Sodium alginate enteric-coated hollow capsule and its preparation method and application

Abstract

The present invention belongs to the technical field of enteric hollow capsules, and specifically relates to a sodium alginate enteric hollow capsule and a preparation method and application thereof. The present invention comprises: using sodium alginate, sodium carboxymethyl cellulose, microcrystalline cellulose, pullulan, and glycerol as raw materials, preparing sodium alginate enteric hollow capsules by sol, gel preservation, gel dipping, calcification, drying, demoulding, and cutting. The enteric hollow capsules prepared by the present invention do not add a gelling agent, have good toughness, are not brittle and stable, do not dissolve in the stomach for two hours, dissolve completely after entering the small intestine for half an hour, and the capsule shell completely disintegrates, have the characteristics of being insoluble in the stomach and enteric, and have stable properties.

Description

Technical Field

[0001] The invention belongs to the technical field of enteric-coated hollow capsules, and in particular relates to a sodium alginate enteric-coated hollow capsule and a preparation method and application thereof. Background Art

[0002] With the development of pharmaceutical technology, the design and development of drug delivery systems have become increasingly important. The optimization of drug delivery systems can not only improve the bioavailability of drugs, but also improve the therapeutic effects of drugs and reduce the risk of adverse reactions. As a common drug carrier, capsules are widely used in the field of pharmaceutical preparations. However, traditional gelatin capsules have some limitations, such as sensitivity to temperature and humidity, and possible animal-derived problems. Therefore, finding new capsule materials has become one of the research focuses.

[0003] Enteric-coated capsules are a special type of capsule designed to remain intact in the stomach acid environment to protect the drug from being destroyed by stomach acid and ensure that the drug is released in the intestine, which is very important for some drugs. However, traditional enteric-coated capsules usually use complex chemical coating processes to achieve enteric function, which not only increases production costs but also may introduce additional chemicals. Therefore, it is particularly important to develop a simple, economical and efficient method for preparing enteric-coated capsules.

[0004] As a natural polysaccharide, sodium alginate has good biocompatibility, biodegradability and non-toxicity, and has received extensive attention in the medical field. Sodium alginate can cross-link with divalent cations (such as calcium ions) to form gels, making it one of the ideal materials for preparing capsules. However, single sodium alginate capsules are often insufficient in physical properties, especially in mechanical strength and drug release control.

[0005] In the prior art, different excipients are often added to improve the physical properties of the capsule, such as increasing mechanical strength, improving drug release characteristics, etc., which can significantly improve the practicality of the capsule. For example, the invention patent with publication number CN 103877587A discloses a plant polysaccharide medicinal enteric hard shell capsule. The viscosity of the gel prepared by sodium alginate used in the capsule is not easy to control, and the stability, compression resistance and flexibility of the gel are poor. The invention patent with publication number CN 104887643A discloses a sodium alginate / starch-based enteric hollow capsule and a one-time molding preparation method thereof. Although the sodium alginate used in the raw material of the hollow capsule is composed of high-viscosity sodium alginate and low-viscosity sodium alginate, a coagulant is added to the sodium alginate / starch-based enteric hollow capsule, which is not conducive to better disintegration of the capsule in the body and there is residue. Summary of the invention

[0006] The purpose of the present invention is to provide a sodium alginate enteric hollow capsule and a preparation method and application thereof, and to prepare a sodium alginate enteric hollow capsule with simple and safe raw material composition, easy manufacture and no gelling agent by optimizing the formula and process. The stability of the capsule in the gastric acid environment and the controlled release in the intestinal alkaline environment are achieved, thereby providing a safer, more effective and easy-to-produce enteric carrier for oral drugs.

[0007] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0008] In a first aspect, the present invention provides a sodium alginate enteric hollow capsule composition, which comprises the following components by weight: 3-5 parts of sodium alginate with 70-90 cps, 4-6 parts of sodium alginate with 8-20 cps, 1-2 parts of sodium carboxymethyl cellulose, 0.5-1.5 parts of microcrystalline cellulose, 1.5-3 parts of pullulan, 3-4 parts of glycerol, and the rest is water; no gelling agent is added to the sodium alginate hollow capsule composition.

[0009] The inventor found in the research process that the viscosity of sodium alginate has a significant effect on the viscosity of the final glue, and affects the thickness, flexibility and integrity of the capsule molding, and has a certain correlation with the disintegration degree of the hollow capsule in the intestine. Sodium alginate with a single viscosity cannot achieve the stability of the mucus and the regulation of viscosity. The present invention uses two sodium alginates with two viscosities close to each other, which is conducive to regulating the stability and viscosity of the mucus. At the same time, in order to improve the mechanical strength and drug release characteristics of the capsule and significantly improve the practicality of the capsule, sodium carboxymethyl cellulose (CMC) is added as a thickener and stabilizer to improve the formability and stability of the capsule; pullulan can enhance the compression resistance of the capsule; glycerol, as a plasticizer, helps to improve the flexibility and durability of the capsule; in addition, the present invention does not add a gelling agent, and there is no effect of the gelling agent on the disintegration, so that the disintegration performance of the product is stable and there is no residue.

[0010] In some other embodiments of the present invention, the sodium alginate enteric hollow capsule composition comprises the following components by weight: 3-5 parts of 70-85 cps sodium alginate, 4-5 parts of 8-20 cps sodium alginate, 1-1.5 parts of sodium carboxymethyl cellulose, 0.5-1 part of microcrystalline cellulose, 1.5-3 parts of pullulan, 3-4 parts of glycerol, and the rest is water;

[0011] Preferably, 5 parts of 85cps sodium alginate, 5 parts of 20cps sodium alginate, 1.5 parts of sodium carboxymethyl cellulose, 1 part of microcrystalline cellulose, 3 parts of pullulan, 4 parts of glycerol, and the rest is water.

[0012] In a second aspect, the present invention provides a method for preparing a sodium alginate enteric-coated hollow capsule, characterized in that it comprises the following steps:

[0013] (1) Ingredients and sol: The sodium alginate hollow capsule composition is prepared according to the first aspect, sodium alginate is mixed with water, sodium carboxymethyl cellulose, microcrystalline cellulose, pullulan and glycerol are added in sequence, stirred into a colloidal liquid, kept warm, and vacuumed to degas to obtain a gel solution;

[0014] (2) Dipping and molding: Before dipping, the mold is preheated and then brushed with a release agent; when dipping, the capsule mold is vertically immersed in the glue liquid;

[0015] (3) Calcification: Calcification is performed after dipping in glue and molding;

[0016] (4) Drying, shelling and cutting: After drying and shaping, shelling and cutting are completed.

[0017] In some other embodiments of the present invention, the temperature for mixing sodium alginate and water is 70-80°C; the stirring time is 30-60min; the insulation temperature is 70-80°C, and the insulation time is 1-1.5h;

[0018] Preferably, the mixing temperature of sodium alginate and water is 77° C.; the stirring time is 50 min; the insulation temperature is 77° C., and the insulation time is 1 h.

[0019] In some other embodiments of the present invention, in step (1), after vacuum degassing, the viscosity of the glue at 60-65° C. is 5000-6000 cps.

[0020] In some other embodiments of the present invention, in step (2), the mold is preheated to a temperature of 30-40°C, the time for vertical immersion in the glue solution is 5-10 seconds, and the temperature of the glue dipping is 55-60°C;

[0021] The release agent is one or more of Tween-80, liquid paraffin, salad oil, corn oil, peanut oil, soybean oil and mustard oil;

[0022] Preferably, the mold is preheated at a temperature of 35° C., the time for vertical immersion in the glue solution is 8 seconds, the temperature for dipping the glue is 58° C., and the mold release agent is Tween-80.

[0023] In some other embodiments of the present invention, in step (3), the calcification solution is one or more of calcium chloride, calcium gluconate or calcium citrate, the concentration of the calcification solution is 3-5wt.%, and the calcification time is 20-30s;

[0024] Preferably, the calcification solution is calcium gluconate, the concentration of the calcification solution is 3.5wt.%, and the calcification time is 20s.

[0025] In some other embodiments of the present invention, in step (4), the drying temperature is 30-35° C., and the moisture content of the capsule is 6-8 wt.%;

[0026] Preferably, the drying temperature is 33° C. and the moisture content of the capsules is 7 wt.%.

[0027] In a third aspect, the present invention provides a hollow capsule, which is prepared according to the sodium alginate enteric-coated hollow capsule composition ingredients described in the first aspect, preferably, according to the preparation method described in the second aspect.

[0028] In a fourth aspect, the present invention provides a use of the sodium alginate enteric hollow capsule composition described in the first aspect in preparing hollow capsules, wherein the hollow capsules are enteric hollow capsules or sustained-release hollow capsules; preferably, the hollow capsules are medicinal hollow capsules.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The main capsule material of the sodium alginate enteric hollow capsule of the present invention is derived from plant polysaccharides extracted from brown algae, does not contain animal components and organic solvents, and is biodegradable. The mixture of two sodium alginate with different viscosities can improve the stability of the gel and control the viscosity of the gel.

[0031] (2) No gelling agent is required in the preparation process of the sodium alginate enteric-coated hollow capsules of the present invention, and there is no effect of the gelling agent on disintegration, so that the disintegration performance of the product is stable and there is no residue. The addition of sodium carboxymethyl cellulose, microcrystalline cellulose and pullulan can improve the formability, mechanical strength and flexibility of the capsule, and maintain the shape and integrity of the capsule under different environmental conditions.

[0032] (3) The sodium alginate of the present invention is very easy to cross-link with calcium ions, and the calcification time is short and the concentration of the calcification solution is low. The capsule shell formed does not disintegrate in the gastric environment, but disintegrates in the alkaline intestinal environment to release the drug without residue. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a picture of the finished capsule prepared in Example 1 of the present invention;

[0034] Figure 2 This is a picture of the finished capsule prepared in Example 2 of the present invention;

[0035] Figure 3 This is a picture of the finished capsule prepared in Example 3 of the present invention;

[0036] Figure 4 This is a picture of the finished capsule product prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0037] The reagents used in the examples of the present invention are all commercially available conventional reagents.

[0038] Among them, sodium alginate was obtained from Qingdao Mingyue Seaweed Group Co., Ltd., with a viscosity of 70-90 cps and 8-20 cps (1wt.% solution);

[0039] Microcrystalline cellulose was obtained from Shandong Liaocheng Ahua Pharmaceutical Co., Ltd., with a particle size of 100-150um and a degree of polymerization of 260-350;

[0040] Pullulan polysaccharide is from Shandong Mimei Biotechnology Co., Ltd., with a kinematic viscosity of 50-100mm 2 / s (10wt.% solution), molecular weight 2x10 5 -3x10 5 Da.

[0041] The following is explained in conjunction with specific embodiments:

[0042] Example 1

[0043] First, heat 87 parts of water to 75°C, then add 3 parts of sodium alginate with a viscosity of 70-90cps and 4 parts of sodium alginate with a viscosity of 8-20cps, and stir until completely dissolved. Add 1 part of sodium carboxymethyl cellulose, 0.5 parts of microcrystalline cellulose, 1.5 parts of pullulan, and 3 parts of glycerol to the slurry in sequence, maintain the temperature at 70°C and stir for 40 minutes to form a uniform colloid liquid, and continue to keep warm for 1 hour. After the insulation is completed, vacuum degas the glue and measure the viscosity of the glue at 60-65°C.

[0044] The stainless steel capsule mold preheated at 33°C was brushed with Tween-80 as a release agent, and then the mold was vertically immersed in a 55°C glue solution for 6 seconds.

[0045] The capsules formed by dipping in the glue are immersed in a 3wt.% calcium chloride solution for calcification for 20s, and then the calcified capsules are placed in a 30°C blast drying oven for drying, shelling and cutting. After drying, the moisture content of the capsules is 7.8wt.%.

[0046] Example 2

[0047] First, heat 80.5 parts of water to 77°C, then add 5 parts of sodium alginate with a viscosity of 70-90cps and 5 parts of sodium alginate with a viscosity of 8-20cps, and stir until completely dissolved. Add 1.5 parts of sodium carboxymethyl cellulose, 1 part of microcrystalline cellulose, 3 parts of pullulan, and 4 parts of glycerol to the slurry in sequence, maintain the temperature at 77°C and stir for 50 minutes to form a uniform colloid liquid, and continue to keep warm for 1 hour. After the insulation is completed, vacuum degas the glue solution and measure the viscosity of the glue solution at 60-65°C.

[0048] The stainless steel capsule mold preheated at 35°C was brushed with Tween-80 as a release agent, and then the mold was vertically immersed in a 58°C glue solution for 8 seconds.

[0049] The capsules formed by dipping in the glue are immersed in a 3.5wt.% calcium gluconate solution for calcification for 20s, and then the calcified capsules are placed in a 33°C forced air drying oven for drying, shelling and cutting. After drying, the moisture content of the capsules is 7.3wt.%.

[0050] Example 3

[0051] First, heat 78.5 parts of water to 77°C, then add 5 parts of sodium alginate with a viscosity of 70-90cps and 6 parts of sodium alginate with a viscosity of 8-20cps, and stir until completely dissolved. Add 2 parts of sodium carboxymethyl cellulose, 1.5 parts of microcrystalline cellulose, 3 parts of pullulan, and 4 parts of glycerol to the slurry in sequence, maintain the temperature at 77°C and stir for 50 minutes to form a uniform colloid liquid, and continue to keep warm for 1 hour. After the insulation is completed, vacuum degas the glue and measure the viscosity of the glue at 60-65°C.

[0052] The stainless steel capsule mold preheated at 35°C was brushed with Tween-80 as a release agent, and then the mold was vertically immersed in a 58°C glue solution for 8 seconds.

[0053] The capsules formed by dipping in the glue are immersed in a 3.5wt.% calcium gluconate solution for calcification for 20s, and then the calcified capsules are placed in a 33°C forced air drying oven for drying, shelling and cutting. After drying, the moisture content of the capsules is 7.3wt.%.

[0054] Example 4

[0055] First, 83 parts of water were heated to 80°C, followed by the addition of 4 parts of sodium alginate with a viscosity of 70-90 cps and 5 parts of sodium alginate with a viscosity of 8-20 cps, and stirred until completely dissolved. 1.5 parts of sodium carboxymethyl cellulose, 0.5 parts of microcrystalline cellulose, 3 parts of pullulan, and 3 parts of glycerol were added to the slurry in sequence, stirred at 80°C for 45 minutes to form a uniform colloid liquid, and then kept warm for 1 hour. After the insulation was completed, the colloid was vacuum degassed and the viscosity of the colloid at 60-65°C was measured.

[0056] The stainless steel capsule mold preheated at 37°C was brushed with Tween-80 as a release agent, and then the mold was vertically immersed in a 60°C glue solution for 7 seconds.

[0057] The capsules formed by dipping in the glue are immersed in a 3.5wt.% calcium citrate solution for calcification for 25s, and then the calcified capsules are placed in a 35°C forced air drying oven for drying, shelling and cutting. After drying, the moisture content of the capsules is 7.1wt.%.

[0058] Comparative Example 1

[0059] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0060] Comparative Example 2

[0061] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0062] Comparative Example 3

[0063] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0064] Comparative Example 4

[0065] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0066] Comparative Example 5

[0067] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0068] Comparative Example 6

[0069] The difference from Example 2 is that the ingredients of the sodium alginate enteric-coated hollow capsules are as shown in Table 1, and the other steps are exactly the same as those of Example 2.

[0070] Table 1 List of original ingredients for sodium alginate enteric-coated hollow capsules

[0071]

[0072] For the sodium alginate enteric hollow capsules prepared in Examples 1-4 of the present invention and Comparative Examples 1-6, friability, disintegration time, dissolution and release tests were carried out according to the methods specified in Part IV of the Chinese Pharmacopoeia 2020 Edition. The quality inspection items and results are shown in Table 2.

[0073] Table 2 Performance indicators of sodium alginate enteric coated hollow capsules

[0074]

[0075] The evaluation results of the formability, mechanical strength and flexibility of sodium alginate enteric hollow capsules are shown in Table 3:

[0076] Table 3 Performance indicators of sodium alginate enteric coated hollow capsules

[0077]

[0078] As can be seen from Table 3, the low capsule forming rate in Comparative Example 1 is mainly due to the failure to use sodium alginate with a viscosity of 70-90cps, resulting in a low viscosity of the produced glue, which is easy to flow during dipping and difficult to form; although Comparative Example 2 has high transparency and a smooth surface, low-viscosity sodium alginate is not used, resulting in a low capsule shell thickness, a decrease in the mechanical strength of the capsule, poor flexibility, and partial disintegration in gastric juice; the capsules prepared in Comparative Examples 3, 4, and 5 are well formed and have smooth surfaces, but the excipients do cause a decrease in the bonding strength and viscosity of the glue in the capsule, so they disintegrate in gastric juice; Comparative Example 6 lacks glycerin, the viscosity of the glue is too high, foam appears during the dipping process, resulting in bubbles in the capsule, and as an important plasticizer, the lack of glycerin will reduce the flexibility of the capsule and make it easier to break.

Claims

1. A sodium alginate enteric coated hollow capsule composition, characterized in that: The composition comprises the following components by weight: 3-5 parts of 70-90 cps sodium alginate, 4-6 parts of 8-20 cps sodium alginate, 1-2 parts of sodium carboxymethyl cellulose, 0.5-1.5 parts of microcrystalline cellulose, 1.5-3 parts of pullulan, 3-4 parts of glycerol, and the rest is water.

2. The sodium alginate enteric-coated empty capsule composition according to claim 1, characterized in that: According to weight ratio, it includes the following components: 3-5 parts of 70-85cps sodium alginate, 4-5 parts of 8-20cps sodium alginate, 1-1.5 parts of sodium carboxymethyl cellulose, 0.5-1 part of microcrystalline cellulose, 1.5-3 parts of pullulan, 3-4 parts of glycerol, and the rest is water.

3. The sodium alginate enteric-coated empty capsule composition according to claim 2, characterized in that: According to weight ratio, it includes the following components: 5 parts of 85cps sodium alginate, 5 parts of 20cps sodium alginate, 1.5 parts of sodium carboxymethyl cellulose, 1 part of microcrystalline cellulose, 3 parts of pullulan, 4 parts of glycerol, and the rest is water.

4. A method for preparing sodium alginate enteric-coated hollow capsules using the sodium alginate hollow capsule composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Ingredients and sol: prepare the ingredients of the sodium alginate hollow capsule composition according to the above, mix sodium alginate and water, add sodium carboxymethyl cellulose, microcrystalline cellulose, pullulan and glycerol in sequence, stir to form a colloidal liquid, keep warm, and vacuumize to degas to obtain a gel solution; (2) Glue dipping molding: Before dipping, preheat the mold and apply a release agent. When dipping, immerse the capsule mold vertically into the glue liquid. (3) Calcification: Calcification is performed after the molding process is completed by dipping in glue; (4) Drying, shelling and cutting: After drying and shaping, shelling and cutting are completed.

5. The preparation method according to claim 4, characterized in that: In step (1), the temperature for mixing sodium alginate and water is 70-80°C; the stirring time is 30-60 minutes; the insulation temperature is 70-80°C, and the insulation time is 1-1.5 hours.

6. The preparation method according to claim 5, characterized in that: In step (1), the temperature for mixing sodium alginate and water is 77°C; the stirring time is 50 minutes; the insulation temperature is 77°C and the insulation time is 1 hour.

7. The preparation method according to claim 4, characterized in that: In step (1), after vacuum degassing, the viscosity of the glue solution at 60-65°C is 5000-6000cps.

8. The preparation method according to claim 4, characterized in that: In step (2), the mold is preheated to a temperature of 30-40°C, the time for vertical immersion in the glue solution is 5-10 seconds, and the temperature of the glue dip is 55-60°C; The release agent is one or more of Tween-80, liquid paraffin, salad oil, corn oil, peanut oil, soybean oil and mustard oil.

9. The preparation method according to claim 8, characterized in that: In step (2), the mold is preheated to 35°C, the time for vertical immersion in the glue solution is 8 seconds, the temperature of the glue dipping is 58°C, and the release agent is Tween-80.

10. The preparation method according to claim 4, characterized in that: In step (3), the calcification solution is one or more of calcium chloride, calcium gluconate or calcium citrate, the concentration of the calcification solution is 3-5wt.%, and the calcification time is 20-30s.

11. The preparation method according to claim 10, characterized in that: In step (3), the calcification solution is calcium gluconate, the concentration of the calcification solution is 3.5 wt.%, and the calcification time is 20 s.

12. The preparation method according to claim 4, characterized in that: In step (4), the drying temperature is 30-35° C., and the moisture content of the capsule is 6-8 wt.%.

13. The preparation method according to claim 12, characterized in that: In step (4), the drying temperature is 33° C. and the moisture content of the capsule is 7 wt.%.

14. A hollow capsule, characterized in that: Obtained according to the preparation method according to any one of claims 4 to 13.

15. Use of the sodium alginate enteric-coated hollow capsule composition according to any one of claims 1 to 3 in preparing hollow capsules, characterized in that: The hollow capsule is an enteric-coated hollow capsule or a sustained-release enteric-coated hollow capsule.

16. The use according to claim 15, characterized in that The hollow capsule is a medicinal hollow capsule.

Images