Special carrageenan for empty capsules as well as preparation method and application of carrageenan

Abstract

The invention relates to carrageenan special for empty capsules and a preparation method and application of the carrageenan, and belongs to the field of material science, the method comprises the following steps: dissolving carrageenan as a raw material in an acid solution with the pH value of 3.1-3.5 to prepare a glue solution with the mass percent of 10%, carrying out hydrolysis by utilizing acidification high temperature, stopping hydrolysis until the viscosity is 300-2000mPa. S, and cooling to room temperature to obtain the carrageenan. And neutralizing, dialyzing to remove impurities, drying and crushing to obtain the carrageenan special for the empty capsule. According to the invention, carrageenan is partially degraded by controlling reaction conditions, only the fragment size of the carrageenan is reduced, the obtained low-viscosity carrageenan does not lose the gelling property and film-forming property and can successfully replace gelatin to prepare hollow capsules, a new raw material is provided for hollow capsule products, the problem that the use amount of macromolecular carrageenan applied to the hollow capsules is limited is solved, and the application prospect is wide. The current situation that carrageenan empty capsules do not exist in the market is solved.

Description

Technical Field

[0001] The invention belongs to the field of material science, and in particular relates to carrageenan special for hollow capsules and a preparation method and application thereof. Background Art

[0002] Empty capsules are hard and flexible cylindrical capsules composed of a cap and a body that can be nested together. They are one of the main excipients of capsules and can be used to hold solid and liquid drugs, such as powders, granules, pellets, oily liquids or semisolids. Capsules have the advantages of masking taste, improving drug stability, and high bioavailability. They are the second largest oral solid preparation after tablets, accounting for 20% to 30% of solid dosage forms.

[0003] The hollow capsule products currently sold on the market are mainly made of gelatin, which is an animal-derived material. The quality of its raw materials is not controlled, and there may be animal-derived viruses, veterinary drugs, antibiotics and other substances that are harmful to the human body. In addition, products made of gelatin are highly hygroscopic, easy to breed microorganisms, and prone to cross-linking reactions, which in turn lead to prolonged disintegration time. In addition, 84% (5.8 billion) of the world's people have religious beliefs, and 18% (1.26 billion) people advocate vegetarianism, which has caused a huge impact on traditional gelatin capsules. Therefore, it has become a top priority to find non-animal-derived gelatin substitutes to develop capsule preparations.

[0004] At present, the raw materials of plant hollow capsules that are studied more are mainly hydroxypropyl methylcellulose (HPMC), pullulan, modified starch and other plant polysaccharide materials. There are no carrageenan hollow capsules prepared with whole carrageenan as the main raw material of capsule material. In the industrial production of capsule shells, carrageenan mainly uses the low-temperature gel property of its glue liquid to achieve the effect of low-temperature solidification when preparing capsules by the dipping method. Its addition amount is not high, usually less than 10%. Liu Liping et al. used HPMC and carrageenan as capsule materials and gel materials in the "Development of Hydroxypropyl Methylcellulose Hollow Capsules". HPMC capsule shells were prepared through sol, gel cultivation, embryo preparation, drying, cutting, and sleeve processes. The formula is HPMC (E5 type) 16.5%, κ-carrageenan 0.9%, of which carrageenan accounts for 5.2%. Kalmer et al. used pullulan polysaccharide film-forming material and κ-carrageenan as gelling agent to prepare hard capsule shell in Design and preparation of a novel pullulan hard capsule formulation: A promising green candidate and study of crucial capsule features. The proportion of carrageenan in the solid content was only 2.83%. Zhang Yihui et al. developed pullulan hollow capsules in Effects of κ-carrageenan on pullulan's rheological and texture properties as well as pullulan hard capsule performances. The amount of κ-carrageenan increased, but the proportion of κ-carrageenan in the solid content was only 5.63%. Although the use of carrageenan in plant hollow capsules is limited, its film-forming and gelling properties are very good, and it has great potential to replace gelatin to prepare capsules. In addition, carrageenan comes from marine algae, which is healthy, green, renewable and does not occupy land resources. The global annual output is more than 300,000 tons. Due to its sufficient raw material supply, good film-forming and gelling properties, and application in the field of hollow capsules, carrageenan is expected to replace gelatin as one of the main raw materials for hollow capsules.

[0005] Carrageenan is a hydrophilic colloid extracted from red algae. Its chemical structure is a linear polysaccharide composed of sulfated or non-sulfated galactose and anhydrogalactose alternately connected. Its molecular weight is above 200,000 and it has good thickening and gelling properties. According to the different connection positions of sulfate and galactose, carrageenan can be divided into 7 main types, namely κ-carrageenan, ι-carrageenan, λ-carrageenan, γ-carrageenan, ν-carrageenan, ξ-carrageenan, and μ-carrageenan. Among them, the first three are mainly produced and used in industry. The commercially available carrageenan has the characteristics of water retention, thickening, gelling and stability, and is mostly used in food processing such as jelly, soft candy, and ice cream. The larger the molecular weight of carrageenan, the better its stability and gelling properties. Therefore, hydrolysis should be avoided in the production process of the above foods. κ-carrageenan has the potential for capsule shells. It is widely used in the current capsule field, mostly using its gelling properties and less dosage. At present, there is no example of preparing hollow capsules with whole carrageenan as raw material. Preparation of hollow capsules requires the glue to have a high solid content and a suitable viscosity. A low solid content will affect the thickness of the capsule shell wall. A small wall thickness will cause the capsule cap and body to not fit tightly, resulting in powder leakage. A high viscosity is not conducive to the capsule dipped in glue to make embryos. A high viscosity of the glue will make it difficult to evenly adhere to the mold to form a capsule. Commercially available carrageenan has a large molecular weight, high viscosity, and a complex spatial structure. It is limited when used at high concentrations, making the glue sticky and agglomerated, and even there is a phenomenon that the dry powder cannot be fully dissolved. Therefore, we need to degrade it to obtain low-viscosity carrageenan. At present, carrageenan degradation methods include oxidative degradation, methanol degradation, strong acid degradation, enzyme degradation, etc. The above methods are used to prepare carrageenan oligosaccharides. Because the reaction is relatively violent and thorough, the final product is an oligosaccharide with a degree of polymerization of 2-10. These products do not have gelation and film-forming properties and cannot be used to prepare hollow capsules. Summary of the invention

[0006] In view of the defects and problems in the background technology, the present invention provides a method for preparing carrageenan specifically for hollow capsules and its application. The present invention partially degrades the carrageenan by controlling the reaction conditions and only reduces the size of its fragments. The obtained low-viscosity carrageenan does not lose its gelling and film-forming properties. It can successfully replace gelatin for preparing hollow capsules, provide new raw materials for hollow capsule products, improve the problem of limited usage of macromolecular carrageenan in hollow capsules, and solve the current situation that there are no carrageenan hollow capsules on the market.

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

[0008] The invention provides a method for preparing carrageenan for hollow capsules. The method comprises the following steps: dissolving carrageenan as a raw material in an acid solution with a pH value of 3.1-3.5 to prepare a 10% glue solution by mass, hydrolyzing the solution by acidification and high temperature, stopping the hydrolysis when the viscosity reaches 300-2000 mPa·s, neutralizing the solution, dialysis to remove impurities, drying the solution and pulverizing the solution to obtain the carrageenan for hollow capsules.

[0009] Furthermore, the acid solution is one or more of dilute hydrochloric acid, dilute sulfuric acid, acetic acid, citric acid, malic acid, and lactic acid.

[0010] Furthermore, the high temperature is above 90°C.

[0011] As a preferred embodiment, at a temperature above 90° C., 0.04% citric acid carrageenan solution is added and boiled for 2-3 hours, 0.05% citric acid carrageenan solution is added and boiled for 1.5-2 hours, and 0.06% citric acid carrageenan solution is added and boiled for 1 hour.

[0012] The present invention also provides a special carrageenan for hollow capsules, which is prepared by the preparation method, and has a viscosity of 3-10 cps compared to a 1% aqueous solution, and the quality meets the national food additive carrageenan GB1886.169-2016, and is subjected to infrared spectrum analysis and thermogravimetric analysis.

[0013] A carrageenan hollow capsule consists of low-viscosity carrageenan prepared by the method, a plasticizer and water.

[0014] Preferably, the plasticizer is one or more of glycerol, maltitol, sorbitol, PEG200, PEG400, propylene alcohol, triacetin, ethyl citrate, castor oil and phthalate derivatives.

[0015] An easily disintegratable carrageenan hollow capsule comprises low-viscosity carrageenan prepared by the method, a plasticizer, a disintegration-promoting agent and water.

[0016] The disintegration-promoting agent is one or more of Tween 80, polyvinyl pyrrolidone, potassium chloride, polysorbate, soybean lecithin, sodium carbonate, mannitol, sorbitol, lactose and silicon dioxide.

[0017] The present invention also provides a method for preparing the hollow carrageenan capsules, which is prepared by compounding the low-viscosity carrageenan prepared by the method with plasticizer glycerin, and then subjecting the mixture to sol-gelling, heat preservation, dipping in glue, drying, shelling, cutting and sheathing.

[0018] Furthermore, the raw materials and weight percentages for preparing the carrageenan hollow capsules are as follows: 8-12% of the hollow capsule-specific carrageenan, 1-3% of glycerol, and 85-91% of water.

[0019] Furthermore, the temperature of the sol is 85-90° C., and the sol time is 1-1.5 h.

[0020] Furthermore, the insulation temperature is 70-80° C., and the insulation time is 1-2 hours.

[0021] Furthermore, the raw materials for preparing the carrageenan hollow capsules also include 0.1-1% (mass percentage) of Tween, a disintegration-promoting agent.

[0022] The beneficial effects of the present invention compared with the prior art are:

[0023] 1. The present invention develops carrageenan for hollow capsules for the first time, which can better replace gelatin raw materials for the preparation of hollow capsules and other situations where gelatin is used in high concentrations. For example, the preparation of soft candies requires a high solid content, and the amount of sucrose can be effectively reduced by increasing the amount of carrageenan, which is beneficial for protecting dental health and reducing obesity. In addition, as a substitute, carrageenan can improve the problems of animal diseases, excessive heavy metals, abuse of antibiotics, and limited application range caused by the source of raw materials of animal gelatin.

[0024] 2. The present invention is the first to use low-viscosity carrageenan as a capsule material to prepare full carrageenan hollow capsules, rather than just using it as a gelling agent in small quantities. As a new type of hollow capsule, carrageenan hollow capsules increase the existing capsule shell types, meet consumers' demand for green, safe, and natural pharmaceutical excipients, and promote the green and healthy development of the pharmaceutical industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Effects of different concentrations of citric acid and boiling time on the state of carrageenan gel: carrageenan gel without citric acid (A), carrageenan gel with 0.01% citric acid (B), carrageenan gel with 0.02% citric acid (C), carrageenan gel with 0.03% citric acid (D), carrageenan gel with 0.04% citric acid (E), carrageenan gel with 0.05% citric acid (F), carrageenan gel with 0.06% citric acid (G);

[0026] Figure 2 The effect of different concentrations of citric acid on the viscosity of carrageenan glue during high temperature cooking: a is the viscosity curve of 0-0.06% citric acid degrading 10% carrageenan within 3 hours, b is the viscosity curve of 0.04-0.06% citric acid degrading carrageenan to a uniform and stable glue solution;

[0027] Figure 3The effects of different concentrations of citric acid on carrageenan gelatin embryo preparation and capsule shell properties during high temperature cooking process.

[0028] Figure 4 Carrageenan raw materials for hollow capsules: commercially available carrageenan (A), carrageenan for hollow capsules (B), 1% commercially available carrageenan solution at room temperature (C), 1% carrageenan solution for hollow capsules at room temperature

[0029] Figure 5 This is the FT-IR image of carrageenan for hollow capsules;

[0030] Figure 6 This is the thermogravimetric analysis diagram of carrageenan for hollow capsules;

[0031] Figure 7 This is the carrageenan empty capsule and disintegration diagram of Example 3;

[0032] Figure 8 This is the disintegration diagram of the carrageenan empty capsules in Example 4;

[0033] Fig. 9 The surface and cross-section scanning electron microscope images of the carrageenan hollow capsules in Example 4 are shown. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described in detail with reference to the following specific examples.

[0035] In the following examples, unless otherwise specified, the experimental methods used are all conventional methods, and the materials and reagents used can be purchased from biological or chemical reagent companies.

[0036] Example 1: Exploration of preparation conditions for carrageenan for hollow capsules

[0037] Weigh 30g carrageenan and stir and disperse it in a citric acid solution (citric acid concentration is 0-0.06%), stir and cook the glue in a 90℃ water bath, observe the glue state, dip the glue and measure the glue viscosity at 0h, 0.5h, 1.0h, 1.5h, 2.0h, 2.5h and 3.0h. The results are shown in Table 1 and Figure 1-3 .

[0038] Table 1. Effects of different citric acid concentrations and boiling times on the thickness of carrageenan hollow capsules

[0039]

[0040] High-concentration carrageenan dispersed in water or citric acid solution appears as a block solid state, and even a small amount of dry powder is not soaked, indicating that high-concentration carrageenan has limited water absorption and expansion performance in cold water. Figure 1As can be seen from A in Figure 1, high temperature treatment has little effect on the viscosity of carrageenan glue. After 3 hours of boiling, the glue is still viscous and has a large number of bubbles. Figure 1 It can be seen from B and C in Figure 1 that after adding 0.01-0.02% citric acid and boiling the carrageenan at high temperature for 3 hours, there are still a lot of bubbles in the carrageenan solution. Therefore, low concentration citric acid solution has limited effect on reducing the viscosity of the carrageenan solution. Figure 1 It can be seen from D in that after adding 0.03% citric acid and boiling the glue at high temperature for 3 hours, the glue liquid becomes clear and transparent without bubbles, indicating that the viscosity of the glue liquid decreases significantly. The viscosity of the glue liquid is measured to drop from 78900mPa·s after boiling the glue for 1.5 hours to 10920mPa·s after boiling the glue for 3 hours. The viscosity decrease is very significant, which proves that citric acid can be used to prepare low-viscosity carrageenan. Continue to increase the concentration of citric acid. When 0.04% citric acid degrades carrageenan liquid, it is observed that the glue liquid is uniform, transparent and bubble-free after boiling the glue at high temperature for 2 hours. When 0.05% citric acid degrades carrageenan liquid, the glue liquid begins to be uniform, transparent and bubble-free after boiling the glue at high temperature for 1.5 hours. The degradation effect of 0.06% citric acid is better. The glue liquid becomes uniform, transparent and bubble-free after boiling the glue at high temperature for 1 hour. After the glue liquid stabilizes, the viscosity of the glue liquid is measured and the hollow capsules are trial-produced. The specifications of the 2# capsules used in the experiment require the wall thickness to be between 0.080-0.115mm. Therefore, we have obtained the wall thickness requirements from Table 1 and Table 2. Figure 2 , 3 It can be concluded that the effect of embryo preparation by dipping in glue is good when carrageenan solution with 0.04% citric acid is boiled at high temperature for 2-3h, carrageenan solution with 0.05% citric acid is boiled at high temperature for 1.5-2h, and carrageenan solution with 0.06% citric acid is boiled at high temperature for 1h. A relatively complete capsule shell can be pulled out and the capsule shell thickness meets the requirements. The corresponding raw material carrageenan solution viscosity is between 300-2000mPa·s, and the pH value of 0.04-0.06% citric acid solution is between 3.1-3.5.

[0041] Figure 2 This is a line chart of the viscosity of the glue after boiling the glue at high temperature for 3 hours, corresponding to Figure 1 , Figure 1 The viscosity of the glue is reduced. Figure 2 The data shows that the viscosity of their glue is decreasing. Figure 3 The glue was boiled at high temperature for 3 hours and then dipped into the glue to make embryos, which proved that the acid-degraded glue solution can be used to prepare hollow capsules. This result is consistent with Table 1 (shell thickness).

[0042] Example 2: Preparation and quality inspection of carrageenan for hollow capsules

[0043] Weigh 30g carrageenan and stir and disperse it in 300mL 0.05% citric acid solution. Stir and cook the carrageenan in a 90℃ water bath until the carrageenan solution is uniform and stable. Measure the viscosity of the carrageenan solution.

[0044] When the pressure is between 300 and 2000 mPa·s, pour the gel into a glass dish to solidify, then put the gel block into pure water to remove impurities for 2-3 days, pre-freeze at -20 for 24 hours, freeze-dry, crush and obtain carrageenan for hollow capsules, and test its quality, FT-IR and thermogravimetric analysis. The results are shown in Table 2. Figure 4-6 .

[0045] Table 2 Quality test results of commercially available carrageenan and carrageenan for hollow capsules

[0046]

[0047] Table 1 shows the quality test results of commercially available carrageenan and carrageenan prepared for hollow capsules. Except for viscosity and pH, other test indicators meet the requirements and do not change much. The change in viscosity is due to the degradation of carrageenan by citric acid and high temperature, which causes the breaking of its connecting chains, shortening of the molecular chains, and reduction of viscosity, making it useful for the preparation of capsule shells. The reduction in pH may be due to the neutralization or removal of the alkali in the original product itself, thus rendering it neutral. In addition, Figure 4 As shown in C and D, C is a room temperature diagram of 1% commercially available carrageenan dissolved at high temperature. After inversion, the gelatin solution is still at the bottom of the bottle and does not fall, which is a solid gel state, indicating that the 1% commercially available carrageenan solution has gelation, while D is the carrageenan specially prepared for hollow capsules in this embodiment. After the 1% solution is inverted, the gelatin solution falls, indicating that the carrageenan concentration after acid degradation is 1% and has lost its gelation.

[0048] The FT-IR spectrum and thermogravimetric analysis of carrageenan are shown in Figure 2. Figure 5 , 6 , FT-IR results show that citric acid degradation does not change the structure of carrageenan and does not introduce new groups. It is only a process of breaking glycosidic bonds and converting long chains of macromolecules into short chains.

[0049] Example 3: Preparation of carrageenan hollow capsules

[0050] Weigh 30g of the carrageenan prepared in Example 2 for hollow capsules, 9g of glycerol, and add pure water to 300g, boil the glue at 90℃ for 1-1.5h until the glue liquid has no coagulation and is uniform, then place the glue liquid in a water bath at 80℃ for 1h to remove bubbles, use a 0# capsule mold to dip the glue to make embryos, let the capsule embryos stand at room temperature overnight to dry, shell them, cut them, and put them together to make hollow carrageenan capsules. The dip glue results and quality inspection results are as follows: Figure 7 , as shown in Table 3.

[0051] Table 3 Carrageenan empty capsule quality test results

[0052]

[0053] The obtained hollow capsules are smooth and translucent, and the tightness and brittleness meet the requirements. The water content of the carrageenan capsule shell is 19.71±0.25%, which is higher than the 12.5-17.5% specified in the Chinese Pharmacopoeia for gelatin hollow capsules. This is related to the properties of carrageenan polysaccharides. Figure 7 As shown in D in the figure, its disintegration time is 40 min. This is because carrageenan is insoluble in cold water and only swells in cold water. Figure 7 As shown in D, the carrageenan absorbs water and swells within 20 minutes, and then the carrageenan is gradually eroded and dissolved. The solubility of the small molecule carrageenan prepared in the experiment is better than that of the commercially available carrageenan. It is in a solution state at low concentrations and does not gel. However, the high concentration carrageenan used in the preparation of carrageenan hollow capsules is in a gel state when cooled, which is conducive to the preparation of hollow capsules by dipping in the gelatin. However, during its disintegration process, it first absorbs water and swells to a gel state, and then slowly dissolves. This gel state will hinder the dissolution of the capsule shell in water, resulting in delayed disintegration.

[0054] Example 4: Preparation of carrageenan hollow capsules

[0055] Weigh 30g of the carrageenan prepared in Example 2, 9g of glycerol, 1g of Tween 80, add pure water to 300g, boil the glue at 90℃ for 1-1.5h until the glue liquid has no coagulation and is uniform, then place the glue liquid in a water bath at 80℃ for 1h to remove bubbles, use a 0# capsule mold to dip the glue to make embryos, let the capsule embryos stand at room temperature overnight to dry, shell, cut, and fit to make carrageenan hollow capsules. Figure 8 , surface and cross-section scanning electron microscopy Fig. 9 .

[0056] Adding a small amount of Tween to the formula of carrageenan empty capsules accelerates the disintegration rate of the capsules, and the disintegration time is shortened to 25 minutes.

[0057] Example 5: The implementation method of this example is the same as that of Example 1, except that citric acid is replaced with one or more of dilute hydrochloric acid, dilute sulfuric acid, acetic acid, malic acid, lactic acid, etc., the pH of the glue solution is adjusted to 3.1-3.5, the boiling time is controlled, and the viscosity of the glue solution is controlled to 300-2000 mPa·s. The same quality of carrageenan hydrolyzed powder can be obtained, and hollow capsules of the same quality can be prepared according to the method described in any one of Examples 2-4.

[0058] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for a person skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to replace some of the technical features therein by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions claimed to be protected by the present invention.

Claims

1. A method for preparing carrageenan for hollow capsules, characterized in that: The method comprises the steps of: dissolving carrageenan as a raw material in an acid solution with a pH of 3.1-3.5 to prepare a 10% carrageenan solution by mass, hydrolyzing it by acidification and high temperature, stopping the hydrolysis when the viscosity reaches 300-2000 mPa·s, and then neutralizing, dialysis to remove impurities, drying, and crushing to obtain carrageenan for hollow capsules.

2. The method for preparing carrageenan for hollow capsules according to claim 1, characterized in that: The acid solution is one or more of dilute hydrochloric acid, dilute sulfuric acid, acetic acid, citric acid, malic acid, and lactic acid.

3. The method for preparing carrageenan for hollow capsules according to claim 1, characterized in that: The high temperature is above 90°C.

4. The method for preparing carrageenan for hollow capsules according to claim 1, characterized in that: At a temperature above 90° C., 0.04% citric acid carrageenan solution was added and boiled for 2-3 hours, 0.05% citric acid carrageenan solution was added and boiled for 1.5-2 hours, and 0.06% citric acid carrageenan solution was added and boiled for 1 hour.

5. A carrageenan for hollow capsules, characterized in that: The carrageenan for hollow capsules is prepared by the method according to any one of claims 1 to 4, and has a viscosity of 3-10 cps in a 1% aqueous solution.

6. A carrageenan hollow capsule, characterized in that: The carrageenan hollow capsules are composed of carrageenan specially used for hollow capsules prepared by the method, a plasticizer and water.

7. The carrageenan hollow capsule according to claim 6, characterized in that: The plasticizer is one or more of glycerol, maltitol, sorbitol, PEG200, PEG400, propylene alcohol, triacetin, ethyl citrate, castor oil and phthalate derivatives.

8. An easily disintegrating carrageenan hollow capsule, characterized in that: The carrageenan hollow capsules are composed of carrageenan specially used for hollow capsules prepared by the method described in any one of claims 1 to 4, a plasticizer, a disintegration accelerator and water.

9. The easily disintegratable carrageenan hollow capsule according to claim 8, characterized in that: The disintegration-promoting agent is one or more of Tween 80, polyvinyl pyrrolidone, potassium chloride, polysorbate, soybean lecithin, sodium carbonate, mannitol, sorbitol, lactose and silicon dioxide.

10. The method for preparing the carrageenan hollow capsules according to claim 6, characterized in that: The carrageenan hollow capsule is prepared by mixing carrageenan specially used for hollow capsules with plasticizer glycerol through water-solubilizing, heat preservation, dipping in glue, drying, shelling, cutting and sheathing; The raw materials and weight percentages for preparing the carrageenan hollow capsules are as follows: 8-12% of the hollow capsule-specific carrageenan, 1-3% of glycerol, and 85-91% of water.

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