, coating method, etc. These methods mainly prepare enteric-coated capsules by mixing omeprazole with appropriate excipients and using capsule filling or coating methods. In order to improve the solubility and bioavailability of omeprazole, some studies have adopted the method of solid dispersion preparation to prepare omeprazole enteric-coated capsules. This kind of preparation usually mixes omeprazole with polymer or carrier materials to form a solid dispersion to increase the solubility and stability of the drug. Microparticle preparation is another common method for preparing omeprazole enteric-coated capsules. This method prepares omeprazole into microparticles, such as nanoparticles, microspheres or microcapsules, and then fills them into enteric-coated capsules. Microparticle preparations can improve the solubility, stability and bioavailability of drugs. In recent years, nanotechnology has been applied to the preparation of omeprazole enteric-coated capsules. Nanonized omeprazole can improve the solubility and bioavailability of drugs and has better drug efficacy. Nanotechnology includes solvent precipitation method, gel method, ultrasonic irradiation method, etc.

[0004] Although certain achievements have been made in the preparation of omeprazole enteric-coated capsules in the prior art, there are still some deficiencies, including: solubility and bioavailability limitations. Omeprazole is a drug with low bioavailability, and its solubility limits its absorption and utilization in the body. Further research and development are needed to improve the quality, stability and bioavailability of omeprazole enteric-coated capsule preparations and simplify the preparation process.

[0005] Chinese authorized invention patent CN109125282B discloses an omeprazole enteric-coated capsule and a preparation method thereof. The capsule is composed of omeprazole enteric-coated pellets filled in a gelatin capsule shell. The omeprazole enteric-coated pellets are composed of an omeprazole-containing pill core, a separating layer and an enteric coating layer from the inside out. The omeprazole-containing pill core is prepared by an extrusion-spheronization method, and the separating layer and the enteric coating layer are prepared by a fluidized bed coating method. Different from the original research product, the omeprazole-containing pill core is added with Tween 80 and low-substituted hydroxypropyl cellulose on the basis of omeprazole, anhydrous lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, hydroxypropyl cellulose and sodium dodecyl sulfate. The omeprazole enteric-coated capsule prepared by this invention not only does not change the stability and reproducibility of the product, but also improves the in vitro dissolution rate of the drug, especially improves the inter-individual uniformity. The peak time of blood drug concentration of different healthy subjects is more consistent, and it has good application value in clinical application. However, the dissolution rate and acid resistance of the omeprazole enteric-coated capsule prepared by this invention are still weak, and the bioavailability is limited. Summary of the Invention

[0006] Aiming at the deficiencies existing in the prior art, the technical problem to be solved by the present invention is: to provide an omeprazole enteric-coated capsule with better dissolution rate and acid resistance and a preparation method thereof.

[0007] In order to achieve the above-mentioned invention purpose, the present invention adopts the following technical solutions:

[0008] A preparation method of an omeprazole enteric-coated capsule is as follows:

[0009] Step 1, preparation of drug-containing pellets: Add sodium citrate to purified water, add soybean phospholipid, and then add omeprazole and stir for 10-20 min to obtain a functional liquid for standby; put mannitol, lactose, corn starch, and hydroxypropyl methyl cellulose into a wet granulator and mix for about 5-15 min to obtain a granulation mixture; mix the granulation mixture and the functional liquid, add it to the pill-making room, put it into an extrusion-spheronization machine, perform pill-making operation, dry the wet pills until the water content is <2.4% - 2.6%, sieve, and collect the drug-containing pellets between 10 and 30 meshes;

[0010] Step 2, separating layer coating: Add hydroxypropyl methyl cellulose ether to purified water and stir thoroughly until it is clear and transparent to obtain a prepared separating layer coating liquid; put the drug-containing pellets into a granulation and coating machine and perform separating layer coating operation; dry the separating layer pellets until the water content is <2.4% - 2.6%; sieve and collect the coated pellets between 10 and 30 meshes;

[0011] Step 3, enteric-coated layer coating: Add Eudragit L30D-55 to purified water, and stir thoroughly to make it evenly mixed. Add triethyl citrate and magnesium stearate, and continue stirring to ensure their uniform mixing to form an enteric-coated layer coating solution; Put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 38 - 42 °C, the inlet air volume to 73 - 78 m 3 / h, the atomization pressure of the spray gun to 1.5 - 1.7 bar, the rotation speed of the peristaltic pump to 5 - 10 rpm, and use the enteric-coated layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature to 50 - 60 °C for drying until the moisture content < 2.4% - 2.6%, and screen using a 10 - 30 mesh sieve to obtain enteric-coated layer pellets;

[0012] Step 4: Load the enteric-coated layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric-coated capsules.

[0013] The weight parts of each substance used in Step 1 are: 10 - 20 parts of sodium citrate, 180 - 220 parts of purified water, 2 - 4 parts of soybean phospholipid, 80 - 120 parts of omeprazole, 600 - 700 parts of mannitol, 30 - 40 parts of lactose, 30 - 40 parts of corn starch, 4 - 6 parts of hydroxypropyl methylcellulose.

[0014] The weight parts of each substance used in Step 2 are: 60 - 80 parts of hydroxypropyl methylcellulose ether, 900 - 1100 parts of purified water.

[0015] The weight parts of each substance used in Step 3 are: 500 - 700 parts of Eudragit L30D-55, 700 - 900 parts of purified water, 15 - 25 parts of triethyl citrate, 60 - 80 parts of magnesium stearate.

[0016] Preferably, the preparation method of the omeprazole enteric-coated capsules is as follows:

[0017] Step 1, preparation of drug-containing pellets: Add sodium citrate to purified water, add soybean phospholipid, and then add omeprazole and stir for 10 - 20 min to obtain a functional liquid for standby; Put mannitol, lactose, corn starch, antioxidant, and hydroxypropyl methylcellulose into a wet granulator and mix for about 5 - 15 min to obtain a granulation mixture; Mix the granulation mixture and the functional liquid, add it to the pill-making room, put it into an extrusion and spheronization machine for pill-making operation, dry the wet pills until the moisture content < 2.4% - 2.6%, and screen to collect the drug-containing pellets between 10 - 30 meshes;

[0018] Step 2. Isolation layer coating: Add hydroxypropyl methylcellulose ether into purified water, and stir thoroughly until it becomes clear and transparent to obtain the prepared isolation layer coating solution; put the drug-loaded pellets into a granulating and coating machine for isolation layer coating operation; dry the isolation layer pellets until the moisture content is <2.4% - 2.6%; sieve and collect the coated pellets between 10 - 30 mesh.

[0019] Step 3. Enteric-coated layer coating: Add Eudragit L30D - 55 into purified water, and stir thoroughly to make it uniformly mixed. Add triethyl citrate and magnesium stearate, and continue stirring to ensure their uniform mixing to form the enteric-coated layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature at 38 - 42 °C, the inlet air volume at 73 - 78 m 3 / h, the atomization pressure of the spray gun at 1.5 - 1.7 bar, the rotation speed of the peristaltic pump at 5 - 10 rpm, and use the enteric-coated layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature at 50 - 60 °C for drying until the moisture content is <2.4% - 2.6%, sieve, and use a 10 - 30 mesh sieve for screening to obtain the enteric-coated layer pellets.

[0020] Step 4. Load the enteric-coated layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric-coated capsules.

[0021] The mass ratio of the omeprazole to the antioxidant is 80 - 120:3 - 5.

[0022] The role of adding an antioxidant in the present invention is to protect omeprazole from oxidative damage, thereby prolonging the stability of the product and maintaining its quality. The antioxidant can react with oxygen free radicals or other oxidants, thereby reducing or preventing its oxidation, protecting it from oxidative damage, maintaining its activity and function, and ensuring that the product can provide the expected effects during use.

[0023] The antioxidant is one of vitamin C and reduced glutathione.

[0024] Both vitamin C and reduced glutathione are powerful antioxidants with good reducibility and antioxidant ability. They can undergo chemical reactions with oxygen free radicals and other oxidizing substances, thereby reducing the impact of oxidation reactions on drug molecules, improving the dissolution rate and acid resistance of the drug.

[0025] Further preferably, the preparation method of the omeprazole enteric-coated capsules is as follows:

[0026] Step 1: Preparation of drug-loaded pellets: Sodium citrate is added to purified water, followed by soybean phospholipid, and then omeprazole is added and stirred for 10 - 20 min to obtain a functional solution for standby. Mannitol, lactose, corn starch, antioxidant, chelating agent, and hydroxypropyl methylcellulose are put into a wet granulator and mixed for about 5 - 15 min to obtain a granulation mixture. The granulation mixture and the functional solution are mixed, added to the pill-making room, and put into an extrusion spheronizer for pill-making operation. The wet pellets are dried to a moisture content of <2.4% - 2.6%, sieved, and drug-loaded pellets between 10 - 30 meshes are collected.

[0027] Step 2: Coating of the isolation layer: Hydroxypropyl methylcellulose ether is added to purified water and stirred thoroughly until it is clear and transparent to obtain a prepared isolation layer coating solution. The drug-loaded pellets are put into a granulation coating machine for isolation layer coating operation. The isolation layer pellets are dried to a moisture content of <2.4% - 2.6%; sieved, and coated pellets between 10 - 30 meshes are collected.

[0028] Step 3: Coating of the enteric layer: Eudragit L30D - 55 is added to purified water and stirred thoroughly to make them evenly mixed. Triethyl citrate and magnesium stearate are added and stirred continuously to ensure their uniform mixing to form an enteric layer coating solution. The coated pellets prepared in Step 2 are put into the fluidized bed material chamber. The inlet air temperature is set at 38 - 42 °C, the inlet air volume is 73 - 78 m 3 / h, the atomization pressure of the spray gun is 1.5 - 1.7 bar, and the rotation speed of the peristaltic pump is 5 - 10 rpm. The enteric layer coating solution is used to coat the coated pellets. After coating is completed, the inlet air temperature is set at 50 - 60 °C for drying until the moisture content is <2.4% - 2.6%, sieved, and screened with a 10 - 30 mesh sieve to obtain enteric layer pellets.

[0029] Step 4: The enteric layer pellets prepared in Step 3 are filled into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0030] Drug molecules are prone to aggregation or complex formation under certain conditions, which hinders the dissolution and release of drugs. The addition of a chelating agent can reduce this adverse effect and improve the dissolution rate and solubility of drugs. And the coordination of the chelating agent can form a protective layer to wrap the drug molecules in it, reducing the interaction between drug molecules and metal ions. This helps to protect the stability and activity of drugs, preventing the degradation, oxidation or other quality losses of drug molecules.

[0031] The mass ratio of the omeprazole to the chelating agent is 80 - 120:5 - 7.

[0032] The chelating agent is at least one of ethylenediaminetetraacetic acid, citric acid, ethylenediaminediacetic acid, and sodium bisulfite.

[0033] Preferably, the chelating agent is a combination of ethylenediaminetetraacetic acid and sodium bisulfite in a mass ratio of 1:1.

[0034] Ethylenediaminetetraacetic acid can form stable complexes with metal ions, preventing the adverse effects of the presence of metal ions on the dissolution and stability of the drug. Sodium bisulfite has reducing properties and can reduce the impact of oxidation reactions on the drug. The combined use of these two chelating agents can provide more comprehensive protection, reduce the damage and degradation of drug molecules, and improve the dissolution rate and acid resistance of the drug. Sodium bisulfite can play a role in adjusting the pH value, keeping the solution within an appropriate range, which is beneficial to the dissolution and stability of the drug.

[0035] Adding a chelating agent (ethylenediaminetetraacetic acid, sodium bisulfite) in combination, using different types of chelating agents can exert a synergistic effect and provide multiple protection functions. At the same time, it can also adjust the pH value of the solution, further enhancing the dissolution rate and stability of the drug.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0037] 1) The present invention uses surfactants such as hydroxypropyl methylcellulose ether and soybean phospholipid. These additives can promote the dissolution and release of the drug, thereby improving the dissolution rate of the drug. In contrast, traditional additives may not provide the same dissolution-enhancing effect.

[0038] 2) The additives used in the present invention have good acid resistance and can protect the drug from the influence of an acidic environment. This helps to improve the stability of the drug and ensure that the effect of the drug is not affected under acidic conditions such as gastric acid. In contrast, traditional additives may be more sensitive to acidic conditions, resulting in quality loss of the drug.

[0039] 3) The omeprazole enteric-coated capsules prepared by the present invention can improve the dissolution rate and stability, and the present invention can improve the bioavailability of the drug. The solubility and stability of the drug in the body directly affect its absorption and distribution. Therefore, improving the performance in these aspects can increase the efficacy and effect of the drug. Detailed implementation mode

[0040] Main sources of substances:

[0041] Soybean phospholipid and hydroxypropyl methylcellulose are both purchased from Merck.

[0042] Lactose: Jiangsu Fushengde Biotechnology Co., Ltd., product number: 101.

[0043] Corn starch: Jiangsu Fuzhan Pharmaceutical Co., Ltd., product number: LHYMDF.

[0044] Hydroxypropyl methylcellulose ether: Shanghai Kaiyuan Chemical Technology Co., Ltd., product number: HPMC-1.

[0045] Reduced Glutathione: Xi'an Jiahe Biotechnology Co., Ltd., single product item number: JH-0110.

[0046] Hydroxypropyl Methylcellulose: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd., CAS: 68553-81-1, item number: for medical use.

[0047] Example 1

[0048] A preparation method of omeprazole enteric-coated capsules is as follows:

[0049] Step 1, preparation of drug-containing pellets: Add 15 g of sodium citrate to 200 g of purified water, add 3 g of soybean phospholipid, then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, and 5 g of hydroxypropyl methylcellulose into a wet granulation mixer, mix for about 10 min to obtain a granulation mixture; mix the granulation mixture and the functional liquid, add it to the pill-making room, put it into an extrusion spheronizer, perform pill-making operations, dry the wet pellets until the moisture content < 2.5%, sieve, and collect the drug-containing pellets between 15 and 25 meshes;

[0050] Step 2, coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-containing pellets into a granulation coating machine and perform isolation layer coating operations; dry the isolation layer pellets until the moisture content < 2.5%; sieve and collect the coated pellets between 15 and 25 meshes;

[0051] Step 3, coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water, and stir well to make them evenly mixed, add 20 g of triethyl citrate and 70 g of magnesium stearate, continue to stir to ensure they are evenly mixed to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, the rotation speed of the peristaltic pump to 8 rpm, use the enteric layer coating solution to coat the coated pellets, after the coating is completed, set the inlet air temperature to 55 °C for drying, dry until the moisture content < 2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0052] Step 4, load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric-coated capsules.

[0053] Example 2

[0054] A preparation method of omeprazole enteric-coated capsules is as follows:

[0055] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, add 3 g of soybean phospholipid, then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of vitamin C, and 5 g of hydroxypropyl methylcellulose into a wet granulation mixer and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture with the functional liquid, add it to the pill-making room, put it into an extrusion spheronizer, and perform pill-making operations. Dry the wet pellets until the moisture content is <2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes.

[0056] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water and stir thoroughly until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation coating machine and perform isolation layer coating operations; dry the isolation layer pellets until the moisture content is <2.5%; sieve and collect the coated pellets between 15 and 25 meshes.

[0057] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir thoroughly to make them evenly mixed. Add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue to stir to ensure they are evenly mixed to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, and the rotation speed of the peristaltic pump to 8 rpm. Use the enteric layer coating solution to coat the coated pellets. After coating is completed, set the inlet air temperature to 55 °C for drying until the moisture content is <2.5%, sieve, and use a sieve between 15 and 25 meshes for screening to obtain enteric layer pellets.

[0058] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0059] Example 3

[0060] A preparation method of omeprazole enteric capsules is as follows:

[0061] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soy lecithin, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, and 5 g of hydroxypropyl methylcellulose into a wet granulation mixer and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture with the functional liquid, add it to the pill-making room, put it into an extrusion-spheronization machine for pill-making operation, dry the wet pellets until the moisture content is <2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes;

[0062] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water and stir thoroughly until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation coating machine for isolation layer coating operation; dry the isolation layer pellets until the moisture content is <2.5%; sieve and collect the coated pellets between 15 and 25 meshes;

[0063] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir thoroughly to make them evenly mixed, add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue to stir to ensure their even mixing to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature at 40 °C, the inlet air volume at 75 m 3 / h, the atomization pressure of the spray gun at 1.6 bar, and the rotation speed of the peristaltic pump at 8 rpm. Use the enteric layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature at 55 °C for drying until the moisture content is <2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0064] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0065] Example 4

[0066] A preparation method of omeprazole enteric capsules is as follows:

[0067] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soybean phospholipid, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; Put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, 6 g of ethylenediaminetetraacetic acid, and 5 g of hydroxypropyl methylcellulose into a wet granulator and mix for about 10 min to obtain a granulation mixture; Mix the granulation mixture with the functional liquid, add it to the pill-making room, put it into an extrusion spheronizer, and perform the pill-making operation. Dry the wet pellets until the moisture content < 2.5%, screen, and collect the drug-loaded pellets between 15 and 25 meshes;

[0068] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water and stir thoroughly until it is clear and transparent to obtain a prepared isolation layer coating solution; Put the drug-loaded pellets into a granulation and coating machine and perform the isolation layer coating operation; Dry the isolation layer pellets until the moisture content < 2.5%; Screen and collect the coated pellets between 15 and 25 meshes;

[0069] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir thoroughly to make them uniformly mixed. Add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue to stir to ensure their uniform mixing to form an enteric layer coating solution; Put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m3 / h, the atomization pressure of the spray gun to 1.6 bar, and the rotation speed of the peristaltic pump to 8 rpm. Use the enteric layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature to 55 °C for drying until the moisture content < 2.5%, screen, and use a sieve with 15 to 25 meshes for screening to obtain the enteric layer pellets;

[0070] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0071] Example 5

[0072] A preparation method of omeprazole enteric capsules is as follows:

[0073] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soybean phospholipid, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, 6 g of citric acid, and 5 g of hydroxypropyl methylcellulose into a wet granulator and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture and the functional liquid, add them to the pill-making room, put them into an extrusion spheronizer for pill-making operation, dry the wet pellets until the moisture content < 2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes;

[0074] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water and stir well until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation coating machine for isolation layer coating operation; dry the isolation layer pellets until the moisture content < 2.5%; sieve and collect the coated pellets between 15 and 25 meshes;

[0075] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir well to make them evenly mixed, add 20 g of triethyl citrate and 70 g of magnesium stearate, continue to stir to ensure their uniform mixing to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, the rotation speed of the peristaltic pump to 8 rpm, use the enteric layer coating solution to coat the coated pellets, after the coating is completed, set the inlet air temperature to 55 °C for drying, dry until the moisture content < 2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0076] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0077] Example 6

[0078] A preparation method of omeprazole enteric capsules is as follows:

[0079] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soy lecithin, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, 6 g of ethylenediaminediacetic acid, and 5 g of hydroxypropyl methylcellulose into a wet granulator and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture and the functional liquid, add it to the pill-making room, put it into an extrusion spheronizer, perform the pill-making operation, dry the wet pills until the moisture content < 2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes;

[0080] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation and coating machine to perform the isolation layer coating operation; dry the isolation layer pellets until the moisture content < 2.5%; sieve and collect the coated pellets between 15 and 25 meshes;

[0081] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water, and stir well to make them evenly mixed. Add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue to stir to ensure their uniform mixing to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, the rotation speed of the peristaltic pump to 8 rpm, use the enteric layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature to 55 °C for drying until the moisture content < 2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0082] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0083] Example 7

[0084] A preparation method of omeprazole enteric capsules is as follows:

[0085] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soybean phospholipid, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, 6 g of sodium bisulfite, and 5 g of hydroxypropyl methylcellulose into a wet granulator and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture with the functional liquid, add it to the pill-making room, put it into an extrusion spheronizer for pill-making operation, dry the wet pellets until the moisture content < 2.5%, screen, and collect the drug-loaded pellets between 15 and 25 meshes;

[0086] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation and coating machine for the isolation layer coating operation; dry the isolation layer pellets until the moisture content < 2.5%; screen and collect the coated pellets between 15 and 25 meshes;

[0087] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir well to make them evenly mixed, add 20 g of triethyl citrate and 70 g of magnesium stearate, continue to stir to ensure their even mixing to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, the rotation speed of the peristaltic pump to 8 rpm, use the enteric layer coating solution to coat the coated pellets, after the coating is completed, set the inlet air temperature to 55 °C for drying, dry until the moisture content < 2.5%, screen, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0088] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0089] Example 8

[0090] A preparation method of omeprazole enteric capsules is as follows:

[0091] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, then add 3 g of soybean phospholipid, and then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, 4 g of reduced glutathione, 3 g of ethylenediaminetetraacetic acid, 3 g of sodium bisulfite, and 5 g of hydroxypropyl methylcellulose into a wet granulator and mix for about 10 min to obtain a granulation mixture; mix the granulation mixture and the functional liquid, add them to the pill-making room, put them into an extrusion spheronizer, perform the pill-making operation, dry the wet pellets until the moisture content < 2.5%, screen them, and collect the drug-loaded pellets between 15 and 25 meshes;

[0092] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until it is clear and transparent to obtain a prepared isolation layer coating solution; put the drug-loaded pellets into a granulation coating machine and perform the isolation layer coating operation; dry the isolation layer pellets until the moisture content < 2.5%; screen them and collect the coated pellets between 15 and 25 meshes;

[0093] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir well to make them evenly mixed, add 20 g of triethyl citrate and 70 g of magnesium stearate, continue to stir to ensure they are evenly mixed to form an enteric layer coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, the rotation speed of the peristaltic pump to 8 rpm, use the enteric layer coating solution to coat the coated pellets, after the coating is completed, set the inlet air temperature to 55 °C for drying, dry until the moisture content < 2.5%, screen, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0094] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0095] Comparative Example 1

[0096] A preparation method of omeprazole enteric capsules is as follows:

[0097] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, add 3 g of soy lecithin, then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; Put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, and 5 g of hydroxypropyl methylcellulose ether into a wet granulator and mix for about 10 min to obtain a granulation mixture; Mix the granulation mixture and the functional liquid, add them to the pill-making room, put them into an extrusion spheronizer, perform pill-making operations, dry the wet pellets until the moisture content is <2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes;

[0098] Step 2: Coating of the isolation layer: Add 70 g of hydroxypropyl methylcellulose to 1000 g of purified water and stir thoroughly until it is clear and transparent to obtain a prepared isolation layer coating solution; Put the drug-loaded pellets into a granulating and coating machine and perform isolation layer coating operations; Dry the isolation layer pellets until the moisture content is <2.5%; Sieve and collect the coated pellets between 15 and 25 meshes;

[0099] Step 3: Coating of the enteric layer: Add 600 g of Eudragit L30D-55 to 800 g of purified water and stir thoroughly to make them uniformly mixed. Add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue to stir to ensure their uniform mixing to form an enteric layer coating solution; Put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature to 40 °C, the inlet air volume to 75 m 3 / h, the atomization pressure of the spray gun to 1.6 bar, and the rotation speed of the peristaltic pump to 8 rpm. Use the enteric layer coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature to 55 °C for drying until the moisture content is <2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric layer pellets;

[0100] Step 4: Load the enteric layer pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0101] Comparative Example 2

[0102] A preparation method of omeprazole enteric capsules is as follows:

[0103] Step 1: Preparation of drug-loaded pellets: Add 15 g of sodium citrate to 200 g of purified water, add 3 g of Tween 80, then add 100 g of omeprazole and stir for 15 min to obtain a functional liquid for standby; Put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, and 5 g of hydroxypropyl methylcellulose ether into a wet granulator and mix for about 10 min to obtain a granulation mixture; Mix the granulation mixture and the functional liquid, add them to the pill-making room, put them into an extrusion spheronizer, perform pill-making operations, dry the wet pellets until the moisture content is <2.5%, sieve, and collect the drug-loaded pellets between 15 and 25 meshes;

[0104] Step 2, enteric coating: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until clear and transparent to obtain the prepared enteric coating solution; put the medicated pellets into a granulating and coating machine for enteric coating operation; dry the enteric-coated pellets until the moisture content is < 2.5%; sieve and collect the coated pellets between 15 and 25 mesh;

[0105] Step 3, enteric coating: Add 600 g of Eudragit L30D-55 to 800 g of purified water, stir well to mix evenly, add 20 g of triethyl citrate and 70 g of magnesium stearate, continue to stir to ensure uniform mixing to form the enteric coating solution; put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature at 40 °C, the inlet air volume at 75 m 3 / h, the atomization pressure of the spray gun at 1.6 bar, the rotation speed of the peristaltic pump at 8 rpm, use the enteric coating solution to coat the coated pellets, after coating, set the inlet air temperature at 55 °C for drying until the moisture content is < 2.5%, sieve and use a sieve between 15 and 25 mesh to screen to obtain the enteric-coated pellets;

[0106] Step 4, load the enteric-coated pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric capsules.

[0107] Comparative Example 3

[0108] A preparation method of omeprazole enteric capsules is as follows:

[0109] Step 1, preparation of medicated pellets: Add 15 g of sodium citrate to 200 g of purified water, add 3 g of Tween 20, then add 100 g of omeprazole and stir for 15 min to obtain the functional liquid for standby; put 650 g of mannitol, 35 g of lactose, 35 g of corn starch, and 5 g of hydroxypropyl methylcellulose ether into a wet granulating machine, mix for about 10 min to obtain the granulating mixture; mix the granulating mixture and the functional liquid, add it to the pill-making room, put it into an extrusion and spheronization machine for pill-making operation, dry the wet pills until the moisture content is < 2.5%, sieve and collect the medicated pellets between 15 and 25 mesh;

[0110] Step 2, enteric coating: Add 70 g of hydroxypropyl methylcellulose ether to 1000 g of purified water, stir well until clear and transparent to obtain the prepared enteric coating solution; put the medicated pellets into a granulating and coating machine for enteric coating operation; dry the enteric-coated pellets until the moisture content is < 2.5%; sieve and collect the coated pellets between 15 and 25 mesh;

[0111] Step 3, enteric coating: Add 600 g of Eudragit L30D-55 to 800 g of purified water, and stir well to make them evenly mixed. Add 20 g of triethyl citrate and 70 g of magnesium stearate, and continue stirring to ensure they are evenly mixed to form an enteric coating solution; Put the coated pellets prepared in Step 2 into the fluidized bed material chamber, set the inlet air temperature at 40 °C, the inlet air volume at 75 m 3 / h, the atomization pressure of the spray gun at 1.6 bar, the rotation speed of the peristaltic pump at 8 rpm, and use the enteric coating solution to coat the coated pellets. After the coating is completed, set the inlet air temperature at 55 °C for drying until the moisture content < 2.5%, sieve, and use a sieve with 15 to 25 meshes for screening to obtain enteric-coated pellets;

[0112] Step 4, load the enteric-coated pellets prepared in Step 3 into gelatin hollow capsules to obtain omeprazole enteric-coated capsules.

[0113] Test Example 1

[0114] Take 30 omeprazole enteric-coated capsules prepared in the examples and comparative examples respectively, refer to the omeprazole enteric-coated capsule part in the second part of the Chinese Pharmacopoeia 2015 edition,

[0115] Evaluate the properties of the omeprazole enteric-coated capsules of the present invention. Take this product, according to the dissolution and release determination method (General Rule 0931, Method 1, Second Method), use 500 ml of hydrochloric acid solution of sodium chloride (take 1 g of sodium chloride, add 3.5 ml of hydrochloric acid, and add water to 500 ml) as the dissolution medium, the rotation speed is 100 revolutions per minute, and operate according to the law. After 120 minutes, add 400 ml of 0.235 mol / L disodium hydrogen phosphate solution preheated to 37 °C to the operating container, keep the rotation speed unchanged, and continue to operate according to the law. After 45 minutes, filter the solution, accurately measure 5 ml of the continued filtrate, accurately add 1 ml of 0.25 mol / L sodium hydroxide solution, shake well, and use it as the test solution; Separately, accurately weigh about 20 mg of omeprazole reference substance, place it in a 100 ml volumetric flask, dissolve it with 10 ml of ethanol, dilute it to the mark with a mixed dissolution medium [hydrochloric acid solution of sodium chloride - 0.235 mol / L disodium hydrogen phosphate solution (5:4)], shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask (20 mg specification) or 100 ml volumetric flask (10 mg specification), and dilute it to the mark with a mixed dissolution medium; Accurately measure 5 ml, accurately add 1 ml of 0.25 mol / L sodium hydroxide solution, shake well, and use it as the reference solution. Take the test solution and the reference solution, and determine according to the method under the content determination item, and calculate the dissolution amount per capsule. The limit is 80% of the labeled amount and should meet the requirements. Take the average value. The test results are shown in Table 1.

[0116] Assay: Determined by high performance liquid chromatography (General Principles 0512). Chromatographic conditions and system suitability test: Octadecylsilyl silica gel is used as the filler; The mobile phase is 0.01 mol / L disodium hydrogen phosphate solution (adjusted to pH 7.6 with phosphoric acid)-acetonitrile (75:25); The detection wavelength is 302 nm. The number of theoretical plates calculated with omeprazole peak is not less than 2000. Assay method: Take 20 capsules of this product, weigh accurately, and calculate the average filling amount. Take the contents, mix evenly, grind finely, weigh accurately an appropriate amount (equivalent to about 20 mg of omeprazole), place it in a 100 ml volumetric flask, add 20 ml of ethanol and about 60 ml of phosphate buffer solution (pH 11.0), sonicate to dissolve omeprazole, dilute to the scale with phosphate buffer solution (pH 11.0), shake well, filter, accurately measure 5 ml of the subsequent filtrate, place it in a 50 ml volumetric flask, dilute to the scale with water, shake well, as the test solution, accurately measure 20 μl and inject it into the liquid chromatograph, record the chromatogram; Separately take about 20 mg of omeprazole reference substance, weigh accurately, place it in a 100 ml volumetric flask, add 20 ml of ethanol and about 60 ml of phosphate buffer solution (pH 11.0), shake to dissolve, dilute to the scale with phosphate buffer solution (pH 11.0), shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, dilute to the scale with water, shake well, and determine in the same way. Calculate by the external standard method with the peak area, and you will get it.

[0117] Table 1 Dissolution test results

[0118]

[0119]

[0120] Test Example 2

[0121] Acid resistance determination

[0122] Take the omeprazole enteric-coated capsules prepared in the examples and comparative examples, according to the dissolution and release determination method (General Principles 0931, Method 1), use 500 ml of hydrochloric acid solution of sodium chloride (take 1 g of sodium chloride, add 3.5 ml of hydrochloric acid, add water to 500 ml) as the dissolution medium, the rotation speed is 100 revolutions per minute, operate according to the law, after 120 minutes, remove the rotating basket, wash the particles in the rotating basket with water until the washing liquid is neutral, transfer the particles to a 100 ml brown volumetric flask with a small amount of phosphate buffer solution (pH 11.0), according to the method under the assay item, start from "add 20 ml of ethanol" and determine according to the law, calculate by the external standard method with the peak area.

[0123] The test results are shown in Table 2.

[0124] Table 2 Acid resistance test results

[0125]

[0126]

[0127] From the test data in Table 1 and Table 2, it can be seen that the omeprazole enteric-coated capsules prepared in Example 8 of the present invention have good dissolution and acid resistance.

[0128] Compared with Example 1, Example 2 added an antioxidant (vitamin C) to the formulation. The antioxidant added in Example 3 is reduced glutathione. This may be because antioxidants can help stabilize the drug molecular structure and prevent oxidation reactions from occurring in solution. This can prevent the degradation and aggregation of drug molecules, thereby improving the dissolution of the drug. Antioxidants can resist oxidation in an acidic environment, thereby protecting drug molecules from being oxidized and damaged. In an acidic environment such as gastric acid, antioxidants can reduce the oxidative damage of drug molecules and improve the stability and tolerance of the drug.

[0129] Comparing Example 1 with Examples 4 to 8, Example 1 did not add a chelating agent, Example 4 added a chelating agent (ethylenediaminetetraacetic acid), Example 5 added a chelating agent (citric acid), Example 6 added a chelating agent (ethylenediaminediacetic acid), Example 7 added a chelating agent (sodium bisulfite), and Example 8 added a compound of chelating agents (ethylenediaminetetraacetic acid and sodium bisulfite). The addition of chelating agents can provide multiple protection effects, inhibit the oxidation and degradation of the drug, and enhance the stability of the drug. Ethylenediaminetetraacetic acid and sodium bisulfite are two different types of chelating agents, and they have different chelating mechanisms and properties. By using these two chelating agents in combination, their synergistic effect can be exerted to improve the dissolution and acid resistance of the drug.

[0130] Comparing Comparative Example 1 with Example 1, hypromellose was used in Comparative Example 1, and hypromellose ether was used in Example 1. Hypromellose ether is a water-soluble polymer with high solubility and swelling properties. It can dissolve rapidly during the dissolution process and form a viscous solution, which helps to increase the dissolution rate of the drug. In contrast, ordinary hypromellose may require a longer time during the dissolution process and has lower solubility, and may not provide a dissolution-enhancing effect similar to that of hypromellose ether. And hypromellose ether generally has good acid resistance.

[0131] In Comparative Example 2 and Comparative Example 3, Tween 80 and Tween 20 were used respectively, as compared with the soybean phospholipid used in Example 1. Among them, Tween 80 and Tween 20 are non-ionic surfactants, and their main functions are dispersion and emulsification, rather than enhancing dissolution. In contrast, soybean phospholipid, as a kind of phospholipid substance, has good solubility and can help drug molecules dissolve and improve dissolution during the dissolution process. Although Tween 80 and Tween 20 can form micelle structures, compared with soybean phospholipid, their micelles may not be stable enough or not suitable for effectively encapsulating drug molecules. This may lead to the inability of drug molecules to be fully dispersed and released in the solution, thus affecting the improvement of dissolution.

Claims

1. A method for preparing omeprazole enteric-coated capsules, characterized in that: Here’s how: Step 1, preparation of drug-containing micro-pellets: sodium citrate is added to purified water, soybean lecithin is added, and then omeprazole is added and stirred for 10 to 20 minutes to obtain a functional liquid for standby use; mannitol, lactose, corn starch, antioxidants, chelating agents, and hydroxypropyl methylcellulose are placed in a wet mixing granulator and mixed for 5 to 15 minutes to obtain a granulation mixture; the granulation mixture and the functional liquid are mixed, added to a pelleting room, placed in an extrusion spheronization machine, and a pelleting operation is performed, the wet pellets are dried to a moisture content of <2.4% to 2.6%, sieved, and drug-containing micro-pellets between 10 and 30 meshes are collected; Step 2, isolation layer coating: add hydroxypropyl methylcellulose ether to purified water, stir thoroughly until clear and transparent, and prepare isolation layer coating solution; put the drug-containing micropellets into a granulating coating machine to perform isolation layer coating operation; dry the isolation layer micropellets to a moisture content of <2.4%~2.6%; sieve and collect coated micropellets between 10~30 mesh; Step 3, enteric layer coating: add Euqite L30D-55 to purified water and stir well to make it evenly mixed, add triethyl citrate and magnesium stearate, continue stirring to ensure that they are evenly mixed to form an enteric layer coating solution; put the coated micropellets prepared in step 2 into the fluidized bed material chamber, set the inlet air temperature to 38~42℃, and the inlet air volume to 73~78m 3 / h, the spray gun atomization pressure is 1.5~1.7bar, the peristaltic pump speed is 5~10rpm, and the enteric layer coating liquid is used to coat the coated micropellets. After the coating is completed, the inlet air temperature is set to 50~60℃ for drying, and the moisture content is <2.4%~2.6%. Sieve, use a 10~30 mesh sieve for screening, and obtain enteric layer micropellets; Step 4, loading the enteric-coated pellets prepared in step 3 into empty gelatin capsules to obtain omeprazole enteric-coated capsules; The mass ratio of omeprazole to antioxidant is 80-120:3-5; The antioxidant is reduced glutathione; The mass ratio of omeprazole to chelating agent is 80-120:5-7; The chelating agent is a combination of ethylenediaminetetraacetic acid and sodium bisulfite in a mass ratio of 1:

1.

2. The method for preparing an omeprazole enteric-coated capsule according to claim 1, characterized in that: The weight parts of the substances used in step 1 are: 10-20 parts of sodium citrate, 180-220 parts of purified water, 2-4 parts of soybean lecithin, 80-120 parts of omeprazole, 600-700 parts of mannitol, 30-40 parts of lactose, 30-40 parts of corn starch, and 4-6 parts of hydroxypropyl methylcellulose; The weight proportions of the substances used in step 2 are: 60-80 parts of hydroxypropyl methylcellulose ether and 900-1100 parts of purified water; The weight portions of the substances used in step 3 are: 500-700 parts of Euqite L30D-55, 700-900 parts of purified water, 15-25 parts of triethyl citrate, and 60-80 parts of magnesium stearate.

3. An omeprazole enteric-coated capsule, characterized in that: The method is prepared by the preparation method according to any one of claims 1 to 2.

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