An enteric-coated empty capsule with good resistance to brittleness and its preparation process

Abstract

This application relates to the field of medical preparations, specifically disclosing an enteric-coated empty capsule with good brittleness resistance and its preparation process. The preparation process of an enteric-coated empty capsule with good brittleness resistance is as follows: S1, gelatin, a first plasticizer, a light-blocking agent, and a colorant are prepared into a glue solution; S2, hydroxypropyl methylcellulose, sodium alginate, chitosan, and a second plasticizer are prepared into a first coating solution; S3, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and a neutralizing agent are prepared into a second coating solution; S4, the capsule mold is dipped in the glue solution, dried to form a capsule base, first coating, dried, second coating, dried, capsule removed, cut, and assembled to obtain the enteric-coated empty capsule. The product of this application has a tight bond between the layers, thus possessing high dissolution rate, acid resistance, and brittleness qualification rate. Experimental data shows that its brittleness qualification rate is not less than 96%, exhibiting good brittleness resistance.

Description

Technical Field

[0001] This application relates to the technical field of medical preparations, and in particular to an enteric-coated empty capsule with good anti-fragility and its preparation process. Background Technology

[0002] Conventional pharmaceutical capsules primarily use gelatin empty capsules. After being filled with medication, they form a formulation that dissolves in the stomach and is absorbed through the small intestine to exert its therapeutic effect. However, some medications irritate the stomach, potentially causing side effects. Additionally, some medications are easily degraded by stomach acid, making conventional empty capsule formulations unsuitable for these types of drugs. To address this, researchers have developed enteric-coated empty capsules that do not dissolve in gastric juice but are absorbed in the intestines. These capsules typically still use gelatin as the core, followed by an outer coating to achieve enteric coagulation. The outer coating usually consists of cellulose acetate phthalate, acrylic resins, and hydroxypropyl methylcellulose phthalate as the main materials, all of which are soluble in intestinal fluid with a pH ≥ 6.0, thus achieving enteric coagulation.

[0003] However, due to the different mechanical strengths of the gelatin-based capsule base and the coating layer, as well as the varying water vapor permeability under dry conditions, the capsule base and coating are prone to delamination, leading to capsule breakage. Based on this, and given the poor brittleness resistance of existing enteric-coated capsules, the engineers believe it is essential to provide an enteric-coated empty capsule with excellent brittleness resistance. Summary of the Invention

[0004] To address the aforementioned technical problems, this application provides an enteric-coated empty capsule with good anti-friability and its preparation process.

[0005] In a first aspect, this application provides an enteric-coated empty capsule with good brittleness resistance, comprising a capsule base, a first coating layer, and a second coating layer arranged sequentially from the inside out; by weight, the capsule base comprises: 35-45 parts gelatin, 15-25 parts first plasticizer, 1-3 parts opacifier, and 0.5-2 parts colorant; the first coating layer comprises: 60-70 parts hydroxypropyl methylcellulose, 25-30 parts sodium alginate, 5-8 parts chitosan, and 3-6 parts second plasticizer; the second coating layer comprises: 15-25 parts hydroxypropyl methylcellulose acetate succinate, 5-10 parts hydroxypropyl methylcellulose phthalate, and 0.8-1.5 parts neutralizer.

[0006] By adopting the above technical solution, this application utilizes a compound of gelatin, a first plasticizer, a light-blocking agent, and a colorant to form a capsule base with good flexibility and stability, which can reduce the possibility of enteric capsules cracking in a dry environment.

[0007] The first coating layer, composed of hydroxypropyl methylcellulose, sodium alginate, chitosan, and a second plasticizer, has low humidity sensitivity and is less prone to cracking in dry environments. Meanwhile, the layer structure with hydroxypropyl methylcellulose as the main material has a large surface roughness and adhesion ability, which can form a tighter bond with the capsule base and the second coating layer, and can also slow down the diffusion of internal moisture into the dry environment. Sodium alginate and chitosan can form a more precise pH gradient response. The gel layer formed by the two in the gastric acid environment can effectively protect the drug in the capsule, and then the two can exert a synergistic effect and dissolve and release in the intestine.

[0008] This application also utilizes a compound of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and a neutralizing agent as the second coating layer. Both hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate are stable in acidic environments, and this application controls their ratio, resulting in a significant synergistic toughening effect. As the outermost protective layer in the overall capsule structure, it can significantly improve the overall mechanical strength of the capsule. In the second coating layer, this application also adds a neutralizing agent for a one-step alkali neutralization film-forming method. During the alkali neutralization process, it can promote the orderly arrangement of polymer molecular chains, resulting in a better barrier effect against gastric acid than other methods, further improving the stability of the capsule in gastric acid.

[0009] In summary, the enteric-coated empty capsule of this application comprises a capsule base, a first coating layer, and a second coating layer arranged sequentially from the inside out. The capsule base possesses good flexibility and stability, the first coating layer has a large surface roughness and adhesion ability, enabling it to form a relatively tight bond with the capsule base and the second coating layer, and the second coating layer has good mechanical strength and low porosity. Therefore, the enteric-coated empty capsule of this application exhibits good overall bonding strength and stability, and excellent resistance to brittleness. Furthermore, the stability of enteric-coated empty capsules is not linearly related to the number of layers. A higher number of layers can lead to interlayer separation and / or poor dissolution, while a lower number of layers can result in poor acid resistance and / or easy capsule breakage. The appropriate number of layers and the effective combination of multiple layers in this application effectively improve the above-mentioned defects, resulting in capsules with high dissolution, acid resistance, and brittleness compliance rates. Experimental data show that its brittleness compliance rate is not less than 96%, dissolution is not less than 96%, and acid resistance is not less than 97%.

[0010] In this application, titanium dioxide is used as the opaque agent, lemon yellow is used as the colorant, and ammonium bicarbonate is used as the neutralizing agent. In actual applications, different substances can be replaced according to different needs, and this should not be used to limit the scope of protection of this application.

[0011] Preferably, the raw materials used in the first coating layer also include microcrystalline cellulose, and the amount of microcrystalline cellulose added is 21-33 parts by weight.

[0012] By adopting the above technical solution, this application adds microcrystalline cellulose to the first coating layer, with an addition amount of 21-33 parts, which can significantly improve the mechanical strength and anti-brittleness of the first coating layer. Furthermore, microcrystalline cellulose can also be used as a filler and thickener, forming a denser network structure within the first coating layer, effectively enhancing the toughness of the first coating layer and reducing cracks caused by dry environment or external stress.

[0013] Preferably, the amount of microcrystalline cellulose added is 24 parts by weight.

[0014] By adopting the above technical solution, this application strictly controls the amount of microcrystalline cellulose added, which can maximize the mechanical strength and anti-brittleness of the capsule without affecting the internal flow effect of the first coating layer, and reduce the generation of cracks caused by the drying environment or external stress.

[0015] Preferably, the first plasticizer in the raw materials used for the capsule base includes glycerol and sorbitol in a weight ratio of 4:(1-1.5).

[0016] By adopting the above technical solution, the first plasticizer in the capsule base is selected from glycerol and sorbitol in a specific weight ratio. The synergistic effect between the two not only improves the extensibility of the capsule base but also optimizes its mechanical strength, thereby reducing the risk of capsule breakage in dry environments. This formulation allows the capsule base to maintain good formability while possessing superior anti-brittleness properties, thus improving the overall stability and reliability of enteric-coated empty capsules.

[0017] Preferably, the second plasticizer in the raw materials used for the first coating layer includes triethyl citrate and triacetyl glycerol in a weight ratio of 3:(1-1.5).

[0018] By adopting the above technical solution, the second plasticizer in the first coating layer is a compound of triethyl citrate and triacetyl glycerol in a specific ratio. This can enhance the binding force between the first coating layer and the capsule base while ensuring the flexibility of the first coating layer. This compounding method not only effectively reduces the compatibility problems that may be caused by a single plasticizer, but also optimizes the mechanical properties of the first coating layer, thereby significantly improving the overall capsule's resistance to brittleness and ensuring that the capsule structure remains stable in a dry environment and is not prone to delamination or breakage.

[0019] Secondly, this application provides a preparation process for enteric-coated empty capsules with good anti-friability, comprising the following steps: S1, preparing a gelatin solution: dispersing gelatin, a first plasticizer, a light-blocking agent, and a colorant in water, and stirring evenly under conditions of 60-80℃ and 0.056-0.068 MPa to obtain a gelatin solution; S2, preparing a first coating solution: dispersing hydroxypropyl methylcellulose, sodium alginate, chitosan, and a second plasticizer in water, and stirring evenly under conditions of 70-85℃ to obtain a first coating solution. S3. Preparation of the second coating solution: Disperse hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate in water, stir evenly at a temperature of 45-55℃, and add a neutralizing agent before use to obtain the second coating solution; S4. Capsule making: Dip the capsule mold in the adhesive solution, dry to form the capsule base, coat it once with the first coating solution, dry to form the first coating layer, coat it a second time with the second coating solution, dry to form the second coating layer, remove the capsule, cut, and fit together to obtain enteric-coated empty capsules.

[0020] By adopting the above technical solution, the temperature and pressure conditions of each step in the preparation process of this application are strictly controlled to ensure the uniform dispersion and full cross-linking of each layer of material, thereby further improving the overall anti-brittleness performance of the capsule.

[0021] Preferably, step S4 includes a strengthening treatment before the second coating, specifically: immersing the product with the first coating layer in a calcium-zinc ion mixture with a concentration of 3-4 wt%, letting it stand for 15-20 seconds, removing it, drying it, and then performing the second coating.

[0022] By adopting the above technical solution, this application strengthens the product with the first coating layer before secondary coating by immersing it in a calcium-zinc ion mixture, which can effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer. This application controls the standing time to 15-20 seconds to ensure that the calcium-zinc ions fully penetrate and act on the surface of the first coating layer, further improving the mechanical properties and minimizing the negative impact caused by excessively long or short treatment times. Furthermore, this application uses a calcium-zinc ion mixture with a concentration of 3-4 wt%, which can ensure the strengthening effect without adversely affecting subsequent coating processes and the performance of the final product, ensuring the friability qualification rate of enteric-coated empty capsules in a dry environment. If the concentration is too low, the strengthening effect will be minimal; if the concentration is too high, the cross-linking rate of calcium and zinc ions with substances in the system will decrease, which will instead damage the mechanical properties of the capsule.

[0023] Preferably, in the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:(1-3).

[0024] By adopting the above technical solution, this application controls the molar ratio of calcium ions to zinc ions, thereby maximizing the overall mechanical strength without excessively affecting the roughness of the capsule. If too much calcium ion is used, the roughness of the capsule will be excessively reduced; if too much zinc ion is used, it will not significantly improve the overall mechanical strength of the capsule.

[0025] Preferably, in the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:2.

[0026] By adopting the above technical solution, this application strictly controls the molar ratio of calcium ions to zinc ions. At this time, the roughness of the first coating layer of the capsule and the overall mechanical strength are in the best balance, and the brittleness qualification rate is the highest.

[0027] In summary, this application has the following beneficial technical effects: The enteric-coated empty capsule of this application has a capsule base, a first coating layer, and a second coating layer arranged sequentially from the inside out. The capsule base has good flexibility and stability, the first coating layer has a large surface roughness and adhesion ability, and can form a relatively tight bond with the capsule base and the second coating layer. The second coating layer has good mechanical strength and low porosity. Therefore, the enteric-coated empty capsule of this application has good overall bonding strength and stability, good resistance to brittleness, and also good dissolution and acid resistance. Experimental data shows that its brittleness qualification rate is not less than 96%. Microcrystalline cellulose and magnesium stearate were added to the first coating layer. The synergistic effect of these two ingredients can improve the mechanical strength and anti-brittleness of the first coating layer without affecting the flowability of the raw materials used in the first coating layer, thereby enhancing the toughness of the first coating layer. In the preparation method of this application, the product with the first coating layer is subjected to a strengthening treatment before the second coating, namely, immersion in a calcium-zinc ion mixture. This can effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer. Furthermore, the temperature and pressure conditions of each step are strictly controlled to ensure the uniform dispersion and full cross-linking of the materials in each layer, thereby further improving the overall anti-brittleness of the capsule. Detailed Implementation

[0028] Material source

[0029] Unless otherwise specified, all raw materials used in this application are commercially available products, specifically:

[0030] The gelatin was purchased from Rousselot (Guangdong) Gelatin Co., Ltd., with a viscosity of 4.6 mPa·s and a moisture content of 9.1%.

[0031] Hydroxypropyl methylcellulose was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., CAS No. 9004-65-3, viscosity 5 mPa·s;

[0032] Sodium alginate was purchased from Shanghai Maclean Reagent Co., Ltd.

[0033] Polyethylene glycol, CAS No. 25322-68-3, molecular weight 6000;

[0034] Hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate were purchased from Taian Ruitai Cellulose Co., Ltd.

[0035] Sorbitol, CAS No. 50-70-4;

[0036] Triethyl citrate, CAS No. 77-93-0;

[0037] Triacetin, CAS No. 102-76-1;

[0038] Carboxymethyl ethyl ether cellulose, CAS No. 37205-99-5.

[0039] The present application will be further described in detail below with reference to embodiments and comparative examples.

[0040] <Example 1.1>

[0041] A process for preparing enteric-coated empty capsules with good brittleness resistance includes the following steps:

[0042] S1. Preparation of adhesive solution: Disperse 350g of gelatin and 250g of the first plasticizer (glycerin) in 875mL of water. Stir evenly at 80℃ and 0.056Mpa. When the foam in the system gradually decreases and stops rising, stop the vacuum, exhaust the air and stop stirring. Then release the mixture from the sol tank and filter it. Add 1g of opacifier (titanium dioxide) and 2g of colorant (tartrazine), stir evenly and keep warm to obtain the adhesive solution.

[0043] S2. Preparation of the first coating solution: 60g hydroxypropyl methylcellulose, 30g sodium alginate, 8g chitosan and 3g second plasticizer (polyethylene glycol) are dispersed in 900mL of water, stirred at 85℃ for 3h, filtered, kept warm, and defoamed under a true pressure of 0.06MPa. After the bubbles are removed, the temperature is lowered to 55℃ and allowed to stand for 8h, then the temperature is lowered to 48℃ and kept warm to obtain the first coating solution.

[0044] S3. Preparation of the second coating solution: 150g of hydroxypropyl methylcellulose acetate succinate and 100g of hydroxypropyl methylcellulose phthalate are dispersed in 1.44L of water and stirred at 55℃ for 3h. When using, add 8g of neutralizing agent (ammonium bicarbonate) to obtain the second coating solution.

[0045] S4. Capsule Preparation: Dip the capsule mold in the adhesive solution and dry it under normal indoor air conditions of 25°C and 55%RH to form the capsule base. Immerse the capsule base in the first coating solution for the first coating. Dry it under normal indoor air conditions of 25°C and 60%RH to form the first coating layer. Then immerse it in the second coating solution for the second coating. Dry it under normal indoor air conditions of 25°C and 55%RH to form the second coating layer. Remove the capsules, cut them, and attach them to obtain enteric-coated empty capsules.

[0046] <Example 1.2>

[0047] A process for preparing enteric-coated empty capsules with good brittleness resistance includes the following steps:

[0048] S1. Preparation of adhesive solution: Disperse 450g of gelatin and 150g of the first plasticizer (glycerin) in 1.2L of water. Stir evenly at a temperature of 60℃ and a pressure of 0.068Mpa. When the foam in the system gradually decreases and stops rising, stop the vacuum, exhaust the air and stop stirring. Then release the mixture from the sol tank and filter it. Add 30g of opacifier (titanium dioxide) and 5g of colorant (tartrazine), stir evenly and keep warm to obtain the adhesive solution.

[0049] S2. Preparation of the first coating solution: Disperse 70g hydroxypropyl methylcellulose, 25g sodium alginate, 5g chitosan and 3g second plasticizer (polyethylene glycol) in 1L of water, stir at 70℃ for 3h, filter, keep warm, remove bubbles under a true pressure of 0.06MPa, after the bubbles are removed, cool to 55℃ and let stand for 8h, then cool to 48℃ and keep warm to obtain the first coating solution;

[0050] S3. Preparation of the second coating solution: Disperse 250g of hydroxypropyl methylcellulose succinate and 50g of hydroxypropyl methylcellulose phthalate in 2.25L of water and stir at 45℃ for 3h. Add 15g of neutralizing agent (ammonium bicarbonate) before use to obtain the second coating solution.

[0051] S4. Capsule Preparation: Dip the capsule mold in the adhesive solution and dry it under normal indoor air conditions of 25°C and 55%RH to form the capsule base. Immerse the capsule base in the first coating solution for the first coating. Dry it under normal indoor air conditions of 25°C and 60%RH to form the first coating layer. Then immerse it in the second coating solution for the second coating. Dry it under normal indoor air conditions of 25°C and 55%RH to form the second coating layer. Remove the capsules, cut them, and attach them to obtain enteric-coated empty capsules.

[0052] <Example 2.1>

[0053] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 21g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0054] <Example 2.2>

[0055] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 24g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0056] <Example 2.3>

[0057] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 27g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0058] <Example 2.4>

[0059] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 33g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0060] <Example 2.5>

[0061] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 15g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0062] <Example 2.6>

[0063] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, 37g of microcrystalline cellulose is added and mixed with hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer, while the rest is the same as in Example 1.1.

[0064] <Example 3.1>

[0065] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S1, the first plasticizer is 200g glycerol and 50g sorbitol, while the rest are the same as in Example 1.1.

[0066] <Example 3.2>

[0067] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S1, the first plasticizer is 182g of glycerol and 68g of sorbitol, while the rest are the same as in Example 1.1.

[0068] <Example 3.3>

[0069] The preparation process of an enteric-coated empty capsule with good anti-friability is different from that of Example 1.1 in that: in step S1, the first plasticizer is 250g of sorbitol, and the rest are the same as in Example 1.1.

[0070] <Example 4.1>

[0071] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, the second plasticizer is 2.25g of triethyl citrate and 0.75g of triacetylglycerol triacetate, while the rest are the same as in Example 1.1.

[0072] <Example 4.2>

[0073] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, the second plasticizer is 2g of triethyl citrate and 1g of triacetylglycerol, while the rest are the same as in Example 1.1.

[0074] <Example 4.3>

[0075] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, the second plasticizer is 2.25g polyethylene glycol and 0.75g triacetin, while the rest is the same as in Example 1.1.

[0076] <Example 4.4>

[0077] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, the second plasticizer is 2.25g of triethyl citrate and 0.75g of polyethylene glycol, while the rest are the same as in Example 1.1.

[0078] <Example 4.5>

[0079] The preparation process of an enteric-coated empty capsule with good anti-friability is different from that of Example 1.1 in that: in step S2, the second plasticizer is 3g of triethyl citrate, and the rest is the same as in Example 1.1.

[0080] <Example 4.6>

[0081] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S2, the second plasticizer is 3g of triacetylglycerol, and the rest is the same as in Example 1.1.

[0082] <Example 5.1>

[0083] A preparation process for an enteric-coated empty capsule with good brittleness resistance differs from that in Example 1.1 in that: in step S4, an enhanced treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in a calcium-zinc ion mixture with a concentration of 4 wt% and a molar ratio of calcium ions to zinc ions of 2:1. After standing for 15 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, a secondary coating is performed. The rest is the same as in Example 1.1.

[0084] <Example 5.2>

[0085] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S4, an enhanced treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in a calcium-zinc ion mixture with a concentration of 3 wt% and a molar ratio of calcium ions to zinc ions of 1:4. After standing for 20 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, the secondary coating is performed. The rest is the same as in Example 1.1.

[0086] <Example 5.3>

[0087] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the molar ratio of calcium ions to zinc ions in the calcium-zinc ion mixture is 1:1, while the rest is the same as in Example 5.1.

[0088] <Example

[0089] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the molar ratio of calcium ions to zinc ions in the calcium-zinc ion mixture is 1:2, while the rest is the same as in Example 5.1.

[0090] ​

[0091] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the molar ratio of calcium ions to zinc ions in the calcium-zinc ion mixture is 1:3, while the rest is the same as in Example 5.1.

[0092] ​

[0093] The preparation process of an enteric-coated empty capsule with good anti-friability is different from that of Example 5.1 in that the calcium-zinc ion mixture is replaced with a zinc ion dispersion with a concentration of 4wt%, and the rest is the same as that of Example 5.1.

[0094] ​

[0095] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the calcium-zinc ion mixture is replaced with a calcium ion dispersion with a concentration of 4 wt%, while the rest is the same as in Example 5.1.

[0096] ​

[0097] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the molar ratio of the calcium-zinc ion mixture is 2wt%, while the rest are the same as in Example 5.1.

[0098] ​

[0099] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 5.1 in that the molar ratio of the calcium-zinc ion mixture is 5wt%, while the rest are the same as in Example 5.1.

[0100] ​

[0101] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 1.1 in that: in step S4, an enhanced treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in a calcium-iron ion mixture with a concentration of 4 wt% and a molar ratio of calcium ions to iron ions of 2:1. After standing for 15 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, the secondary coating is performed. The rest is the same as in Example 1.1.

[0102] ​

[0103] A preparation process for an enteric-coated empty capsule with good brittleness resistance differs from that in Example 1.1 in that: in step S4, an enhanced treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in an iron-zinc ion mixture with a concentration of 4 wt% and a molar ratio of iron ions to zinc ions of 2:1. After standing for 15 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, a secondary coating is performed. The rest is the same as in Example 1.1.

[0104] ​

[0105] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 2.2 in that: in step S4, an enhancement treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in a calcium-zinc ion mixture with a concentration of 4 wt% and a molar ratio of calcium ions to zinc ions of 1:2. After standing for 15 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, the secondary coating is performed. The rest is the same as in Example 2.2.

[0106] ​

[0107] The preparation process of an enteric-coated empty capsule with good brittleness resistance differs from that of Example 2.2 in that: in step S4, an enhancement treatment is performed before the secondary coating. Specifically, the product with the first coating layer is immersed in a calcium-zinc ion mixture with a concentration of 3 wt% and a molar ratio of calcium ions to zinc ions of 1:2. After standing for 20 seconds, it is taken out and dried under normal indoor air conditions at a temperature of 30°C and a humidity of 60%RH. Then, a secondary coating is performed. The rest is the same as in Example 2.2.

[0108] ​

[0109] The difference from Example 1.1 is that in step S2, all hydroxypropyl methylcellulose is replaced with hydroxypropyl methylcellulose phthalate, while the rest is the same as in Example 1.1.

[0110] ​

[0111] The difference from Example 1.1 is that in step S2, all hydroxypropyl methylcellulose is replaced with carboxymethyl ethyl ether cellulose, while the rest is the same as in Example 1.1.

[0112] ​

[0113] The difference from Example 1.1 is that in step S3, hydroxypropyl methylcellulose succinate is removed, and the amount of hydroxypropyl methylcellulose phthalate is 250g. The rest are the same as in Example 1.1.

[0114] ​

[0115] The difference from Example 1.1 is that in step S3, hydroxypropyl methylcellulose phthalate is removed, and the amount of hydroxypropyl methylcellulose acetate succinate is 250g. The rest are the same as in Example 1.1.

[0116] ​

[0117] The difference from Example 1.1 is that in step S3, the amount of hydroxypropyl methylcellulose succinate is 100g and the amount of hydroxypropyl methylcellulose phthalate is 150g, while the rest are the same as in Example 1.1.

[0118] ​

[0119] The difference from Example 1.1 is that in step S3, the amount of hydroxypropyl methylcellulose succinate is 300g and the amount of hydroxypropyl methylcellulose phthalate is 25g, while the rest are the same as in Example 1.1.

[0120] ​

[0121] The difference from Example 1.1 is that in step S3, hydroxypropyl methylcellulose acetate succinate is replaced with hydroxypropyl methylcellulose, and the rest is the same as in Example 1.1.

[0122] ​

[0123] The difference from Example 1.1 is that in step S3, hydroxypropyl methylcellulose phthalate is replaced with hydroxypropyl methylcellulose, and the rest is the same as in Example 1.1.

[0124] ​

[0125] The difference from Example 1.1 is that the raw materials of the first coating solution and the second coating solution are interchanged, specifically:

[0126] S2. Preparation of the first coating solution: 150g of hydroxypropyl methylcellulose acetate succinate and 100g of hydroxypropyl methylcellulose phthalate are dispersed in 1.44L of water and stirred at 55℃ for 3h. When using, add 8g of neutralizing agent (ammonium bicarbonate) to obtain the first coating solution.

[0127] S3. Preparation of the second coating solution: Disperse 600g hydroxypropyl methylcellulose, 300g sodium alginate, 80g chitosan and 30g second plasticizer (polyethylene glycol) in 1.2L of water, stir at 85℃ for 3h, filter, keep warm, remove bubbles under a true pressure of 0.06MPa, after the bubbles are removed, cool to 55℃ and let stand for 8h, then cool to 48℃ and keep warm to obtain the first coating solution.

[0128] ​

[0129] The difference from Example 1.1 is that the second coating layer is removed, and the rest is the same as Example 1.1.

[0130] ​

[0131] The difference from Example 1.1 is that the first coating layer is removed and the second coating layer is prepared directly on the surface of the capsule base; otherwise, it is the same as Example 1.1.

[0132] ​

[0133] S1. Preparation of the adhesive solution: Disperse 350g gelatin, 250g glycerol, 60g hydroxypropyl methylcellulose, 30g sodium alginate, 8g chitosan, and 0.2L of a calcium-zinc ion mixture with a concentration of 20wt% and a molar ratio of calcium ions to zinc ions of 2:1 in 1.8L of water. Stir evenly at a temperature of 80℃ and a pressure of 0.056Mpa. When the foam in the system gradually decreases and stops rising, stop the vacuum, exhaust the air and stop stirring. Then release the mixture from the sol tank and filter it. Add 1g of opacifier (titanium dioxide) and 2g of colorant (tartrazine), stir evenly and keep warm to obtain the adhesive solution.

[0134] S2. Preparation of coating solution: Disperse 150g of hydroxypropyl methylcellulose succinate and 100g of hydroxypropyl methylcellulose phthalate in 1.44L of water and stir at 55℃ for 3h. Add 8g of neutralizing agent (ammonium bicarbonate) before use to obtain the coating solution.

[0135] S3. Capsule preparation: Dip the capsule mold in the adhesive solution and dry it under normal indoor air conditions of 25°C and 55%RH to form the capsule base. Then, immerse it in the coating solution for coating and dry it under normal indoor air conditions of 30°C and 60%RH to form the coating layer. Remove the capsule, cut it, and fit it together to obtain enteric-coated empty capsules.

[0136] ​

[0137] S1. Preparation of the adhesive solution: Disperse 350g gelatin, 250g glycerin, 60g hydroxypropyl methylcellulose, 30g sodium alginate, 8g chitosan, 150g hydroxypropyl methylcellulose acetate succinate, 100g hydroxypropyl methylcellulose phthalate, and 0.2L of a calcium-zinc ion mixture with a concentration of 20wt% and a molar ratio of calcium to zinc ions of 2:1 in 2.3L of water. Stir evenly at a temperature of 70℃ and a pressure of 0.056Mpa. When the foam in the system gradually decreases and stops rising, stop the vacuum, exhaust the air and stop stirring. Then release the mixture from the sol tank and filter it. Add 1g of opacifier (titanium dioxide) and 2g of colorant (tartrazine), stir evenly and keep warm to obtain the adhesive solution.

[0138] S2. Capsule making: Dip the capsule mold in adhesive solution, dry it under normal indoor air conditions of 30℃ and 60%RH, remove the capsule, cut it, and fit it together to obtain enteric-coated empty capsules.

[0139] Performance testing

[0140] 1. Friability test: Take 50 capsules from each of the examples and comparative examples, place them in a petri dish, and put them in a desiccator containing saturated magnesium nitrate solution. Keep the desiccator at 25±1℃ for 24 hours. Remove the capsules and immediately place them one by one into a glass tube (24mm inner diameter, 200mm long) standing upright on a wooden board (2cm thick). Drop a cylindrical weight (polytetrafluoroethylene, 22mm diameter, 20±0.1g mass) freely from the opening of the glass tube. Count the number of capsules that do not break and calculate the percentage of unbroken capsules. Record this percentage as the friability pass rate.

[0141] 2. Dissolution and acid resistance testing: Take 30 enteric-coated empty capsules each from the examples and comparative examples, and fill the capsules with omeprazole using a quantitative filling technique with a tube-type metering device. The humidity in the filling area should be controlled to ≤30%RH, and nitrogen protection should be applied (oxygen content <0.5%) to obtain the capsules to be tested. Following the dissolution and release determination method (General Rule 0931, Method 2, Method 1), use 500mL of sodium chloride hydrochloric acid solution (1g sodium chloride, 3.5mL hydrochloric acid, and water to 500mL) as the dissolution medium, and operate at 100r / min. After 120 minutes, add 400mL of 0.235mol / L disodium hydrogen phosphate solution preheated to 37℃ to the operating container, maintaining the same rotation speed, and continue operating according to the method. After 45 minutes, filter the solution, accurately measure 5 mL of the filtrate, accurately add 1 mL of 0.25 mol / L sodium hydroxide solution, and shake well to obtain the test solution; separately, accurately weigh approximately 20 mg of omeprazole reference standard, place it in a 100 mL volumetric flask, add 10 mL of ethanol to dissolve it, and then dilute to the mark with a mixed dissolution medium [sodium chloride hydrochloric acid solution - 0.235 mol / L disodium hydrogen phosphate solution (5:4)], shake well, accurately measure 5 mL of the solution, place it in a 50 mL volumetric flask (20 mg specification) or a 100 mL volumetric flask (10 mg specification), dilute to the mark with the mixed dissolution medium, and shake well; accurately measure 5 mL of the solution, accurately add 1 mL of 0.25 mol / L sodium hydroxide solution, and shake well to obtain the reference solution. Take the test solution and the reference solution, and determine the dissolution rate of each particle in each group of the examples and comparative examples according to the method under the content determination section. Record the average value in Table 1. According to the dissolution and release determination method (General Rule 0931 Method 1), use 500 mL of sodium chloride hydrochloric acid solution (1g sodium chloride, 3.5 mL hydrochloric acid, and water to 500 mL) as the dissolution medium, rotate at 100 r / min, and operate according to the method. After 120 minutes, remove the rotating basket, wash the particles in the rotating basket with water until the washing solution is neutral, and transfer the particles to a 100 mL brown volumetric flask with a small amount of phosphate buffer (pH=11.0). Determine the acid resistance according to the method under the content determination section, starting from "add 20 mL of ethanol". Calculate the acid resistance by peak area according to the external standard method and record the average value in Table 1.

[0142] 3. Peel strength test: The capsules obtained in the examples and comparative examples were torn apart and the delamination phenomenon of the layer structure was observed. The results are recorded in Table 1, where A represents no delamination, B represents a certain degree of delamination between the three layers, and C represents a clear gap between each layer.

[0143] Table 1 Performance Test Table

[0144]

[0145] Data Analysis:

[0146] As can be seen from Table 1, the friability qualification rate of Examples 1.1-1.2 of this application reached 96%, the dissolution rate was 98.1-98.3%, the acid resistance reached 97.2-97.5%, and no delamination phenomenon was observed in the peel resistance test. This proves that the enteric-coated empty capsules of this application not only have good acid resistance and enteric effect, but also have good flexibility and stability due to the capsule base, the large surface roughness and adhesion of the first coating layer, which can form a relatively tight bond with the capsule base and the second coating layer. The second coating layer has good mechanical strength and low porosity. Therefore, the whole has good bonding strength and stability and good friability resistance.

[0147] The difference between Examples 2.1-2.6 and Example 1.1 is that a certain amount of microcrystalline cellulose was added to the first coating layer in this application. The friability pass rate of Examples 2.1-2.4 was significantly increased, and no delamination was observed in the peel resistance test. The friability pass rate of Example 2.2 even reached 100%. This proves that by adding microcrystalline cellulose, this application can significantly improve the mechanical strength and friability resistance of the first coating layer. Furthermore, microcrystalline cellulose can also act as a filler and thickener, forming a denser network structure within the first coating layer, effectively enhancing the first... The coating layer's toughness reduces cracking caused by dry environments or external stress. The amount of microcrystalline cellulose in Example 2.5 was significantly lower than that in Examples 2.1-2.4, and the results showed that it could not improve the resistance to brittleness. The amount of microcrystalline cellulose in Example 2.6 was significantly higher than that in Examples 2.1-2.4, and the results showed that its acid resistance was actually reduced. This proves that by strictly controlling the amount of microcrystalline cellulose added, this application can maximize the mechanical strength and resistance to brittleness of the capsule without affecting the internal flow effect of the first coating layer, and reduce cracking caused by dry environments or external stress.

[0148] The difference between Examples 3.1-3.2 and Example 1.1 is that the composition of the first plasticizer was changed in this application. The brittleness pass rate of Examples 3.1-3.2 was higher than that of Example 1.1, and no delamination phenomenon was observed in the peel resistance test. This proves that the synergistic effect between glycerol and sorbitol not only improved the extensibility of the capsule base, but also optimized its mechanical strength, thereby reducing the risk of capsule breakage in a dry environment. Example 3.3 replaced the first plasticizer with sorbitol. The results showed no significant difference between the performance of Examples 1.1 and that of Example 1.1. This further proves that the specific ratio of glycerol and sorbitol selected in this application enables the capsule base to maintain good formability while having better anti-brittleness properties, thereby improving the overall stability and reliability of the enteric-coated empty capsule.

[0149] The difference between Examples 4.1-4.2 and Example 1.1 is that the composition of the second plasticizer was changed in this application. The results showed that the friability pass rate was higher than that of Example 1.1, and no delamination was observed in the peel resistance test. This proves that the compounding of triethyl citrate and triacetyl ester in a specific ratio can enhance the bonding force between the first coating layer and the capsule base while ensuring the flexibility of the first coating layer. This compounding method not only effectively reduces the compatibility problems that may be caused by a single plasticizer, but also optimizes the mechanical properties of the first coating layer, thereby significantly improving the overall capsule's friability resistance and ensuring that the capsule structure remains stable in a dry environment, and is not prone to delamination or breakage. Examples 4.3-4.6 also changed the composition of the second plasticizer. The results showed that the friability pass rate was basically the same as or even lower than that of Example 1.1, further proving that the compounding of triethyl citrate and triacetyl ester in a specific ratio has a significant synergistic effect.

[0150] The difference between Examples 5.1-5.2 and Example 1.1 is that this application also carried out a strengthening treatment before the second coating. The results showed that the brittleness qualification rate was significantly improved, and no delamination phenomenon was found in the peel resistance test. This proves that by immersing the product with the first coating layer in a calcium-zinc ion mixture, this application can effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer.

[0151] The difference between Examples 5.3-5.5 and Example 5.1 is that this application changed the molar ratio of calcium ions to zinc ions in the calcium-zinc ion mixture. The results showed that the brittleness qualification rate was significantly improved, and no delamination phenomenon was observed in the peel resistance test. This proves that this application improved the overall mechanical strength as much as possible without excessively affecting the roughness of the capsule by controlling the molar ratio of calcium ions to zinc ions. If too much calcium ion is used, the roughness of the capsule will be excessively reduced; if too much zinc ion is used, it will not be able to significantly improve the overall mechanical strength of the capsule.

[0152] The difference between Examples 5.6-5.7 and Example 5.1 is that the calcium-zinc ion mixture was replaced with zinc ion dispersion and calcium ion dispersion of equal concentration, respectively. The results showed that the brittleness qualification rate was not significantly improved, which proved that the calcium ions and zinc ions in the calcium-zinc ion mixture had a good synergistic effect.

[0153] The difference between Examples 5.8-5.9 and Example 5.1 is that the concentration of the calcium-zinc ion mixture was changed. The results showed that the friability qualification rate decreased instead of increasing, and some stratification occurred in the peel resistance test. This proves that if the concentration is too low, the reinforcing effect is almost zero. If the concentration is too high, it will also cause the cross-linking rate of calcium and zinc ions with substances in the system to decrease, which will lead to damage to the mechanical properties of the capsule.

[0154] The difference between Examples 5.10-5.11 and Example 5.1 is that the first coating layer was strengthened using calcium-iron ion mixture and iron-zinc ion mixture, respectively. The results showed a significant decrease in dissolution. Technicians speculate that this is because iron ions form a denser cross-linked structure inside the system, resulting in insufficient flexibility of the first coating layer and difficulty in releasing the drug from the capsule.

[0155] The difference between Examples 6.1-6.2 and Example 2.2 is that, in addition to adding microcrystalline cellulose to the first coating layer, this application also adds a calcium-zinc ion mixture with the optimal calcium-zinc molar ratio. The results show that the brittleness qualification rate is still not 100%, and the acid resistance is significantly improved, proving that the calcium-zinc ion mixture of this application can indeed effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer.

[0156] The difference between Comparative Examples 1.1-1.2 and Example 1.1 is that the hydroxypropyl methylcellulose in step S2 was replaced with hydroxypropyl methylcellulose phthalate and carboxymethyl ethyl ether cellulose, respectively. The results showed that the brittleness qualification rate decreased and some delamination occurred in the peel resistance test. This proves that the layer structure with hydroxypropyl methylcellulose as the main material has a large surface roughness and adhesion ability, which can form a relatively tight bond with the capsule base and the second coating layer, and can also slow down the diffusion of internal moisture to the dry environment, reducing the risk of breakage.

[0157] The difference between Comparative Examples 2.1-2.2 and Example 1.1 is that hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate were removed in step S3. The results showed that the acid resistance and brittleness pass rate decreased, proving that hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate have a good synergistic effect. The intestinal environment dissolution rate of the compound system increased, and it has a significant synergistic toughening effect. As the outermost protective layer in the overall capsule structure, it can significantly improve the overall mechanical strength of the capsule.

[0158] The difference between Comparative Examples 2.3-2.4 and Example 1.1 is that the compounding ratio of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate was changed. The results showed that the acid resistance and brittleness pass rate decreased, proving that the present application can significantly improve the intestinal environment dissolution rate and mechanical strength of the capsule by controlling the ratio of the two.

[0159] The difference between Comparative Examples 2.5-2.6 and Example 1.1 is that hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate were replaced with hydroxypropyl methylcellulose. The results showed that the acid resistance was significantly reduced, further proving that hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate have a good synergistic effect and can effectively resist the gastric acid environment.

[0160] The difference between Comparative Examples 3.1-3.3 and Example 1.1 is that this application changed the layer structure relationship between the first coating layer and the second coating layer. The results showed that the friability qualification rate and acid resistance decreased, while the dissolution rate did not improve. Furthermore, certain delamination phenomena appeared in the peel resistance test of Comparative Examples 3.1 and 3.3. This is because the stability of enteric-coated empty capsules is not linearly related to the number of layers. When there are more layers, there will be problems of interlayer separation and / or poor acid resistance. When there are fewer layers, there will be problems of poor acid resistance and / or easy capsule breakage. Multiple factors strongly prove that the combination effect between the capsule base, the first coating layer and the second coating layer arranged from the inside to the outside in this application is good. The combination effect between the multiple layers effectively improves the above defects, so that the capsule has high dissolution rate, acid resistance and friability qualification rate.

[0161] In Comparative Example 4.1, this application used a new adhesive solution by blending the adhesive solution, the first coating solution, and the calcium-zinc ion mixture. Then, the original second coating solution was used for coating. The results showed that the dissolution rate was low. During the dissolution rate test, the technicians observed that the capsule layer structure was severely delaminated, and the gaps between the layers were clearly visible. It is speculated that this was because the new adhesive solution had an excessive degree of cross-linking and an overly dense structure, resulting in poor dissolution ability. Furthermore, the calcium-zinc ion mixture had already been sufficiently cross-linked inside the capsule base, occupying some of the active sites of other components, which led to a significant reduction in the binding force between the capsule base and the coating layer.

[0162] In Comparative Example 4.2, this application used a blend of adhesive, first coating solution, calcium-zinc ion mixture and second coating solution as a new adhesive. The results showed that the dissolution rate was low. The technician speculated that this was because the new adhesive had a large number of components, resulting in excessive internal cross-linking and an overly dense structure, which led to poor dissolution ability.

[0163] The embodiments described in this specific implementation are preferred embodiments of this application and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. A preparation process for enteric-coated empty capsules with good anti-fragility, characterized in that, Includes the following steps: S1. Preparation of adhesive solution: Disperse gelatin, first plasticizer, opacifier and colorant in water, and stir evenly under the conditions of temperature of 60-80℃ and pressure of 0.056-0.068Mpa to obtain adhesive solution; S2. Preparation of the first coating solution: Disperse hydroxypropyl methylcellulose, sodium alginate, chitosan and the second plasticizer in water, and stir evenly at a temperature of 70-85℃ to obtain the first coating solution. S3. Preparation of the second coating solution: Disperse hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate in water, stir evenly at a temperature of 45-55℃, and add a neutralizing agent before use to obtain the second coating solution. S4. Capsule preparation: Dip the capsule mold in the adhesive solution, dry it to form the capsule base, apply the first coating solution for a first coating, dry it to form the first coating layer, apply the second coating solution for a second coating, dry it to form the second coating layer, remove the capsule, cut it, and fit it together to obtain enteric-coated empty capsules. The enteric-coated empty capsule comprises, from the inside out, a capsule base, a first coating layer, and a second coating layer; The first plasticizer in the raw materials used for the capsule base includes glycerol and sorbitol in a weight ratio of 4:(1-1.5); the second plasticizer in the raw materials used for the first coating layer includes triethyl citrate and triacetyl ester in a weight ratio of 3:(1-1.5).

2. The preparation process of an enteric-coated empty capsule with good anti-fragility according to claim 1, characterized in that, The raw materials used in the first coating layer also include microcrystalline cellulose.

3. The preparation process of an enteric-coated empty capsule with good anti-fragility according to claim 1, characterized in that, In step S4, a strengthening treatment is also included before the secondary coating, specifically: The product with the first coating layer is immersed in a calcium-zinc ion mixture with a concentration of 3-4 wt%, left to stand for 15-20 seconds, then removed and dried, and then coated a second time. In the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:(1-3).

4. The preparation process of an enteric-coated empty capsule with good anti-fragility according to claim 3, characterized in that, In the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:2.

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