A micro-pellet type omeprazole enteric-coated capsule and a preparation method thereof

Abstract

The application discloses a kind of micro-pellet type omeprazole enteric-coated capsules and preparation method thereof, including drug-containing pills, isolation layer and enteric layer, wherein the drug-containing pills comprise omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, binder, filler and stabilizer;The mass ratio of omeprazole, carboxymethyl chitosan and low-substituted hydroxypropyl cellulose is 1:0.2-0.4:0.05-0.25;The micro-pellet type omeprazole enteric-coated capsule of the application does not contain organic solvent and surfactant, and the auxiliary material is simple, the micro-pellet particle size is uniform, the roundness is good, the surface finish is good, not easy to break, and the drug release effect is stable.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to pellet-type omeprazole enteric-coated capsules and a preparation method thereof. Background Art

[0002] Omeprazole, CAS: 73590-58-6; Chemical name: 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfoxide)-1H-benzimidazole; Molecular formula: C 12 H 19 N3O3S, its structural formula is as follows:

[0003]

[0004] Omeprazole, the first proton pump inhibitor developed by Astra Zeneca of Sweden, is a potent inhibitor of gastric acid secretion. Its effects are dose-dependent and its primary clinical use is for duodenal ulcers and Zollinger-Ellison syndrome, but it can also be used for gastric ulcers and reflux esophagitis. Omeprazole is weakly alkaline and easily broken down and rendered ineffective by the acidic environment of the stomach after oral administration. Therefore, oral omeprazole preparations are typically formulated as enteric-coated preparations, with an enteric coating that does not dissolve in acidic gastric fluid but dissolves in alkaline intestinal fluid. Currently, the main commercial dosage forms are enteric-coated tablets and capsules. Currently, omeprazole enteric-coated capsules are typically composed of enteric-coated micropellets enclosed in a conventional capsule shell. Immature enteric coating technology and processes, or substandard excipients, can lead to partial dissolution of the active ingredient in gastric fluid or infiltration of gastric fluid into the micropellets, destroying and rendering ineffective the active ingredient. Alternatively, incomplete dissolution of the enteric-coated micropellets in intestinal fluid can result, preventing therapeutic efficacy.

[0005] The preparation technology of micropills at present mainly includes extrusion spheronization, centrifugal granulation, melting method, etc. Among them, the extrusion spheronization method has the advantages of high efficiency, simple operation, narrow particle size distribution, good roundness of pellets, smooth surface, and is suitable for further coating. However, due to the fact that omeprazole itself is easily unstable due to the influence of light, humidity, heat, and organic solvents, and is insoluble in water, the technical personnel of the present application found that, when extrusion spheronization granulation is performed, incompatibility of auxiliary materials and loose powder are easily caused, the yield of the obtained micropills is low, the uniformity and roundness are poor, and the release of the obtained enteric-coated pills is unstable and has large differences. In addition, excessive auxiliary materials in the prescription, the use of organic solvents, etc. are easy to cause the total impurity content of the preparation to be higher after long-term storage.

[0006] Chitosan is a natural macromolecular substance and an alkaline polysaccharide. It is insoluble in water but soluble in acidic solutions and has been used in the research of sustained-release and controlled-release formulations. For example, Chinese patent CN202111277447.X discloses an omeprazole microsphere core-shell enteric-coated capsule, comprising an omeprazole-chitosan microsphere pellet and a coating layer. The omeprazole-chitosan microsphere pellet contains 20-25 parts omeprazole, 32-48 parts chitosan / ethanol solution, 4-9 parts casein, 20-28 parts microcrystalline cellulose, 20-25 parts glyceryl behenate, 8-15 parts soy lecithin, and 18-22 parts vitamin E. This invention uses a specific ratio of omeprazole, chitosan / ethanol solution, casein, microcrystalline cellulose, behenic acid glyceride, soy lecithin and vitamin E to prepare omeprazole chitosan microsphere pills through an emulsification-dispersion process. Although this can solve the problems of compatibility and stability of omeprazole excipients, the preparation process is too complicated and difficult to implement.

[0007] Carboxymethyl chitosan (CMC) is a chitosan derivative produced by the carboxymethylation of chitosan with chloroacetic acid under alkaline conditions. It is a unique amphoteric polysaccharide. Its unique chemical structure imparts unique biological activities such as excellent dispersibility, moisture retention, film-forming properties, and thickening properties. It also promotes intestinal absorption. CMC is currently being increasingly studied and applied in the field of medical biomaterials. Furthermore, existing research (Yang Zhao. Properties of Polymeric Carboxymethyl Chitosan and Its Hemostatic and Wound-Healing Functions. Graduate Thesis. Ocean University of China. 2012) indicates that the solubility and water swelling properties of CMC are related to its molecular weight.

[0008] Combined with the existing records on omeprazole enteric-coated preparations, the main disadvantages are poor biocompatibility of raw materials and excipients, unstable omeprazole, unstable drug release, excessive addition of excipients and organic solvent residues in the prescription, which can easily lead to a high total impurity content in the preparation. Summary of the Invention

[0009] In view of the shortcomings of the existing technology, the present invention aims to provide micro-pellet omeprazole enteric-coated capsules to address the problems of existing omeprazole enteric-coated capsules, such as complex production process, poor excipient compatibility, and unstable drug release. These micro-pellet omeprazole enteric-coated capsules contain no organic solvents or surfactants, utilize simple excipients, and exhibit uniform particle size, good roundness, smooth surface finish, resistance to breakage, and stable drug release.

[0010] To achieve the above objectives, the present invention technicians have conducted a lot of experimental research and improvements on existing formulations and processes, and obtained the following technical solutions:

[0011] A micro-pellet type omeprazole enteric-coated capsule comprises a drug-containing pellet, an isolation layer and an enteric layer. The drug-containing pellet comprises omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, a binder, a filler and a stabilizer; wherein the mass ratio of omeprazole, carboxymethyl chitosan and low-substituted hydroxypropyl cellulose is 1:(0.2-0.4):(0.05-0.25); the isolation layer coating material is water-soluble cellulose, and the isolation layer coating weight gain is 2-10%; the enteric layer comprises an enteric material, a plasticizer and a lubricant, and the enteric layer coating weight gain is 18-26%.

[0012] In the present invention, the composition and mass ratio of omeprazole, carboxymethyl chitosan, and low-substituted hydroxypropyl cellulose are key technical factors in achieving the desired effect. Those skilled in the art will appreciate that the extrusion and spheronization process involves dry powder mixing, soft material preparation, extrusion, spheronization, and drying. The composition of the excipients and the compatibility and biocompatibility between the raw and excipients significantly influence the formation and quality of the micropellets obtained through extrusion and spheronization. Furthermore, to prevent the extrudate from being subjected to excessive extrusion forces or excessive extrusion speeds during the extrusion process, which can result in surface defects and incompleteness, a common practice is to add a binder to increase the viscosity of the materials. Therefore, the preparation of the soft material generally requires the addition of a relatively large amount of solvent, such as water or ethanol, to maintain material wettability. However, excessive solvents, particularly organic solvents, can easily deteriorate omeprazole during the extrusion and spheronization process. Through extensive screening experiments, those skilled in the art have discovered that the introduction of highly hygroscopic carboxymethyl chitosan, which contains numerous amino and hydroxyl groups in its molecular structure and can form hydrogen bonds with water, significantly reduces solvent usage while improving compatibility between the excipients. In addition, during the mixing process of raw materials and excipients, carboxymethyl chitosan and excipients work together to wrap the active ingredients in a polymer network, which absorbs water and swells in alkaline intestinal fluid, and can help promote disintegration. Therefore, in this solution, carboxymethyl chitosan has the effect of solubilizing and lubricating in the preparation of drug-containing pills, which can reduce the amount of adhesives and solvents used, and at the same time cooperates with low-substituted hydroxypropyl cellulose to disintegrate the micropills. For this case, in order to achieve the expected technical effect, the carboxymethyl chitosan is selected from carboxymethyl chitosan with a molecular weight of 220-260KD and a carboxylation degree greater than 85%. When the molecular weight is lower than 220KD, it has a high water solubility but no swelling ability, which is not conducive to the disintegration of the micropills; when the molecular weight is higher than 260KD, it is easy to rapidly swell when absorbing water, and the swelling ability is too large, the compatibility of the excipients decreases, and the drug release is blocked.

[0013] More specifically, the inventors found through a large number of experiments that the mass ratio of omeprazole, carboxymethyl chitosan and low-substituted hydroxypropyl cellulose is 1: (0.25-0.35): (0.10-0.20), preferably 1: 0.3: 0.15, which is conducive to the stability of omeprazole and ensures good compatibility between the excipients.

[0014] In the present invention, the particle size selection of omeprazole and filler is an important technical key to achieving the technical effect. If the raw material particle size is small, it will have a large specific surface area, the drug release will be too fast, and it will be easily adhered into agglomerates during the granulation process; if the particle size is too large, it will be unfavorable for mixing with the excipients, the preparation mixing uniformity will be poor, and the subsequent release will be affected. Therefore, the appropriate particle size can further ensure its smooth release effect. For this solution, the particle size of the omeprazole is D90≤30μm, more preferably, the particle size of the omeprazole is D90≤20μm, and most preferably D90≤15μm. For this solution, the particle size of the filler is 25μm≤D90≤100μm, more preferably, the particle size of the filler is 40μm≤D90≤60μm.

[0015] In the present invention, in the micro-pellet type omeprazole enteric-coated capsules, the filler in the drug-containing pellets is selected from one or a combination of two or more in any proportions of microcrystalline cellulose, sugar alcohol, mannitol, and dextrin. The amount of microcrystalline cellulose has a large specific surface area and high internal porosity, good compressibility and hydrophilicity, and is conducive to extrusion. In this case, the amount of microcrystalline cellulose is reduced, and the amount of fine powder in the drug-containing pellets is increased; the amount of microcrystalline cellulose is increased, and the prepared micro-pellets have high strength and hardness, and the drug dissolution is slowed down. Mannitol has good water solubility, but is not hygroscopic and has poor plasticity. In this case, the drug release is slow when the amount of mannitol is reduced; the appearance and yield of the prepared micro-pellets are not ideal when the amount of mannitol is increased. When the fillers are in an appropriate proportion, the release rate and micro-pellet quality can meet the requirements. Preferably, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose to mannitol is 1:(23-27); preferably 1:(24-26); specifically 1:24, 1:24.5, 1:25, 1:25.6, 1:26.

[0016] In the present invention, the selection of the formulation for the drug-containing micropills is one of the key factors in achieving the technical effect. Generally, the key factors in pelleting by the extrusion spheronization method are the material properties and the humidity of the material during the pelleting process. In particular, for omeprazole, which is unstable and poorly soluble, the type and amount of added excipients have a significant impact on the appearance quality of the micropills and the drug release effect. For example, too much filler will result in uneven drug release; too much binder will not be conducive to spheronization, increase friability, and reduce yield. Too much stabilizer will not be conducive to drug release. In this case, the mass ratio of omeprazole to filler in the drug-containing pellets is 1:(5-8), preferably 1:(6-7), and more preferably 1:(6.5-6.9). In this case, the mass ratio of omeprazole to binder in the drug-containing pellets is 1:(0.01-0.1), preferably 1:(0.03-0.08), and more preferably 1:0.03, 1:0.05, 1:0.06, and 1:0.08. In this case, in the drug-containing pills, the mass ratio of omeprazole to stabilizer is 1:(0.3-1.2), preferably 1:(0.6-1.0), and more preferably 1:0.6, 1:0.8, 1:0.9 and 1:1.0.

[0017] In the present invention, the binder is selected from one or a combination of two or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone in any proportion, preferably hydroxypropyl methylcellulose; the stabilizer is selected from one or a combination of two or more of L-arginine, anhydrous sodium bicarbonate, and anhydrous disodium hydrogen phosphate in any proportion, preferably a mixture of L-arginine and anhydrous sodium bicarbonate, and the mass ratio of L-arginine to anhydrous sodium bicarbonate is 1:(1-3), specifically preferably 1:1, 1:1.5, 1:2, 1:2.5 and 1:3.

[0018] In the present invention, the isolation layer coating material is selected from water-soluble cellulose, preferably hypromellose. The isolation layer coating weight gain should be appropriate. Excessive weight gain can affect drug release, while too little weight gain can prevent complete separation between the primary drug layer and the acidic enteric layer, failing to protect the primary drug. In this case, the isolation layer coating weight gain needs to be maintained within a range of 2-10%, preferably 7-10%, to meet acid resistance and release requirements.

[0019] In the present invention, the enteric material in the enteric coating is an acrylic resin aqueous dispersion (Eudragit L30D-55) or a combination of one or more of hydroxypropyl methylcellulose phthalate in any proportion, preferably an acrylic resin aqueous dispersion. The plasticizer is a combination of one or more of triethyl citrate and a polyethylene glycol series in any proportion, preferably polyethylene glycol 400 and polyethylene glycol 600. The lubricant is a combination of one or more of titanium dioxide and glyceryl monostearate in any proportion. In this case, in the enteric layer coating, the mass ratio of the enteric material, plasticizer, and lubricant is 1:(0.06-0.12):(0.005-0.015). Furthermore, the mass ratio of the enteric material, plasticizer, and lubricant is 1:(0.07-0.10):(0.008-0.012), and the optimal ratio is 1:0.08:0.010. In this case, the enteric layer coating weight gain needs to be maintained at 18-26%, and more preferably, the enteric layer coating weight gain is in the range of 20-24% to meet the acid resistance and release requirements.

[0020] In addition, the inventors found that during the enteric layer coating process, as the solution evaporates, the viscosity of the enteric material on the surface of the micropills gradually increases. This may be due to the friction of the polymer material that easily generates static electricity, which causes the micropills to easily stick together. Therefore, it is very important to choose a suitable lubricant to solve the micropill adhesion phenomenon during the enteric layer coating process. The inventors found that when a mixed lubricant is used, the effect is better than using a single type of lubricant. Specifically, the lubricant is a mixture of titanium dioxide and glyceryl monostearate, and the mass ratio of titanium dioxide to glyceryl monostearate is 1: (1-3); preferably, the mass ratio of titanium dioxide to glyceryl monostearate is 1:2, 2:3, and 1:3.

[0021] Specifically, a preferred technical solution of the micro-pellet type omeprazole enteric-coated capsules of the present invention is composed as follows:

[0022]

[0023] The purified water used in the processes of preparing the soft material for the drug-containing pills, coating the isolation layer, and coating the enteric layer is dried and removed and not included in the prescription amount; in the process of preparing the soft material for the drug-containing pills, the amount of water added is 12-18% of the prescription amount of the drug-containing pills; in the process of coating the isolation layer, the coating liquid is a 4-6% aqueous solution of hypromellose; in the process of coating the enteric layer, the amount of water added is equivalent to the amount used in Eudragit L30D-55.

[0024] Those skilled in the art will understand that the "coating weight gain" herein refers to the difference between the weight of the pellets after coating and the weight of the pellets before coating, expressed as a percentage of the weight of the pellets before coating. For example, the weight gain of the isolation layer coating is calculated using the formula: (weight of the isolation layer coated pellets - weight of the drug-containing pellets) / weight of the drug-containing pellets * 100%; the weight gain of the enteric layer coating is calculated using the formula: (weight of the enteric layer coated pellets - weight of the isolation layer coated pellets) / weight of the isolation layer coated pellets * 100%.

[0025] The actual usage amount of the isolation layer coating solution and the enteric layer coating solution in the present invention can be converted by those skilled in the art according to the coating weight gain and the weight of the pellets before coating.

[0026] The micro-pellet type omeprazole enteric-coated capsules of the present invention are available in specifications of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg and 120 mg, with specifications of 20 mg and 40 mg being preferred.

[0027] The present invention also provides a preparation process for the above-mentioned micro-pellet-type omeprazole enteric-coated capsules. The preparation process adopts an extrusion-spheronization method to prepare drug-containing micro-pellets, and then adopts a multifunctional fluidized bed to coat and dry them to obtain micro-pellet-type omeprazole enteric-coated capsules. The method comprises the following steps:

[0028] S1. Preparation of drug-containing pills:

[0029] 1) Preparation: Weigh omeprazole and each excipient according to the prescribed amount. Except for omeprazole and fillers, all other excipients are sieved through a 60-mesh sieve and set aside.

[0030] 2) Premixing: Add the prescribed amount of omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, filler and binder into a wet mixing granulator and premix for 10 minutes to obtain a premix;

[0031] 3) Preparing the soft material: dissolving the stabilizer in purified water, and adding the resulting solution to the premix to prepare the soft material;

[0032] 4) Extrusion and spheronization: The above soft material is placed in an extruder, and the feeding speed is set to 30-70 rpm and the extrusion speed is set to 20-70 rpm to obtain an extruded strip; the obtained extruded strip is transferred to a spheronization disk and spheronized to obtain micropellets, and the spheronization speed is set to 220-270 rpm and the spheronization time is 50-60 s;

[0033] 5) Drying: After the moisture content of the pellets is controlled at 1.0%, the pellets are sieved and the pellets with 14-24 mesh are collected to be the drug-containing pellets.

[0034] S2. Seal coating:

[0035] 1) Preparation of isolation layer coating solution: Add hydroxypropyl methylcellulose to purified water, stir evenly, and prepare a 4-6% hydroxypropyl methylcellulose aqueous solution for standby use.

[0036] 2) Seal Coating: The drug-containing pellets are placed in a multifunctional fluidized bed machine for coating to obtain seal-coated pellets. The liquid feed rate is controlled at 0.30-0.65 kg / min and the material temperature is maintained at 33-41°C. After spraying, the seal-coated pellets are dried to a moisture content of <1.0%, then cooled to a temperature of <40°C. The pellets are discharged, sieved, and pellets with a mesh size of 12-24 are collected as seal-coated pellets.

[0037] S3. Enteric coating

[0038] 1) Preparation of coating solution: Weigh the prescribed amount of polyethylene glycol-4000 and Eudragit L30D-55, add them to purified water in sequence, stir evenly, then add titanium dioxide and glyceryl monostearate, stir evenly, and pass through a 60-mesh sieve for later use.

[0039] 2) Enteric Layer Coating: The isolation layer pellets are placed in a multifunctional granulation coating machine for coating to obtain enteric layer pellets. The liquid feed rate should be controlled at 8-12 g / min and the material temperature at 34-37°C. After the liquid spraying is completed, the enteric layer pellets are dried to a moisture content of <1.0%, then cooled to a material temperature of <40°C. The pellets are discharged and sieved to collect pellets with a mesh size of 12-24. These are the enteric coated pellets.

[0040] S4. Filling capsules: Fill enteric-coated micropellets into No. 2 gelatin hollow capsules according to the required specifications and content to obtain micropellet-type omeprazole enteric-coated capsules.

[0041] The present invention has the following advantages and beneficial effects compared to the prior art:

[0042] 1. This solution adds carboxymethyl chitosan to the drug-containing pills and coordinates the amount of low-substituted hydroxypropyl cellulose to obtain a product with uniform particle size, good roundness, good surface finish, not easy to break, and stable drug release effect.

[0043] 2. The omeprazole enteric-coated capsules prepared by this scheme are beneficial to the stability of the product and improve the in vitro dissolution rate of the drug.

[0044] 3. The prescription ingredients of this solution are simple, especially lactose-free, which is suitable for patients with lactose intolerance. The excipients have good biocompatibility, the product yield is high, and there is no obvious increase in impurities after long-term maintenance, which meets the preparation requirements. DETAILED DESCRIPTION

[0045] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0046] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

[0047] Unless otherwise specified, the drugs, auxiliary materials and equipment used in the present invention can be purchased from the market.

[0048] Example 1

[0049] A micro-pellet type omeprazole enteric-coated capsule, the prescription composition of which is as follows:

[0050]

[0051]

[0052] The specific preparation method is as follows:

[0053] S1. preparing drug-containing pills;

[0054] 1) Preparation: Weigh omeprazole and each excipient according to the prescribed amount. Except for omeprazole and fillers, all other excipients are sieved through a 60-mesh sieve and set aside.

[0055] 2) Premixing: Add the prescribed amount of omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, filler and binder into a wet mixing granulator and premix for 10 minutes to obtain a premix;

[0056] 3) Preparing the soft material: dissolving the stabilizer in an appropriate amount of purified water, and adding the resulting solution to the premix to prepare the soft material;

[0057] 4) Extrusion and Spheronization: Place the above soft material into an extruder, set the feed speed to 30-70 rpm and the extruder speed to 20-70 rpm to obtain an extruded strip. Transfer the obtained extruded strip to a spheronization plate and spheronize to obtain pellets. Set the spheronization speed to 220-270 rpm and the spheronization time to 50-60 seconds.

[0058] 5) Drying: After the moisture content of the pellets is controlled at 1.0%, the pellets are sieved and the pellets with 14-24 mesh are collected to be the drug-containing pellets.

[0059] S2. Seal coating:

[0060] 1) Preparation of isolation layer coating solution: Add hydroxypropyl methylcellulose to purified water, stir evenly, and prepare a 4-6% hydroxypropyl methylcellulose aqueous solution for standby use.

[0061] 2) Seal Coating: The drug-containing pellets are placed in a multifunctional fluidized bed machine for coating to obtain seal-coated pellets. The liquid feed rate is controlled at 0.30-0.65 kg / min and the material temperature is maintained at 33-41°C. After spraying, the seal-coated pellets are dried to a moisture content of <1.0%, then cooled to a temperature of <40°C before discharge. Sieve and collect pellets with a mesh size of 12-24, which are the seal-coated pellets.

[0062] S3. Enteric coating

[0063] 1) Preparation of coating solution: Weigh the prescribed amount of polyethylene glycol-4000 and Eudragit L30D-55, add them to purified water in sequence, stir evenly, then add titanium dioxide and glyceryl monostearate, stir evenly, and pass through a 60-mesh sieve for later use.

[0064] 2) Enteric Layer Coating: Place the isolation layer pellets in a multifunctional granulator and coat them to obtain enteric layer pellets. The liquid feed rate should be controlled at 8-12 g / min and the material temperature at 34-37°C. After spraying, the enteric layer pellets are dried to a moisture content of <1.0%, cooled to a temperature of <40°C, and discharged. Sieve and collect pellets with a mesh size of 12-24 to obtain the enteric-coated pellets.

[0065] S4. Filling capsules: Fill enteric-coated micropellets into No. 2 gelatin hollow capsules at a content of 20 mg / pill to obtain micropellet-type omeprazole enteric-coated capsules.

[0066] Example 2

[0067] A micro-pellet type omeprazole enteric-coated capsule, the formulation of which is as follows, and the preparation method is the same as in Example 1:

[0068]

[0069] Example 3

[0070] A micro-pellet type omeprazole enteric-coated capsule, the formulation of which is as follows, and the preparation method is the same as in Example 1:

[0071]

[0072] Example 4

[0073] A micro-pellet type omeprazole enteric-coated capsule, the formulation of which is as follows, and the preparation method is the same as in Example 1:

[0074]

[0075]

[0076] Comparative Example 1

[0077] A micro-pellet type omeprazole enteric-coated capsule, in which carboxymethyl chitosan is not added, has the following composition and is prepared by the same method as in Example 1:

[0078]

[0079]

[0080] Comparative Example 2

[0081] A micro-pellet type omeprazole enteric-coated capsule, wherein the carboxymethyl chitosan added in the formulation has a relatively high molecular weight. The formulation composition is shown below, and the preparation method is the same as that in Example 1:

[0082]

[0083]

[0084] Comparative Example 3

[0085] A micro-pellet type omeprazole enteric-coated capsule, wherein the carboxymethyl chitosan added in the formulation has a relatively low molecular weight. The formulation composition is shown below, and the preparation method is the same as that in Example 1:

[0086]

[0087] Comparative Example 4

[0088] A micro-pellet type omeprazole enteric-coated capsule, wherein the particle sizes of omeprazole and the filler mannitol are relatively large, the formulation composition is as follows, and the preparation method is the same as that of Example 1:

[0089]

[0090] Comparative Example 5

[0091] A micro-pellet type omeprazole enteric-coated capsule, the formulation of which is as follows, wherein magnesium stearate is used as a lubricant in the enteric layer coating, and the preparation method is the same as that in Example 1:

[0092]

[0093]

[0094] Example 5

[0095] Table 1: Analysis of the pellets obtained in Examples 1-4 and Comparative Examples 1-5

[0096]

[0097]

[0098] Analyzing the data in Table 1, it is known that in Examples 1-4, the carboxymethyl chitosan with a specific molecular weight is added, and the yield by extrusion spheronization granulation is higher, which is 92.1% to 93.4%, and the excipient biocompatibility is better, without fine powder; and in the subsequent isolation layer and enteric layer coating, the hardness of the micropills meets the requirements, without the occurrence of fragmentation or adhesion into agglomeration, and the isolation coating and enteric coating yields are higher, greater than 97%. In Comparative Example 1, the lack of carboxymethyl chitosan prescription extrusion spheronization into pills has a poor effect, is more subdivided, and more micropills are broken in the isolation coating. In Comparative Example 2, the added carboxymethyl chitosan molecular weight is higher (300-320KD), and the quality of the obtained drug-containing pills meets the requirements by extrusion spheronization granulation into pills and in the coating process, without obvious fragmentation, but the overall yield is lower than that of Examples 1-4. In Comparative Example 3, the added carboxymethyl chitosan had a low molecular weight (160-180 kD), resulting in poor roundness of the pellets produced by extrusion spheronization, with a high proportion of elongated pellets. Furthermore, pellets broke during the coating process. This indicates that the molecular weight of the added carboxymethyl chitosan has an impact on the quality of the medicinal pellets in this solution.

[0099] In Comparative Example 4, the omeprazole and mannitol particles used were relatively large in size. Although the pellets were well granulated by extrusion and spheronization, their friability was low. During the subsequent isolation coating, many pellets were damaged, and the quality of the drug-containing pellets did not meet the requirements. This shows that the particle size of omeprazole and mannitol in this solution has a significant impact on the quality of the resulting drug-containing pellets.

[0100] In Comparative Example 5, when magnesium stearate was used as a lubricant during the enteric layer coating process, blockage occurred during the coating process and the quality of the obtained micropills was sticky and lumpy, which did not meet the requirements.

[0101] Example 6 Acid resistance test results

[0102] Referring to the determination method of the content and acid resistance of omeprazole enteric-coated capsules in the 2020 edition of the Chinese Pharmacopoeia, 6 products from the same batch of Examples 1-4 and Comparative Example 5 were taken to test the acid resistance of the omeprazole capsules obtained in this application at pH values ​​of 1.2 and 4.5. The results are shown in Table 1.

[0103] Table 1: Acid resistance test results

[0104] batch number Example 1 Example 2 Example 3 Example 4 Comparative Example 5 Acid resistant (pH 1.2) 95.1％ 97.6％ 96.8％ 96.4％ 92.8％ Acid resistant (pH 4.5) 96.7％ 96.2％ 97.2％ 96.8％ 83.1％

[0105] As shown in Table 1 above, the examples in this solution all have sufficient acid resistance when using a mixture of titanium dioxide and glyceryl monostearate as a lubricant for the enteric layer coating. In Comparative Example 5, magnesium stearate is used for the enteric layer coating, and the acid resistance of the resulting product is reduced.

[0106] Example 7 Multi-media Dissolution Investigation Results

[0107] Experimental method: Six omeprazole enteric-coated capsules from the same batch prepared in Examples 1-4 and Comparative Examples 2-4 were selected respectively, and the dissolution and release rate determination method in the second method of 0931 of the fourth general rule of the 2020 edition of the "Chinese Pharmacopoeia" was referred to. The test was carried out by the medium slurry method: first, the medium was transferred in 500 ml of hydrochloric acid-sodium chloride solution (pH 1.2) for 2 hours, and then 400 ml of disodium hydrogen phosphate pH adjusting solution was added according to the mixed dissolution medium and continued to transfer for 60 minutes. The average results of the 6 samples are shown in Table 2 below.

[0108] Table 2: Dissolution test results

[0109]

[0110]

[0111] As shown in the table, the dissolution results of the pH 6.8 (1.2 in acid) medium (simulated intestinal drug release) show that the product release rate is greater than 95% in 30-45 min in Examples 1-4 of this solution, and the drug release effect is complete. There is no significant difference between the drug release rate and the drug release behavior of commercially available omeprazole enteric-coated capsules. In Comparative Example 2, the drug release rate is lower, which is speculated to be due to the high molecular weight carboxymethyl chitosan and low-substituted hydroxypropyl cellulose having higher swelling rates, and the two swellings intersecting to form too dense "network" spaces, which retard the dissolution of the active ingredient. In Comparative Example 4, the drug release rate is lower, which is speculated to be due to the larger mannitol particle size and the slower dissolution rate, which cannot provide a space quickly for omeprazole to release. Simultaneously, the omeprazole particle size is larger and dissolves more slowly.

[0112] In a pH 6.0 (1.2 in acid) medium, omeprazole enteric-coated capsules gradually degrade during dissolution, resulting in a low overall drug release rate. However, the products obtained in Examples 1-4 of this solution still maintained a release rate greater than 85% within 45 minutes, indicating that the formulation ingredients in Examples 1-4 contribute to the stability of omeprazole.

[0113] Example 8 Preparation Stability Study

[0114] The products of Example 1 and Comparative Example 1 were subjected to stability tests, and the results are shown in Table 3. Test conditions: 25±2°C, 60%±5% RH, the bottles were opened once a day, and the products were tested after 28 days of opening.

[0115] Table 3: Preparation stability test results

[0116]

[0117] As shown in Table 3 above, the omeprazole enteric-coated capsule samples prepared by adding carboxymethyl chitosan to the formulation of Example 1 and using a specific excipient content ratio showed no significant increase in impurity content during long-term storage, exhibited good stability, and showed no difference in release behavior or acid resistance. In the stability results of Comparative Example 1, the omeprazole content decreased, while the impurity content exceeded the limit standard. This suggests that the addition of carboxymethyl chitosan with a relatively high molecular weight cannot completely inhibit the degradation of the raw materials, or is detrimental to the long-term stability of the excipients, resulting in an increase in total impurities after long-term storage.

[0118] In the subsequent industrial production, the properties of the prepared drug-containing pills, isolated pills and enteric-coated pills as well as the final product showed consistent effects. It can be seen that the prescription of the micro-pellet type omeprazole enteric-coated capsules in this scheme is suitable for industrial scale-up production.

[0119] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A micro-pellet-type omeprazole enteric-coated capsule, comprising a drug-containing pellet, a separation layer, and an enteric layer, wherein the drug-containing pellet comprises omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, a binder, a filler, and a stabilizer; wherein the mass ratio of omeprazole, carboxymethyl chitosan, and low-substituted hydroxypropyl cellulose in the drug-containing pellet is 1:0.2-0.4:0.05-0.25; the coating material of the separation layer is water-soluble cellulose, and the weight gain of the separation layer coating is 2-10%; the enteric layer comprises an enteric material, a plasticizer, and a lubricant, and the weight gain of the enteric layer coating is 18-26%; in: The molecular weight of the carboxymethyl chitosan is 220-260KD; The particle size of the omeprazole is D90≤15 μm; The particle size of the filler is 40 μm ≤ D90 ≤ 60 μm; The mass ratio of omeprazole to filler is 1:5-8, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose to mannitol is 1:23-27; The mass ratio of omeprazole to binder in the drug-containing pills is 1:0.01-0.1; the binder is selected from one or a combination of two or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone in any proportion; The mass ratio of omeprazole to stabilizer is 1:0.3-1.2; the stabilizer is selected from one or a combination of two or more of L-arginine, anhydrous sodium bicarbonate, and anhydrous disodium hydrogen phosphate in any proportion; The mass ratio of the enteric material, plasticizer and lubricant in the enteric layer is 1:0.06-0.12:0.005-0.015, the enteric material is one or a combination of two of an acrylic resin aqueous dispersion and hydroxypropyl methylcellulose phthalate; the plasticizer is one or a combination of two or more of triethyl citrate and a polyethylene glycol series; the lubricant is a mixture of titanium dioxide and glyceryl monostearate, and the mass ratio of titanium dioxide to glyceryl monostearate is 1:1-3.

2. The micropellet-type omeprazole enteric-coated capsule according to claim 1, characterized in that: The mass ratio of omeprazole, carboxymethyl chitosan and low-substituted hydroxypropyl cellulose in the drug-containing pills is 1:0.25-0.35:0.10-0.

20.

3. The micropellet-type omeprazole enteric-coated capsule according to claim 2, characterized in that: The mass ratio of omeprazole, carboxymethyl chitosan and low-substituted hydroxypropyl cellulose in the drug-containing pills is 1:0.3:0.

15.

4. The micropellet-type omeprazole enteric-coated capsule according to claim 1, characterized in that: The mass ratio of the microcrystalline cellulose to mannitol is 1:24-26.

5. The micropellet-type omeprazole enteric-coated capsule according to claim 1, characterized in that: The binder is selected from hydroxypropyl methylcellulose.

6. The micropellet-type omeprazole enteric-coated capsule according to claim 1, characterized in that: The stabilizer is selected from a mixture of L-arginine and anhydrous sodium bicarbonate, and the mass ratio of L-arginine to anhydrous sodium bicarbonate is 1:1-3.

7. The enteric-coated omeprazole capsules according to claim 1, characterized in that: It contains the following components:

8. A process for preparing the micropellet-type omeprazole enteric-coated capsules according to claim 7, characterized in that: The process includes the following steps: S1. preparing drug-containing pills; 1) Preparation: Weigh omeprazole and each excipient according to the prescribed amount. Except for omeprazole and mannitol, all other excipients are sieved through a 60-mesh sieve and set aside. 2) Premixing: Add the prescribed amount of omeprazole, carboxymethyl chitosan, low-substituted hydroxypropyl cellulose, fillers microcrystalline cellulose and mannitol, and binder hydroxypropyl cellulose into a wet mixing granulator and premix for 10 minutes to obtain a premix; 3) Preparing the soft material: dissolving the stabilizer L-arginine and sodium bicarbonate in purified water, and adding the resulting solution to the premix to prepare the soft material; 4) Extrusion and spheronization: The above soft material is placed in an extruder, and the feeding speed is set to 30-70 rpm and the extrusion speed is set to 20-70 rpm to obtain an extruded strip. The obtained extruded strip is transferred to a spheronization disk and spheronized to obtain micropellets. The spheronization speed is set to 220-270 rpm and the spheronization time is 50-60 s. 5) Drying: After the moisture content of the pellets is controlled at 1.0%, sieve and collect the pellets with 14-24 mesh; these are the drug-containing pellets; S2. Seal coating: 1) Preparation of the isolation layer coating solution: Add hypromellose to purified water and stir evenly to prepare a 4-6% aqueous solution of hypromellose for later use; 2) Seal layer coating: The drug-containing pellets are placed in a multifunctional fluidized bed machine for coating to obtain isolate layer pellets, wherein the liquid supply rate needs to be controlled at 0.30-0.65 kg / min and the material temperature needs to be controlled at 33-41°C. After the liquid spraying is completed, the isolate layer pellets are dried until the moisture content is less than 1.0%, cooled to a material temperature of less than 40°C, discharged, sieved, and pellets of 12-24 mesh size are collected; these are isolater pellets; S3. Enteric coating 1) Coating solution preparation: Weigh the prescribed amount of plasticizer polyethylene glycol-400 and enteric material Eudragit L30D-55, add them to purified water, stir evenly, then add lubricant titanium dioxide and glyceryl monostearate, stir evenly, and pass through a 60-mesh sieve for later use; 2) Enteric layer coating: Place the isolation layer pellets in a multifunctional granulating coating machine for coating to obtain enteric layer pellets, wherein the liquid supply rate needs to be controlled at 8-12 g / min and the material temperature at 34-37°C. After the liquid spraying is terminated, the enteric layer pellets are dried until the moisture content is less than 1.0%, cooled to a material temperature of less than 40°C, discharged, sieved, and small pellets with a mesh size of 12-24 are collected as enteric coated pellets; S4. Filling capsules: Fill enteric-coated micropellets into No. 2 gelatin hollow capsules according to the required specifications and content to obtain micropellet-type omeprazole enteric-coated capsules.

Images