Enteric hollow capsule with good friability resistance and preparation process thereof

Abstract

The invention relates to the field of medical preparations, and particularly discloses an enteric-coated hollow capsule with good friability resistance and a preparation process of the enteric-coated hollow capsule. The preparation process of the enteric hollow capsule with good friability resistance comprises the following steps: S1, preparing gelatin, a first plasticizer, an opacifying agent and a coloring agent into a glue solution; s2, hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer are prepared into a first coating solution; s3, preparing a second coating solution from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate and a neutralizer; and S4, dipping the capsule mold in the glue solution, drying, forming a capsule base, carrying out primary coating, drying, carrying out secondary coating, drying, pulling out the capsule, cutting and sleeving to obtain the enteric hollow capsule. According to the present invention, the layers of the product are tightly combined, such that the high dissolution rate, the high acid resistance and the high friability qualification rate are provided, the experimental data show that the friability qualification rate is not less than 96%, and the good friability resistance is provided.

Description

Technical Field

[0001] The present application relates to the technical field of medical preparations, and in particular to an enteric-coated hollow capsule with good anti-brittleness and a preparation process thereof. Background Art

[0002] Ordinary pharmaceutical packaging capsule materials are mainly gelatin hollow capsules, which are filled with medicine to form a preparation. After oral administration, they dissolve in the stomach and exert their medicinal effects after being absorbed by the small intestine. However, since some drugs are irritating to the stomach, patients may experience certain side effects after taking them. At the same time, some drugs are easily degraded by gastric acid. Therefore, these drugs are not suitable for the use of ordinary hollow capsule preparations. To this end, researchers have invented an enteric-coated hollow capsule that does not dissolve in gastric juice but dissolves and is absorbed in the intestine. This type of capsule usually still uses gelatin as the skeleton capsule base, and then an outer coating is applied to achieve an enteric effect. The outer coating is usually made of cellulose acetate phthalate, acrylic resins, and hydroxypropyl methylcellulose phthalate as the main materials. All three can dissolve in intestinal fluid with a pH ≥ 6.0 to achieve an enteric effect.

[0003] However, due to the different mechanical strengths of the gelatin-based capsule and the coating layer, as well as their varying water vapor transmission rates in dry environments, the capsule base and coating can easily delaminate, leading to overall capsule breakage. Given the poor brittle resistance of existing enteric-coated capsules, researchers believe it is necessary to develop an enteric-coated hollow capsule with improved brittle resistance. Summary of the Invention

[0004] In order to solve the above technical problems, the present application provides an enteric-coated hollow capsule with good anti-brittleness and a preparation process thereof.

[0005] In the first aspect, the present application provides an enteric hollow capsule with good anti-brittleness, comprising a capsule base, a first coating layer and a second coating layer arranged in sequence from the inside to the outside; the raw materials used for the capsule base include, by weight: 35-45 parts of gelatin, 15-25 parts of a first plasticizer, 1-3 parts of a sunscreen and 0.5-2 parts of a colorant; the raw materials used for the first coating layer include: 60-70 parts of hypromellose, 25-30 parts of sodium alginate, 5-8 parts of chitosan and 3-6 parts of a second plasticizer; the raw materials used for the second coating layer include: 15-25 parts of hypromellose acetate succinate, 5-10 parts of hypromellose phthalate and 0.8-1.5 parts of a neutralizer.

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

[0007] The first coating layer composed of hydropropyl methylcellulose, sodium alginate, chitosan and the second plasticizer has low moisture sensitivity and is not prone to cracking in a dry environment. At the same time, the layer structure with hydropropyl methylcellulose as the main ingredient has a large surface roughness and adhesion ability, which can form a relatively close bond with the capsule base and the second coating layer, and can also slow down the diffusion of internal moisture to a dry environment. Sodium alginate and chitosan can form a more accurate pH gradient response. The gel layer formed by the two in the gastric acid environment can effectively protect the drug filled in the capsule. Subsequently, the two can play a synergistic role in the intestine and dissolve and release.

[0008] The present application also utilizes a compound of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and a neutralizer as the second coating layer, wherein both hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate can stably exist in an acidic environment, and the present application controls the ratio of the two, which has a significant synergistic toughening effect. As the outermost protective layer in the overall capsule layer structure, it can significantly improve the overall mechanical strength of the capsule; the present application also adds a neutralizer to the second coating layer for a one-step alkali neutralization film-forming method, which can promote the orderly arrangement of polymer molecular chains during the alkali neutralization process, and the barrier effect against gastric acid is better than other methods, further improving the stability of the capsule of the present application in gastric acid.

[0009] In summary, the enteric-coated hollow capsules of the present application have a capsule base, a first coating layer, and a second coating layer arranged in sequence from the inside to the outside. 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 hollow capsules of the present application have good bonding strength and stability as a whole, and have good resistance to brittleness. In addition, the stability of the enteric-coated hollow capsules does not have a linear relationship with the number of layers. When the number of layers is large, there will be problems of interlayer detachment and / or poor solubility. When the number of layers is small, there will be problems of poor acid resistance and / or easy breakage of the capsule. The appropriate number of layers of the present application and the coordination effect between the multiple layers effectively improve the above defects, so that the capsules have a high solubility, acid resistance, and brittleness qualified rate. Experimental data show that its brittleness qualified rate is not less than 96%, the solubility is not less than 96%, and the acid resistance is not less than 97%. ‌‌ The sunscreen in this application is titanium dioxide, the colorant is lemon yellow, and the neutralizer is ammonium bicarbonate. In actual applications, different substances can be replaced according to different needs, and this cannot limit the scope of protection of this application.

[0010] Preferably, the raw materials used for the first coating layer further include microcrystalline cellulose, and the amount of microcrystalline cellulose added is 21-33 parts by weight.

[0011] By adopting the above-mentioned technical solution, the present application adds microcrystalline cellulose to the first coating layer in an amount of 21-33 parts, which can significantly improve the mechanical strength and anti-brittleness performance of the first coating layer. In addition, the microcrystalline cellulose can also be used as a filler and thickener, which can form a denser network structure in the first coating layer, effectively enhance the toughness of the first coating layer, and reduce the occurrence of cracks caused by dry environment or external stress.

[0012] Preferably, the amount of microcrystalline cellulose added is 24 parts by weight.

[0013] By adopting the above technical solution, the present application strictly controls the amount of microcrystalline cellulose added, which can maximize the mechanical strength and anti-brittleness performance of the capsule without affecting the internal flow effect of the first coating layer, and reduce the occurrence of cracks caused by dry environment or external stress.

[0014] Preferably, among the raw materials used for the capsule base, the first plasticizer includes glycerol and sorbitol in a weight ratio of 4:(1-1.5).

[0015] By adopting this 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 ductility of the capsule base but also optimizes its mechanical strength, thereby reducing the risk of capsule breakage in dry environments. This selection of ratios ensures that the capsule base maintains good formability while possessing superior anti-brittleness properties, thereby improving the stability and reliability of the overall enteric-coated hollow capsule.

[0016] Preferably, in the raw materials used for the first coating layer, the second plasticizer includes triethyl citrate and triacetin in a weight ratio of 3:(1-1.5).

[0017] By adopting the above technical solution, the second plasticizer in the first coating layer is compounded with triethyl citrate and triacetin in a specific ratio. This can ensure the flexibility of the first coating layer while enhancing its bonding with the capsule base. This compounding method not only effectively reduces the compatibility issues that may be caused by a single plasticizer, but also optimizes the mechanical properties of the first coating layer, thereby significantly improving the resistance of the entire capsule to brittleness, ensuring that the capsule structure remains stable in a dry environment and is not prone to delamination or breakage.

[0018] In the second aspect, the present application provides a preparation process for enteric hollow capsules with good anti-brittleness, comprising the following steps: S1, preparing a glue solution: dispersing gelatin, a first plasticizer, a sunscreen and a colorant in water, stirring evenly at a temperature of 60-80°C and a pressure of 0.056-0.068Mpa to obtain a glue solution; S2, preparing a first coating solution: dispersing hydroxypropyl methylcellulose, sodium alginate, chitosan and a second plasticizer in water, stirring evenly at a temperature of 70-85°C to obtain a first coating solution. liquid; S3, preparing a second coating liquid: dispersing hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate in water, stirring evenly at a temperature of 45-55° C., and adding a neutralizer when using to obtain a second coating liquid; S4, capsule making: dipping a capsule mold with glue liquid, drying to form a capsule base, coating once with the first coating liquid, drying to form a first coating layer, coating twice with the second coating liquid, drying to form a second coating layer, removing the capsule, cutting, and fitting to obtain enteric hollow capsules.

[0019] By adopting the above technical solution, the temperature and pressure conditions of each step in the preparation process of the present application are strictly controlled to ensure the uniform dispersion and sufficient cross-linking of the materials in each layer, thereby further improving the overall anti-brittleness performance of the capsule.

[0020] Preferably, in step S4, before the secondary coating, a strengthening treatment is further included, specifically: immersing the product having formed the first coating layer in a calcium-zinc ion mixture with a concentration of 3-4wt%, standing for 15-20s, taking it out, drying it, and then performing the secondary coating.

[0021] By adopting the above technical solution, the present application strengthens the product with the first coating layer formed before the secondary coating, that is, immerses 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; the present application controls the standing time to 15-20s, which can ensure that the calcium-zinc ions fully penetrate and act on the surface of the first coating layer, further improve the mechanical properties, and avoid the negative effects caused by too long or too short treatment time as much as possible; and the present application uses a calcium-zinc ion mixture with a concentration of 3-4wt%, which can ensure the strengthening effect while not adversely affecting the subsequent coating process and the performance of the final product, ensuring the friability qualified rate of the enteric hollow capsules in a dry environment. If the concentration is too low, the reinforcement effect is 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 in turn damage the mechanical properties of the capsule.

[0022] Preferably, in the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:(1-3).

[0023] By adopting the above technical solution, the present application controls the molar ratio of calcium ions to zinc ions, and improves the overall mechanical strength as much as possible 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 be possible to significantly improve the overall mechanical strength of the capsule.

[0024] Preferably, in the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:2.

[0025] By adopting the above technical solution, the present 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, with the highest friability qualified rate.

[0026] In summary, the present application has the following beneficial technical effects: the enteric-coated hollow capsule of the present application has a capsule base, a first coating layer and a second coating layer arranged in sequence from the inside to the outside, 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, so the enteric-coated hollow capsule of the present application has good bonding strength and stability as a whole, good anti-brittleness, and also good dissolution and acid resistance. Experimental data show that its friability qualified rate is not less than 96%; the present application Microcrystalline cellulose and magnesium stearate are added to the first coating layer. The synergistic combination of the two can improve the mechanical strength and anti-brittleness performance of the first coating layer and enhance the toughness of the first coating layer without affecting the fluidity of the raw materials used in the first coating layer. In the preparation method of the present application, the product with the first coating layer formed is subjected to a strengthening treatment before the secondary coating, that is, it is immersed 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, and the temperature and pressure conditions of each step are strictly controlled as a whole to ensure the uniform dispersion and sufficient cross-linking of the materials of each layer, thereby further improving the overall anti-brittleness performance of the capsule. DETAILED DESCRIPTION

[0027] Material Source Unless otherwise specified, the raw materials used in this application are all commercially available products, specifically: Gelatin was purchased from Rousselot (Guangdong) Gelatin Co., Ltd. with a viscosity of 4.6 mPa·s and a moisture content of 9.1%; Hydroxypropyl methylcellulose was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., CAS number 9004-65-3, viscosity 5 mPa·s; Sodium alginate was purchased from Shanghai MacLean Reagent Co., Ltd.; Polyethylene glycol, CAS number 25322-68-3, molecular weight 6000; Hydroxypropyl methylcellulose acetate succinate and hypromellose phthalate were purchased from Taian Ruitai Cellulose Co., Ltd.; Sorbitol, CAS No. 50-70-4; Triethyl citrate, CAS No. 77-93-0; Glyceryl triacetate, CAS No. 102-76-1; Carboxymethyl ethyl ether cellulose, CAS No. 37205-99-5.

[0028] The present application is further described in detail below with reference to the following examples and comparative examples.

[0029] <Example 1.1> A preparation process of enteric-coated hollow capsules with good anti-brittleness comprises the following steps: S1. Prepare glue solution: Disperse 350 g of gelatin and 250 g of the first plasticizer (glycerol) in 875 mL of water, and stir evenly at a temperature of 80°C and a pressure of 0.056 MPa. When the foam in the system gradually decreases and no longer rises, stop vacuuming, exhaust, and stop stirring. Then, release the mixed solution from the sol tank and filter it. Then, add 1 g of a sunscreen (titanium dioxide) and 2 g of a colorant (tartrazine), stir evenly, and keep warm to obtain glue solution. S2. Prepare a first coating solution: disperse 60 g of hypromellose, 30 g of sodium alginate, 8 g of chitosan, and 3 g of a second plasticizer (polyethylene glycol) in 900 mL of water, stir at 85° C. for 3 h, filter, and keep warm. Defoam under a true pressure of 0.06 MPa. After the bubbles are removed, cool to 55° C. and let stand for 8 h, then cool to 48° C. and keep warm to obtain a first coating solution. S3. Prepare a second coating solution: disperse 150 g of hypromellose acetate succinate and 100 g of hypromellose phthalate in 1.44 L of water, stir at 55° C. for 3 h, and add 8 g of a neutralizer (ammonium bicarbonate) before use to obtain a second coating solution; S4. Capsule making: Dip the capsule mold in glue liquid, dry it under normal indoor air conditions of temperature 25°C and humidity 55% RH to form a capsule base, immerse the capsule base in the first coating liquid, perform a coating once, dry it under normal indoor air conditions of temperature 25°C and humidity 60% RH to form a first coating layer, immerse it in the second coating liquid for a second coating, dry it under normal indoor air conditions of temperature 25°C and humidity 55% RH to form a second coating layer, remove the capsule, cut it, and put it together to obtain enteric-coated hollow capsules.

[0030] <Example 1.2> A preparation process of enteric-coated hollow capsules with good anti-brittleness comprises the following steps: S1. Prepare glue solution: Disperse 450 g of gelatin and 150 g of the first plasticizer (glycerol) in 1.2 L of water, and stir evenly at a temperature of 60°C and a pressure of 0.068 MPa. When the foam in the system gradually decreases and no longer rises, stop the vacuum, exhaust, and stop stirring. Then, release the mixed solution from the sol tank and filter it. Then, add 30 g of a sunscreen (titanium dioxide) and 5 g of a colorant (tartrazine), stir evenly, and keep warm to obtain glue solution. S2. Prepare a first coating solution: disperse 70 g of hypromellose, 25 g of sodium alginate, 5 g of chitosan, and 3 g of a second plasticizer (polyethylene glycol) in 1 L of water, stir at 70° C. for 3 h, filter, and keep warm. Defoam under a true pressure of 0.06 MPa. After the bubbles are removed, cool to 55° C. and let stand for 8 h, then cool to 48° C. and keep warm to obtain a first coating solution. S3. Prepare a second coating solution: disperse 250 g of hypromellose acetate succinate and 50 g of hypromellose phthalate in 2.25 L of water, stir at 45° C. for 3 h, and add 15 g of a neutralizing agent (ammonium bicarbonate) before use to obtain a second coating solution; S4. Capsule making: Dip the capsule mold in glue liquid, dry it under normal indoor air conditions of temperature 25°C and humidity 55% RH to form a capsule base, immerse the capsule base in the first coating liquid, perform a coating once, dry it under normal indoor air conditions of temperature 25°C and humidity 60% RH to form a first coating layer, immerse it in the second coating liquid for a second coating, dry it under normal indoor air conditions of temperature 25°C and humidity 55% RH to form a second coating layer, remove the capsule, cut it, and put it together to obtain enteric-coated hollow capsules.

[0031] <Example 2.1> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 21 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0032] <Example 2.2> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 24 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0033] <Example 2.3> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 27 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0034] <Example 2.4> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 33 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0035] <Example 2.5> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 15 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0036] <Example 2.6> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, 37 g of microcrystalline cellulose is further added to blend with hypromellose, sodium alginate, chitosan and a second plasticizer, and the rest is the same as that of Example 1.1.

[0037] <Example 3.1> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S1, the first plasticizer is 200g glycerol and 50g sorbitol, and the rest is the same as that of Example 1.1.

[0038] <Example 3.2> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S1, the first plasticizer is 182g glycerol and 68g sorbitol, and the rest is the same as that of Example 1.1.

[0039] <Example 3.3> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S1, the first plasticizer is 250g sorbitol, and the rest is the same as that of Example 1.1.

[0040] <Example 4.1> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, the second plasticizer is 2.25g of triethyl citrate and 0.75g of triacetin, and the rest is the same as that of Example 1.1.

[0041] <Example 4.2> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, the second plasticizer is 2g of triethyl citrate and 1g of triacetin, and the rest is the same as that of Example 1.1.

[0042] <Example 4.3> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, the second plasticizer is 2.25g polyethylene glycol and 0.75g triacetin, and the rest is the same as that of Example 1.1.

[0043] <Example 4.4> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different 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, and the rest is the same as that of Example 1.1.

[0044] <Example 4.5> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, the second plasticizer is 3 g of triethyl citrate, and the rest is the same as that of Example 1.1.

[0045] <Example 4.6> A preparation process of enteric-coated hollow capsules with good anti-brittleness is different from that of Example 1.1 in that: in step S2, the second plasticizer is 3g of triacetin, and the rest is the same as that of Example 1.1.

[0046] <Example 5.1> A preparation process for enteric-coated hollow capsules with good anti-brittleness, which differs from Example 1.1 in that: in step S4, a strengthening treatment is performed before the secondary coating. Specifically, the product with the first coating layer formed is immersed in a calcium-zinc ion mixture with a concentration of 4 wt% and a molar ratio of calcium ion to zinc ion of 2:1, and is taken out after standing for 15 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 1.1.

[0047] <Example 5.2> A preparation process for enteric hollow capsules with good anti-brittleness, which differs from Example 1.1 in that: in step S4, a strengthening treatment is performed before the secondary coating. Specifically, the product with the first coating layer formed is immersed in a calcium-zinc ion mixture with a concentration of 3wt% and a molar ratio of calcium ion to zinc ion of 1:4, and is taken out after standing for 20 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 1.1.

[0048] <Example 5.3> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different 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, and the rest is the same as that of Example 5.1.

[0049] <Example 5.4> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different 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, and the rest is the same as that of Example 5.1.

[0050] <Example 5.5> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different 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, and the rest is the same as that of Example 5.1.

[0051] <Example 5.6> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 5.1 in that the calcium-zinc ion mixture is replaced by a zinc ion dispersion with a concentration of 4 wt %. The rest is the same as that of Example 5.1.

[0052] <Example 5.7> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 5.1 in that the calcium-zinc ion mixture is replaced by a calcium ion dispersion with a concentration of 4 wt %. The rest is the same as that of Example 5.1.

[0053] <Example 5.8> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 5.1 in that the molar ratio of the calcium-zinc ion mixture is 2 wt %, and the rest is the same as that of Example 5.1.

[0054] <Example 5.9> A preparation process for enteric-coated hollow capsules with good anti-brittleness is different from that of Example 5.1 in that the molar ratio of the calcium-zinc ion mixture is 5 wt %, and the rest is the same as that of Example 5.1.

[0055] <Example 5.10> A preparation process for enteric-coated hollow capsules with good anti-brittleness, which differs from Example 1.1 in that: in step S4, a strengthening treatment is performed before the secondary coating. Specifically, the product with the first coating layer formed is immersed in a calcium-iron ion mixture with a concentration of 4 wt% and a molar ratio of calcium ion to iron ion of 2:1, and then taken out after standing for 15 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 1.1.

[0056] <Example 5.11> A preparation process for enteric-coated hollow capsules with good anti-brittleness, which differs from Example 1.1 in that: in step S4, a strengthening treatment is further performed before the secondary coating. Specifically, the product having formed the first coating layer is immersed in an iron-zinc ion mixture with a concentration of 4 wt% and a molar ratio of iron ion to zinc ion of 2:1, and is taken out after standing for 15 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 1.1.

[0057] <Example 6.1> A preparation process for enteric-coated hollow capsules with good anti-brittleness, which differs from Example 2.2 in that: in step S4, a strengthening treatment is performed before the secondary coating. Specifically, the product with the first coating layer formed is immersed in a calcium-zinc ion mixture with a concentration of 4 wt% and a molar ratio of calcium ion to zinc ion of 1:2, and is taken out after standing for 15 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 2.2.

[0058] <Example 6.2> A preparation process for enteric-coated hollow capsules with good anti-brittleness, which differs from Example 2.2 in that: in step S4, a strengthening treatment is further performed before the secondary coating. Specifically, the product with the first coating layer formed is immersed in a calcium-zinc ion mixture with a concentration of 3wt% and a molar ratio of calcium ion to zinc ion of 1:2, and is taken out after standing for 20 seconds. It is dried under conventional indoor air conditions of a temperature of 30°C and a humidity of 60% RH, and then a secondary coating is performed. The rest is the same as Example 2.2.

[0059] <Comparative Example 1.1> The difference from Example 1.1 is that in step S2, all the hypromellose is replaced by hypromellose phthalate, and the rest is the same as Example 1.1.

[0060] <Comparative Example 1.2> The difference from Example 1.1 is that in step S2, all the hypromellose is replaced by carboxymethyl ethyl ether cellulose, and the rest is the same as Example 1.1.

[0061] <Comparative Example 2.1> The difference from Example 1.1 is that in step S3, the hypromellose acetate succinate is removed and the amount of hypromellose phthalate used is 250 g. The rest is the same as Example 1.1.

[0062] <Comparative Example 2.2> The difference from Example 1.1 is that in step S3, hypromellose phthalate is removed and the amount of hypromellose acetate succinate is 250 g. The rest is the same as Example 1.1.

[0063] <Comparative Example 2.3> The difference from Example 1.1 is that in step S3, the amount of hypromellose acetate succinate is 100 g, and the amount of hypromellose phthalate is 150 g. The rest is the same as Example 1.1.

[0064] <Comparative Example 2.4> The difference from Example 1.1 is that in step S3, the amount of hypromellose acetate succinate is 300 g, and the amount of hypromellose phthalate is 25 g. The rest is the same as Example 1.1.

[0065] <Comparative Example 2.5> The difference from Example 1.1 is that in step S3, hypromellose acetate succinate is replaced by hypromellose, and the rest is the same as Example 1.1.

[0066] <Comparative Example 2.6> The difference from Example 1.1 is that in step S3, hypromellose phthalate is replaced by hypromellose, and the rest is the same as Example 1.1.

[0067] <Comparative Example 3.1> The difference from Example 1.1 is that the raw materials of the first coating solution and the second coating solution are interchanged, specifically: S2. Prepare a first coating solution: disperse 150 g of hypromellose acetate succinate and 100 g of hypromellose phthalate in 1.44 L of water, stir at 55° C. for 3 h, and add 8 g of a neutralizing agent (ammonium bicarbonate) before use to obtain a first coating solution; S3. Prepare the second coating solution: disperse 600 g of hydropropyl methylcellulose, 300 g of sodium alginate, 80 g of chitosan and 30 g of the second plasticizer (polyethylene glycol) in 1.2 L of water, stir at 85°C for 3 h, filter, keep warm, and remove bubbles at a true pressure of 0.06 MPa. After the bubbles are removed, cool to 55°C and let stand for 8 h, then cool to 48°C and keep warm to obtain the first coating solution.

[0068] <Comparative Example 3.2> The difference from Example 1.1 is that the second coating layer is removed, and the rest is the same as Example 1.1.

[0069] <Comparative Example 3.3> The difference from Example 1.1 is that the first coating layer is removed and the second coating layer is directly prepared on the surface of the capsule base. The rest is the same as Example 1.1.

[0070] <Comparative Example 4.1> S1. Prepare glue: 350 g gelatin, 250 g glycerol, 60 g hydroxypropyl methylcellulose, 30 g sodium alginate, 8 g chitosan, and 0.2 L of a 20 wt % calcium-zinc ion mixture with a molar ratio of calcium ion to zinc ion of 2:1 were dispersed in 1.8 L of water, and stirred at a temperature of 80 ° C. and a pressure of 0.056 MPa. When the foam in the system gradually decreased and no longer turned up, the vacuum was stopped, the exhaust was stopped, and the stirring was stopped. The mixture was then discharged from the sol tank and filtered. 1 g of a sunscreen (titanium dioxide) and 2 g of a colorant (tartrazine) were added, and the mixture was stirred evenly and kept warm to obtain a glue; S2. Prepare a coating solution: disperse 150 g of hypromellose acetate succinate and 100 g of hypromellose phthalate in 1.44 L of water, stir at 55° C. for 3 h, and add 8 g of a neutralizer (ammonium bicarbonate) before use to obtain a coating solution. S3. Capsule making: Dip the capsule mold into glue liquid, dry it under normal indoor air conditions of temperature 25°C and humidity 55% RH to form a capsule base, then immerse it in coating liquid for coating, dry it under normal indoor air conditions of temperature 30°C and humidity 60% RH to form a coating layer, remove the capsule, cut it, and put it together to obtain enteric-coated hollow capsules.

[0071] <Comparative Example 4.2> S1, prepare glue: 350g gelatin, 250g glycerol, 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 ion to zinc ion of 2:1 were dispersed in 2.3L of water, and stirred evenly under the conditions of a temperature of 70°C and a pressure of 0.056MPa. When the foam in the system gradually decreased and no longer turned up, the vacuum was stopped, the exhaust was stopped and the stirring was stopped, and then the mixture was discharged from the sol tank and filtered, and then 1g of a sunscreen (titanium dioxide) and 2g of a colorant (tartrazine) were added, and the mixture was stirred evenly and kept warm to obtain a glue; S2. Capsule making: Dip the capsule mold into glue liquid, dry it under normal indoor air conditions of temperature 30°C and humidity 60% RH, extract the capsule, cut it, and put it together to obtain enteric-coated hollow capsules.

[0072] Performance testing 1. Anti-friability test: Capsules prepared in the Examples and Comparative Examples, 50 capsules per group, were placed in a watch glass, and placed in a desiccator filled with saturated magnesium nitrate solution. The solution was kept at a constant temperature of 25±1°C for 24 hours. The capsules were removed and immediately placed one by one into a glass tube (24 mm inner diameter, 200 mm long) placed upright on a wooden board (2 cm thick). A cylindrical weight (made of polytetrafluoroethylene, 22 mm diameter, mass 20±0.1 g) was allowed to fall freely from the mouth of the glass tube. The number of unbroken capsules was counted, and the proportion of unbroken capsules was calculated, which was recorded as the friability pass rate (%); 2. Dissolution and acid resistance test: Take 30 enteric-coated hollow capsules prepared in each of the examples and comparative examples, and fill the capsules with omeprazole using a quantitative filling technology cannula-type quantitative device. The humidity in the filling area is controlled at ≤30% RH, and nitrogen is filled for protection (oxygen content <0.5%) to obtain capsules to be tested. According to the dissolution and release rate determination method (General Rule 0931, Method 2, Method 1), 500 mL of sodium chloride hydrochloric acid solution (1 g of sodium chloride, 3.5 mL of hydrochloric acid, and water to 500 mL) is used as the dissolution medium. The speed is 100 r / min and the operation is carried out in accordance with the law. After 120 minutes, 400 mL of 0.235 mol / L disodium hydrogen phosphate solution preheated to 37°C is added to the operating container. The speed is unchanged and the operation is continued in accordance with the law. 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, shake well, and use it as the test solution; accurately weigh about 20 mg of omeprazole reference substance, place it in a 100 mL volumetric flask, add 10 mL of ethanol to dissolve it, and dilute it to the scale 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, place it in a 50 mL volumetric flask (20 mg specification) or a 100 mL volumetric flask (10 mg specification), dilute it to the scale with a mixed dissolution medium, and shake well; accurately measure 5 mL, accurately add 1 mL of 0.25 mol / L sodium hydroxide solution, shake well, and use it as the reference solution. Take the test solution and the reference solution, measure according to the method under the content determination item, calculate the dissolution rate of each particle in each group in the examples and comparative examples, and take the average value and record it in Table 1; according to the dissolution and release determination method (General Rule 0931 Method 1), use 500mL of sodium chloride hydrochloric acid solution (sodium chloride 1g, hydrochloric acid 3.5mL, add water to 500mL) as the dissolution medium, rotate at 100r / min, operate according to the law, after 120 minutes, remove the rotating basket, wash the particles in the rotating basket with water until the washing solution is neutral, use a small amount of phosphate buffer (pH=11.0) to transfer the particles to a 100mL brown volumetric flask, and measure according to the method under the content determination item from "add 20mL of ethanol" according to the law, calculate the acid resistance by peak area according to the external standard method, and take the average value and record it in Table 1; 3. Peel Strength Test: The capsules obtained in the Examples and Comparative Examples were torn apart and the layer structures were observed for delamination. The results are recorded in Table 1, where A represents no delamination, B represents some delamination between the three layers, and C represents clear gaps between the layers.

[0073] Table 1 Performance test table

[0074] Data Analysis: As can be seen from Table 1, the friability qualified rate of Examples 1.1-1.2 of the present application reached 96%, the solubility was 98.1-98.3%, the acid resistance reached 97.2-97.5%, and no delamination occurred in the peeling resistance test, which proves that the enteric hollow capsules of the present application not only have good acid resistance and enteric effect, but also have good flexibility and stability due to the good flexibility and stability of the capsule base, the first coating layer has a large surface roughness and adhesion ability, and can form a relatively close bond with the capsule base and the second coating layer. The second coating layer has good mechanical strength and low porosity, so the overall bonding strength and stability are good, and the anti-friction property is better.

[0075] The difference between Examples 2.1-2.6 and Example 1.1 is that a certain amount of microcrystalline cellulose is added to the first coating layer in this application. The friability qualified rate of Examples 2.1-2.4 is significantly increased, and no delamination phenomenon occurs in the peeling resistance test. The friability qualified rate of Example 2.2 even reaches 100%, which proves that the mechanical strength and anti-friability performance of the first coating layer can be significantly improved by adding microcrystalline cellulose. In addition, microcrystalline cellulose can also be used as a filler and thickener to form a denser network structure in the first coating layer, effectively enhancing the first coating layer. The toughness of the coating layer can reduce the cracks caused by dry environment or external stress; the amount of microcrystalline cellulose used in Example 2.5 is significantly lower than that in Examples 2.1-2.4, and the results show that it cannot improve the anti-brittleness. The amount of microcrystalline cellulose used in Example 2.6 is significantly higher than that in Examples 2.1-2.4, and the results show that its acid resistance is reduced. This proves that the application can maximize the mechanical strength and anti-brittleness performance of the capsule without affecting the internal flow effect of the first coating layer by strictly controlling the amount of microcrystalline cellulose added, thereby reducing the cracks caused by dry environment or external stress.

[0076] The difference between Examples 3.1-3.2 and Example 1.1 is that the present application changes the composition of the first plasticizer. The friability qualified rates of Examples 3.1-3.2 are all higher than that of Example 1.1, and no delamination phenomenon occurs in the peeling resistance test, which proves that the synergistic effect between glycerol and sorbitol not only improves the ductility of the capsule base, but also optimizes its mechanical strength, thereby reducing the risk of capsule breakage in a dry environment; Example 3.3 replaces the first plasticizer with sorbitol. The results show that there is no significant difference between the various properties of Example 1.1, which further proves that the present application selects a specific ratio of glycerol and sorbitol so that the capsule base has better anti-friability while maintaining good formability, thereby improving the stability and reliability of the overall enteric-coated hollow capsule.

[0077] The difference between Examples 4.1-4.2 and Example 1.1 is that the present application changes the composition of the second plasticizer. The results show that the friability qualified rate is higher than that of Example 1.1, and no delamination phenomenon occurs in the peeling resistance test, which proves that triethyl citrate and triacetin are compounded in a specific proportion, which can ensure the flexibility of the first coating layer while enhancing the binding force between it and the capsule base. 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 friability resistance of the entire capsule, ensuring that the capsule structure remains stable in a dry environment and is not prone to delamination or fragmentation; Examples 4.3-4.6 also change the composition of the second plasticizer. The results show that the friability qualified rate is basically the same as or even lower than that of Example 1.1, further proving that triethyl citrate and triacetin compounded in a specific proportion have significant synergistic effects.

[0078] The difference between Examples 5.1-5.2 and Example 1.1 is that the present application also performs a strengthening treatment before the secondary coating. The results show that the qualified rate of friability is significantly improved, and no delamination phenomenon occurs in the peeling resistance test. This proves that the present application can effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer by immersing the product with the first coating layer in a calcium-zinc ion mixture.

[0079] The difference between Examples 5.3-5.5 and Example 5.1 is that the present application changes the molar ratio of calcium ions to zinc ions in the calcium-zinc ion mixture. The results show that the friability qualification rate is significantly improved, and no delamination phenomenon occurs in the peeling resistance test. This proves that the present application improves 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 the amount of calcium ions used is too much, the roughness of the capsule will be excessively reduced; if the amount of zinc ions used is too much, it will not be able to significantly improve the overall mechanical strength of the capsule.

[0080] 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 concentrations, respectively. The results showed that the friability qualified rate was not significantly improved, proving that the calcium ions and zinc ions in the calcium-zinc ion mixture had a good synergistic effect.

[0081] The difference between Examples 5.8-5.9 and Example 5.1 lies in that the concentration of the calcium-zinc ion mixture was changed. The results showed that the friability qualification rate decreased instead of increasing, and a certain degree of stratification occurred in the peeling resistance test. This proves that if the concentration is too low, not only will the reinforcement effect be almost zero, but if the concentration is too high, the cross-linking rate of calcium and zinc ions with the substances in the system will be reduced, which in turn will impair the mechanical properties of the capsule.

[0082] The difference between Examples 5.10-5.11 and Example 5.1 is that the present application uses a calcium-iron ion mixture and an iron-zinc ion mixture to strengthen the first coating layer, respectively. The results show that the solubility is greatly reduced. Technicians speculate that this is because the iron ions form a denser cross-linked structure inside the system, resulting in insufficient flexibility of the first coating layer and difficulty in releasing drugs from the capsule.

[0083] 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, a calcium-zinc ion mixture with an optimal calcium-zinc molar ratio is added in the present application. The results show that the qualified rate of friability is still not 100%, and the acid resistance is significantly improved, proving that the calcium-zinc ion mixture of the present application can indeed effectively enhance the density of the capsule structure and the mechanical strength of the first coating layer.

[0084] The difference between Comparative Examples 1.1-1.2 and Example 1.1 is that the hydroxypropyl methylcellulose in step S2 is replaced by hydroxypropyl methylcellulose phthalate and carboxymethyl ethyl ether cellulose, respectively. The results show that the qualified rate of friability is reduced, and a certain stratification phenomenon occurs in the peeling resistance test, which proves that the layer structure with hydroxypropyl methylcellulose as the main ingredient has a large surface roughness and adhesion ability, can form a relatively close bond with the capsule base and the second coating layer, and can also slow down the diffusion of internal moisture to a dry environment, thereby reducing the risk of breakage.

[0085] The difference between Comparative Examples 2.1-2.2 and Example 1.1 is that the hydropropyl methylcellulose acetate succinate and hydropropyl methylcellulose phthalate in step S3 are respectively removed. The results show that the acid resistance and friability qualified rates are reduced, which proves that hydropropyl methylcellulose acetate succinate and hydropropyl methylcellulose phthalate have a good synergistic effect. The dissolution rate of the composite system of the two in the intestinal environment is increased, and it has a significant synergistic toughening effect. As the outermost protective layer in the overall capsule layer structure, it can significantly improve the overall mechanical strength of the capsule.

[0086] The difference between Comparative Examples 2.3-2.4 and Example 1.1 is that the compounding ratio of hydropropyl methylcellulose acetate succinate and hydropropyl methylcellulose phthalate was changed. The results showed that the acid resistance and friability qualified rates 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.

[0087] The difference between Comparative Examples 2.5-2.6 and Example 1.1 is that hypromellose acetate succinate and hypromellose phthalate are respectively replaced with hypromellose. The results show that the acid resistance is significantly reduced, further proving that hypromellose acetate succinate and hypromellose phthalate have a good synergistic effect and can effectively resist the gastric acid environment.

[0088] The difference between Comparative Examples 3.1-3.3 and Example 1.1 is that the present application changes the layer structure relationship between the first coating layer and the second coating layer. The results show that the qualified rate of friability and acid resistance show a downward trend, while the dissolution rate does not improve at all. In addition, a certain degree of stratification occurs in the peeling resistance test of Comparative Examples 3.1 and 3.3. This is because the stability of the enteric hollow capsule does not have a linear relationship with the number of layers. When the number of layers is large, there will be problems of interlayer detachment and / or poor acid resistance. When the number of layers is small, there will be problems of poor acid resistance and / or easy rupture of the capsule. Various factors strongly prove that the capsule base, the first coating layer and the second coating layer arranged in sequence from the inside to the outside of the present application have a good coordination effect, and the coordination effect between the multiple layers effectively improves the above-mentioned defects, so that the capsule has a high dissolution rate, acid resistance and friability qualified rate.

[0089] In Comparative Example 4.1, the present application blended the glue, the first coating solution and the calcium-zinc ion mixture as a new glue, and then used the original second coating solution for coating. The results showed that the solubility was low, and during the dissolution test, the technicians observed that the layer structure of the capsule was severely peeled, and the gaps between the layer structures were clearly visible. It is speculated that this is because the degree of internal cross-linking of the new glue is too large and the structure is too dense, resulting in its poor solubility. In addition, the calcium-zinc ion mixture is relatively fully cross-linked inside the capsule base, and the active sites of other components are also occupied to a certain extent, resulting in a significant reduction in the binding force between the capsule base and the coating layer.

[0090] In Comparative Example 4.2, the present application blended the glue, the first coating liquid, the calcium-zinc ion mixture and the second coating liquid as a new glue. The results showed that the solubility was low. The technicians speculated that this was because the new glue contained more material components, resulting in excessive internal cross-linking and an overly dense structure, which led to poor solubility.

[0091] The embodiments of this specific implementation method are all preferred embodiments of the present application and are not intended to limit the scope of protection of the present application. Therefore, any equivalent changes made based on the structure, shape, and principle of the present application should be included in the scope of protection of the present application.

Claims

1. An enteric-coated hollow capsule with good anti-friability, characterized in that: The method comprises a capsule base, a first coating layer and a second coating layer which are sequentially arranged from the inside to the outside; By weight, The raw materials used for the capsule base include: 35-45 parts of gelatin, 15-25 parts of a first plasticizer, 1-3 parts of a sunscreen, and 0.5-2 parts of a colorant; The raw materials used for the first coating layer include: 60-70 parts of hypromellose, 25-30 parts of sodium alginate, 5-8 parts of chitosan and 3-6 parts of the second plasticizer; The raw materials used for the second coating layer include: 15-25 parts of hypromellose acetate succinate, 5-10 parts of hypromellose phthalate and 0.8-1.5 parts of a neutralizer.

2. The enteric-coated hollow capsule with good anti-friability according to claim 1, characterized in that: The raw materials used for the first coating layer also include microcrystalline cellulose, and the amount of microcrystalline cellulose added is 21-33 parts by weight.

3. The enteric-coated hollow capsule with good anti-friability according to claim 2, characterized in that: The amount of microcrystalline cellulose added is 24 parts by weight.

4. The enteric-coated hollow capsule with good anti-friability according to claim 1, characterized in that: Among the raw materials used for the capsule base, the first plasticizer includes glycerol and sorbitol in a weight ratio of 4:(1-1.5).

5. The enteric-coated hollow capsule with good anti-friability according to claim 1, characterized in that: Among the raw materials used for the first coating layer, the second plasticizer includes triethyl citrate and triacetin in a weight ratio of 3:(1-1.5).

6. A process for preparing the enteric-coated hollow capsule with good anti-brittleness according to any one of claims 1 to 5, characterized in that: The following steps are involved: S1. Preparing a glue solution: dispersing gelatin, a first plasticizer, a sunscreen, and a colorant in water, and stirring the mixture at a temperature of 60-80° C. and a pressure of 0.056-0.068 MPa to obtain a glue solution; S2. Prepare a first coating solution: disperse hypromellose, sodium alginate, chitosan, and a second plasticizer in water, and stir uniformly at a temperature of 70-85° C. to obtain a first coating solution; S3. Prepare a second coating solution: disperse hypromellose acetate succinate and hypromellose phthalate in water, stir evenly at a temperature of 45-55° C., and add a neutralizing agent when using to obtain a second coating solution; S4. Capsule making: Dip the capsule mold into glue liquid, dry it to form a capsule base, coat it once with a first coating liquid, dry it to form a first coating layer, coat it twice with a second coating liquid, dry it to form a second coating layer, remove the capsule, cut it, and put it together to obtain enteric-coated hollow capsules.

7. The process for preparing an enteric-coated hollow capsule with good anti-friability according to claim 6, characterized in that: In the 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 3-4wt%, left to stand for 15-20s, taken out, dried, and then coated for the second time.

8. The process for preparing an enteric-coated hollow capsule with good anti-friability according to claim 7, characterized in that: In the calcium-zinc ion mixture, the molar ratio of calcium ions to zinc ions is 1:(1-3).

9. The process for preparing enteric-coated hollow capsules with good anti-friability according to claim 8, 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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