A pullulan hollow capsule with high smoothness and a method for improving the smoothness of pullulan hollow capsules

Abstract

The present invention discloses a highly smooth pullulan hollow capsule and a method for improving the smoothness of pullulan hollow capsules. For the first time, by controlling the conductivity of pullulan polysaccharide within the range of 0.1 ms / cm to 0.8 ms / cm, the surface smoothness of the prepared pullulan capsule shell is improved; and by using pullulan polysaccharide with a small molecular weight of 10,000 to 600,000 daltons, and introducing sodium periodate + cystine + diaminopolyethylene glycol as a linker reagent to connect the pullulan polysaccharide head to tail for cyclization, the entanglement and friction between pullulan polysaccharide molecules are reduced, the frictional force of the capsule shell is fundamentally reduced, and the smoothness of its surface is improved.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a high-smoothness pullulan hollow capsule and a method for improving the smoothness of a pullulan hollow capsule. Background Art

[0002] A pullulan hollow capsule, namely a pullulan polysaccharide hollow capsule, is a hollow capsule made of pullulan polysaccharide as a raw material. Pullulan polysaccharide is a natural polysaccharide produced by the fermentation of Aureobacidium pullulans. It is a non-animal-derived polymer material, without the potential risk of leaving and accumulating hormones or drugs in the body, and has unique advantages such as non-toxic, odorless, biodegradable, and excellent oxygen barrier performance. It has been widely used in the fields of medicine and health products, especially in protecting sensitive ingredients, improving bioavailability, and meeting vegetarian and religious requirements.

[0003] The surface smoothness of a hollow capsule is an important parameter in its quality control, which directly affects the filling efficiency and appearance quality of the capsule on a fully automatic filling machine. Therefore, it has always been the focus of attention and research by manufacturers. The existing production process of pullulan hollow capsules mainly improves their surface smoothness by controlling the raw material formula, production process, and quality inspection standards. In terms of the raw material formula, pullulan polysaccharide is mainly mixed with carrageenan, etc. to improve the surface smoothness of the capsule shell, or a plasticizer and a lubricant are added to the glue solution to reduce the viscosity of the pullulan polysaccharide and carrageenan solution, and increase its flexibility and surface smoothness. In terms of the production process, it is mainly to accurately control the proportions of pullulan polysaccharide, carrageenan, plasticizer, lubricant, and water, the heating and insulation time, etc., to ensure the uniformity and appropriate viscosity of the glue solution, and control the parameters of drying and pressing forming to ensure the forming quality of the capsule shell. The quality inspection standard is mainly to detect the thickness and water content of the capsule shell, because research shows that the thickness and water content of the capsule shell have an obvious impact on the adhesion of the capsules.

[0004] Experiments show that the use of lubricants is crucial for improving the surface smoothness of capsule shells. It can not only reduce the friction of capsule shells on filling machines, but also reduce the generation of static electricity and improve the physical properties of capsule shells. In actual production, common lubricants include glycerin, magnesium stearate, sorbitol, propylene glycol, polyethylene glycol, vegetable oil, etc. The action mechanisms of these lubricants can generally be divided into two categories. One is to reduce the frictional force of capsule shells, making the friction on filling machines smaller, ensuring smoothness during the feeding and filling processes of capsules, reducing blockage and wear, reducing the adhesion of medicinal powder on the surface of capsule shells, keeping the capsule shells clean and smooth, and improving the appearance of the final product. The other is to reduce the cohesive force between pullulan and related component molecules, improve the fluidity of materials, reduce the intermolecular electrostatic interaction, so as to improve the fluidity and uniformity during the processing of rubber materials, thereby improving the smoothness of the capsule shell surface and making the appearance of the capsule smoother and more beautiful.

[0005] However, in order to ensure the gas barrier property and impact resistance of capsules, the molecular weights of pullulan raw materials used in existing pullulan capsules are relatively high. For example, a high molecular weight pullulan additive and its application in capsule preparation disclosed in CN108721632A uses high molecular weight pullulan and mixes it with gellan gum to make capsules. The weight average molecular weight of pullulan is ≥1.8×10^5 (i.e., ≥180,000 daltons), and specifically can be 771200, which is significantly higher than the molecular weight of the standard pullulan. Since pullulan is formed by connecting α-D-glucose rings through 2 α-1,4-glycosidic bonds to form maltotriose, and then connecting with another maltotriose through α-1,6-glycosidic bonds at both ends, and repeating this connection to form a linear macromolecule. Therefore, although using high molecular weight pullulan as a raw material can ensure the mechanical properties of the prepared capsule shell, it also increases the viscosity of the rubber solution, especially affecting the dispersion of pullulan, making it easy for cross-linking and entanglement to exist between its molecules, resulting in certain internal frictional force and electrostatic interaction inside the rubber solution. This limits the effects of externally added lubricants, plasticizers, etc., and cannot fundamentally improve the smoothness of the capsule shell.

[0006] In addition, conductivity, also known as electrical conductivity, is an important indicator for detecting the quality control of capsule shells. It is generally used to evaluate the dissolution rate of capsule shells, the compatibility between capsule shells and contents, as well as the control levels of the hygroscopicity, water content, aldehyde and trivalent metal ion impurities of capsule shells. In existing research, there is no report on the relationship between conductivity and the surface smoothness of capsule shells. Summary of the Invention

[0007] Regarding the problem that the high-molecular-weight pullulan polysaccharide as the raw material increases the viscosity of the glue solution, affects dispersion, makes it easy for cross-linking and entanglement to exist between its molecules, resulting in certain internal frictional force and electrostatic action inside the glue solution, and the externally added lubricants, plasticizers, etc. cannot fundamentally improve the smoothness of the capsule shell, the present invention provides a method for improving the smoothness of pullulan hollow capsules and explores the influence of the conductivity of the raw material on the surface smoothness of the capsule shell. The present invention controls the surface smoothness of the pullulan capsule shell prepared by controlling the conductivity of pullulan polysaccharide for the first time; in addition, by controlling the molecular weight of pullulan polysaccharide within a lower range and introducing a specific linker reagent, the linear pullulan polysaccharide is connected end to end and cyclized, thereby reducing the entanglement and friction between pullulan polysaccharide molecules, fundamentally reducing the frictional force of the capsule shell and improving the smoothness of its surface. The specific technical solutions are as follows:

[0008] First of all, the present invention provides a high-smoothness pullulan hollow capsule, and the conductivity of the pullulan polysaccharide used in the hollow capsule is controlled within the range of 0.1 ms / cm to 0.8 ms / cm.

[0009] The aforementioned high-smoothness pullulan hollow capsule is prepared from the following components by mass fraction: 75-90 wt% of pullulan polysaccharide, 0.5-5 wt% of gelling agent, 0.01-0.15 wt% of moisturizing agent, 0.1-1 wt% of lubricant, and the balance is pure water.

[0010] Preferably, for the aforementioned high-smoothness pullulan hollow capsule, the molecular weight of the pullulan polysaccharide is controlled within 10,000 to 600,000 daltons, and the proportion of pullulan polysaccharide below 100,000 daltons and above 500,000 daltons does not exceed 20%, and the average molecular weight is 250,000 to 350,000 daltons.

[0011] Further preferably, for the aforementioned high-smoothness pullulan hollow capsule, the pullulan polysaccharide is a pullulan polysaccharide with a cyclized structure formed by treatment with a cyclization linker composition; the cyclization linker composition is composed of sodium periodate, cystine and diaminopolyethylene glycol, wherein: the dosage of sodium periodate is 0.01%-0.1% of the weight of pullulan polysaccharide; the dosage of cystine is 1%-5% of the weight of pullulan polysaccharide; the dosage of diaminopolyethylene glycol is 5%-10% of the weight of pullulan polysaccharide.

[0012] Further preferably, for the aforementioned high-smoothness pullulan hollow capsule, among the components of the cyclization linker composition, the dosage of sodium periodate is 0.01%-0.05% of the weight of pullulan polysaccharide; the dosage of cystine is 1%-2% of the weight of pullulan polysaccharide; the dosage of diaminopolyethylene glycol is 5%-6% of the weight of pullulan polysaccharide; the molecular weight of the diaminopolyethylene glycol is preferably 5k-10k daltons.

[0013] The aforementioned pullulan hollow capsule with high smoothness, wherein the gelling agent is one or a mixture of several of curdlan, gellan gum, carrageenan, locust bean gum, pectin, xanthan gum, konjac gum; the moisturizing agent is one or a mixture of several of glycerol, sorbitol, glycerin, mannitol, triethyl citrate, sodium docusate; the lubricant is one or a mixture of several of sodium stearyl fumarate, sucrose esters, corn starch, colloidal silicon dioxide, magnesium stearate, poloxamer, copovidone, glyceryl palmitostearate.

[0014] Secondly, the present invention provides a method for improving the smoothness of pullulan hollow capsules, comprising the following technological steps:

[0015] 1) Preparation of pullulan polysaccharide:

[0016] Prepare or directly weigh pullulan polysaccharide with a molecular weight range of 10,000 to 600,000 daltons, wherein the proportion of pullulan polysaccharide with a molecular weight below 100,000 daltons and above 500,000 daltons does not exceed 20%, and the average molecular weight is 250,000 to 350,000 daltons; use sodium periodate, cystine and diaminopolyethylene glycol as a linker composition to treat pullulan polysaccharide to form a cyclic structure; and detect its conductivity, controlling it within the range of 0.1 ms / cm to 0.8 ms / cm;

[0017] 2) Material ratio:

[0018] Weigh 75 - 90 wt% of the cyclic structure of pullulan polysaccharide, 0.5 - 5 wt% of the gelling agent, 0.01 - 0.15 wt% of the moisturizing agent, 0.1 - 1 wt% of the lubricant by mass fraction, and the balance is cold pure water, totaling 100 parts;

[0019] 3) Preparation of the glue solution:

[0020] Add the gelling agent to cold pure water and stir, then raise the temperature to above 90 °C and incubate for 30 - 90 min until completely dissolved, then add the moisturizing agent and the lubricant and continue to stir until completely dissolved, and finally add pullulan polysaccharide and incubate and stir until completely dissolved to form a glue solution, and keep it warm and stable at 50 - 60 °C for standby;

[0021] 4) Dipping and forming:

[0022] Dip the stable glue solution into a mold for forming, and quickly dry it in an oven at 40 - 45 °C for 20 - 60 min to obtain the capsule cap and body blank, and use a demolding device for demolding, cutting and fitting to obtain the high - smoothness pullulan hollow capsule.

[0023] As a preferred technical solution, in step 1), the process of using sodium periodate, cystine and diaminopolyethylene glycol as a linker composition to treat pullulan polysaccharide to form a cyclic structure is as follows:

[0024] 1-1) Dissolve pullulan in distilled water, add sodium periodate at 0.01% - 0.1% of the weight of pullulan, control the reaction temperature at 0 - 8°C, pH value at 5.0 - 5.5, and carry out the reaction for 6 - 20 hours under light-shielded conditions. After the reaction, remove the unreacted sodium periodate to obtain an oxidized pullulan solution;

[0025] 1-2) Add cystine at 1% - 5% of the weight of pullulan to the oxidized pullulan solution, keep the pH environment unchanged, and carry out a condensation reaction for 4 - 8 hours at room temperature to form a condensed pullulan solution;

[0026] 1-3) Then add diaminopolyethylene glycol at 5% - 10% of the weight of pullulan to the condensed pullulan solution and react for 2 - 6 hours to obtain a pullulan polysaccharide molecule with weak head-to-tail connections and cyclization;

[0027] 1-4) Purify the cyclized pullulan and detect that the purity of the product reaches 99% or more for standby.

[0028] As a preferred technical solution, in step 3), the specific process of preparing the glue solution is as follows:

[0029] 3-1) Add the gelling agent to cold pure water, stir until dissolved, with a stirring speed of 60 - 120 r / min, and then heat the solution to above 90°C and incubate for 1 h;

[0030] 3-2) Add the moisturizing agent and lubricant, stir until completely dissolved, with a stirring speed of 60 - 120 r / min;

[0031] 3-3) Add the cyclized pullulan, stir evenly, and incubate for 4 - 5 hours, stirring once per hour, with a stirring speed of 60 - 120 r / min;

[0032] 3-4) After the pullulan is completely dissolved, keep it warm and stable at 50 - 60°C for 2 - 3 h for dip-coating and forming.

[0033] As a further preferred technical solution, in step 3-1), the temperature for dissolving and incubating the gelling agent is 90 - 98°C. It is found through experiments that when the temperature of the gelling agent is increased to this temperature, the dissolution of the gelling agent is better.

[0034] Advantages of the present invention:

[0035] 1) The present invention first proposes the concept of improving the surface smoothness of the prepared pullulan capsule shell by controlling the conductivity of pullulan. By controlling the conductivity of pullulan at 0.1 ms / cm - 0.8 ms / cm, it ensures relatively complete dissolution and uniform film-forming texture, thereby improving the surface smoothness of the prepared film.

[0036] 2) By controlling the molecular weight of pullulan polysaccharide within 10,000 - 600,000 Daltons in the present invention, and the proportion of pullulan polysaccharide with a molecular weight below 100,000 Daltons and above 500,000 Daltons not exceeding 20% (about 300,000 Daltons on average), the entanglement and friction between small - molecular - weight pullulan polysaccharide molecules are small, which is conducive to dispersion. Moreover, the interaction between small - molecular - weight pullulan polysaccharide and auxiliary components is small, facilitating uniform mixing, and thus improving the smoothness of the surface of the prepared capsule shell.

[0037] 3) By introducing a specific linker reagent in the present invention, the linear pullulan polysaccharide is connected end - to - end to form a cyclic structure, making it easier for molecules to slide, thereby avoiding cross - linking and entanglement between pullulan polysaccharide molecules, further reducing the entanglement and friction between pullulan polysaccharide molecules, and fundamentally reducing the entanglement friction between capsule shell materials, and further improving the smoothness of its surface.

[0038] 4) In the present invention, sodium periodate + cystine + diaminopolyethylene glycol is used as the pullulan polysaccharide linker composition to achieve weak end - to - end cyclization of pullulan polysaccharide molecules. Among them, sodium periodate is used to oxidize pullulan polysaccharide to form oxidized pullulan polysaccharide containing two carbonyl groups; cystine contains free sulfhydryl groups (-SH), which can undergo a condensation reaction with the carbonyl groups of oxidized pullulan polysaccharide to form thione bonds, and diaminopolyethylene glycol can further react with cystine to form a stable cyclic structure, realizing the end - to - end connection of pullulan polysaccharide molecules. The reaction principle is clear, the technical route is simple, the reaction process is controllable, and it has good practical value.

[0039] 5) The present invention precisely controls the dosage of sodium periodate and reaction conditions. The addition amount is 0.01% - 0.1% of the weight of pullulan polysaccharide, and the reaction temperature is controlled at 0 - 8 °C, the pH value is 5.0 - 5.5, and the reaction is carried out for 6 - 20 hours under light - shielding conditions, so that it only oxidizes the carbon - carbon bond between adjacent hydroxyl groups at the end of the pullulan polysaccharide chain. The introduction of cystine and diaminopolyethylene glycol is aimed at specific positions of oxidized pullulan polysaccharide. This specific modification does not interfere with other regions of pullulan polysaccharide, realizes end - to - end connection, which ensures the integrity of the pullulan polysaccharide structure and guarantees the gas - barrier advantage of the capsule. Secondly, the cyclic pullulan polysaccharide has better three - dimensional elasticity than the linear pullulan polysaccharide, which can improve the internal impact resistance of the capsule shell.

[0040] 6) For the linker reagent composition introduced in the present invention, sodium periodate only oxidizes the ends of pullulan, and the unreacted sodium periodate will be removed without affecting its structure and safety. Cystine itself widely exists in the organism, and its introduction in the cyclization reaction of pullulan only targets both ends of pullulan after oxidation, and will not have a negative impact on the safety of the capsule; diaminopolyethylene glycol is a commonly used biocompatible polymer with good water solubility and biocompatibility, and is often used in drug delivery systems, so it will not affect the safety of pullulan either, ensuring the application of the prepared hollow capsules in the fields of medicine and health products. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 It is a schematic diagram of the molecular structure of pullulan. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0042] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments.

[0043] Example 1

[0044] This example is a method for preparing cyclic pullulan. As Figure 1 shown, pullulan is formed by connecting two α-D-glucose rings through α-1,4-glycosidic bonds to form maltotriose, and the two ends are further combined with another maltotriose through α-1,6-glycosidic bonds, and so on to form a linear macromolecule with a molecular weight that can be as high as several million daltons. In the prior art, in order to ensure the impact resistance of the capsule shell, high-molecular pullulan is mostly used. However, cross-linking and entanglement are likely to exist between high-molecular pullulan molecules, and there are certain internal frictional forces and electrostatic effects inside the glue solution. The viscosity of the glue solution is large and the dispersibility is poor, which affects the surface microstructure of the film formation. The externally added lubricants and plasticizers cannot fundamentally solve this problem. Therefore, it is difficult to further improve the surface smoothness of the capsule shell. To solve this problem, this example provides a measure to prepare a cyclic pullulan with weak head-to-tail connections through a linker composition, thereby reducing the entanglement and friction between pullulan molecules, fundamentally reducing the frictional force of the capsule shell, improving its surface microstructure, and thus improving the smoothness of the capsule shell surface.

[0045] In this embodiment, sodium periodate + cystine + diaminopolyethylene glycol is used as the pullulan linker composition. Among them, sodium periodate can be used to oxidize pullulan. Sodium periodate is a strong oxidant that specifically oxidizes the carbon-carbon bond between adjacent hydroxyl groups. By precisely controlling the use concentration and reaction conditions of sodium periodate, only the carbon-carbon bond between adjacent hydroxyl groups at the end of the pullulan chain can be oxidized to form oxidized pullulan containing two carbonyl groups; cystine contains free sulfhydryl groups (-SH), which can undergo a condensation reaction with the carbonyl group of oxidized pullulan to form a thione bond. Diaminopolyethylene glycol can further react with cystine to form a stable cyclic structure. The reaction process is as follows:

[0046] Both ends of the pullulan chain + sodium periodate → oxidized pullulan (containing carbonyl groups at both ends),

[0047] Oxidized pullulan + cystine (-SH) → intermediate product with thione bonds connecting the carbonyl groups at both ends of oxidized pullulan,

[0048] Intermediate product + diaminopolyethylene glycol (PEG(NH2)2) → pullulan with a cyclized head-to-tail connection.

[0049] In this embodiment, in order to ensure the joint strength and the impact resistance of the pullulan capsule, the molecular weight of the diaminopolyethylene glycol is preferably 5k to 10k daltons. To ensure that sodium periodate only oxidizes both ends of the pullulan, its addition amount is controlled to be 0.01% to 0.1% of the weight of the pullulan, preferably 0.01% to 0.05%, and the reaction temperature is controlled at 0 to 8°C, the pH value is 5.0 to 5.5, and the reaction is carried out for 6 to 20 hours under light-shielded conditions. After the reaction, unreacted sodium periodate and glycerol are removed by ultrafiltration to ensure the safety of the product.

[0050] In this embodiment, the cyclized pullulan molecules are more likely to slide between each other, thus avoiding cross-linking and entanglement between pullulan molecules, further reducing the entanglement and friction between pullulan molecules, fundamentally reducing the entanglement friction between capsule shell materials, and further improving the smoothness of its surface. It not only realizes the weak connection cyclization of the head and tail of pullulan molecules, but also improves the smoothness of pullulan capsules. At the same time, the linker composition used in this embodiment does not affect the properties of pullulan. Sodium periodate is a strong oxidant. Under reasonable control of the dosage and reaction conditions, the oxidation of pullulan is controllable and will not affect the safety of pullulan, ensuring that the capsule shell has the required gas barrier property. Moreover, the cyclized pullulan has better three-dimensional elasticity than the linear pullulan, which can improve the internal impact resistance of the capsule shell. Cystine is a sulfur-containing amino acid, and its mercapto group (-SH) has reducibility and can form a thione bond with the oxidized pullulan. Moreover, cystine itself is widely present in organisms and is generally considered safe, so it will not have a negative impact on the safety of the capsule. Diamino polyethylene glycol is a commonly used biocompatible polymer. Due to its good water solubility and biocompatibility, it is often used in drug delivery systems. Therefore, the use of diamino polyethylene glycol in the cyclization of pullulan polysaccharide capsules is also safe.

[0051] In this embodiment, the dosage of sodium periodate is 0.01% of the weight of pullulan, the dosage of cystine is 1% of the weight of pullulan, and the dosage of diamino polyethylene glycol is 5% of the weight of pullulan. The following is a detailed example of the specific process of cyclic pullulan polysaccharide as follows:

[0052] First, prepare small molecule pullulan. Through experiments, it is found that the entanglement and friction between pullulan molecules with small molecular weights are small, which is conducive to dispersion. Moreover, the interaction between pullulan with small molecular weights and auxiliary components is small, facilitating uniform mixing, and thus can improve the smoothness of the surface of the prepared capsule shell to a certain extent. In this example, pullulan purchased from the market (Hebei Runying Biotechnology Co., Ltd., Yujian Kangyuan, 091), with a molecular weight of 20,000 to 2,000,000 Daltons, is treated with pullulanase to obtain small molecular weight pullulan. The specific process of enzymatic hydrolysis can refer to the prior art or adopt the following preparation method: Prepare 1000 g of pullulan into a 6% (w / v) concentration, adjust the pH to 5.2, and heat at 58 °C for 30 minutes for pre-gelatinization; add 2 g of pullulanase (200 ASPU / g) for treatment. During the treatment, record the molecular weight distribution of pullulan after enzyme treatment. It is appropriate that the proportion of pullulan with a molecular weight between 10,000 and 600,000 Daltons, less than 100,000 Daltons and more than 500,000 Daltons does not exceed 20%, and the average molecular weight is about 300,000 Daltons to ensure that the prepared pullulan hollow capsule has appropriate hardness and impact resistance. After enzymatic hydrolysis, centrifuge at 3000 r / min for 3 minutes and collect the centrifuged precipitate, wash it 3 times with an ethanol aqueous solution, and finally dry it by freeze-drying. In other examples, pullulan with a molecular weight of 25 - 35 Daltons (for example, with a molecular weight of 300,000 Daltons) can also be directly used as the raw material.

[0053] Then, dissolve 1000 g of pullulan with a suitable molecular weight in distilled water, control the reaction temperature at 4 °C, pH value at 5.5, add 0.1 g of sodium periodate, and carry out the reaction for 16 hours under light-shielded conditions to oxidize the carbon-carbon bond between adjacent hydroxyl groups at the end of the pullulan chain to form oxidized pullulan containing two carbonyl groups; after the reaction, remove the unreacted sodium periodate by ultrafiltration (filter membrane 0.22 μm - 0.45 μm); then add 10 g of cystine to the obtained oxidized pullulan solution, keep the pH environment unchanged (pH = 5.5), and carry out the condensation reaction for 6 hours at room temperature (22 °C) to form a thione bond; finally, add 50 g of diaminopolyethylene glycol to the condensed pullulan solution and carry out the linking reaction for 4 hours to obtain a pullulan molecule with a weakly linked head-to-tail cyclization.

[0054] Finally, purify the cyclized pullulan in the cyclized pullulan solution by dialysis ultrafiltration to remove the unreacted reagents, and then evaluate the purity of the cyclized product by high performance liquid chromatography. It is qualified when its purity reaches 99% or above and reserve it for use.

[0055] Example 2 This example is for the preparation of pullulan hollow capsules. As proposed in Example 1, using high molecular weight pullulan as the raw material can ensure the impact resistance of the capsule shell. However, cross-linking and entanglement are likely to occur between high molecular weight pullulan molecules, and there are strong frictional and electrostatic forces inside the glue solution, resulting in high viscosity and poor dispersibility of the glue solution, which affects the surface microstructure of film formation. To solve this problem, the present invention uses low molecular weight pullulan as the raw material to prepare pullulan hollow capsules. The pullulan used in this example is the low molecular weight pullulan treated with enzymes as described in Example 1 or the low molecular weight pullulan directly purchased with an average molecular weight of about 300,000 Daltons. The specific preparation process is as follows:

[0056] Add 30 g of gelling agent (gellan gum) to 134.6 g of cold pure water and stir until dissolved at a stirring speed of 100 r / min; then heat the solution to 95 °C and incubate for 1 h, add 0.4 g of humectant (glycerol), 35 g of lubricant (sucrose ester) and stir until completely dissolved. Then add 800 g of pullulan (pullulan with a molecular weight range of 10,000 to 600,000 Daltons, where the proportion of pullulan with a molecular weight below 100,000 Daltons and above 500,000 Daltons does not exceed 20%, and the average molecular weight is 250,000 to 350,000 Daltons). After stirring (100 r / min) evenly, incubate for 4 hours and stir once every hour. After the pullulan is completely dissolved, keep it at a stable temperature of 55 °C for 2 h. Finally, dip the glue solution through a mold to form a film, dry it at 42 °C for 30 min to obtain the capsule cap body blank, and use a demolding device for demolding, cutting, and fitting to obtain pullulan hollow capsule 1 (abbreviated as hollow capsule 1).

[0057] Example 3

[0058] This example is also for the preparation of pullulan hollow capsules. Through experiments, it is found that the conductivity of pullulan affects the surface roughness of the capsule. When the conductivity of the 20% pullulan solution is within 0.1 ms / cm to 0.8 ms / cm, the surface smoothness of the capsule can be further improved.

[0059] In this example, except for controlling the conductivity of pullulan, the component dosage and preparation method are the same as those in Example 2, and pullulan hollow capsule 2 (abbreviated as hollow capsule 2) is obtained.

[0060] In this example, an ultrafiltration device is used to separate impurities in the pullulan solution. After detection, the conductivity of the obtained pullulan solution is 0.4 ms / cm. Example 4

[0061] This example is also for the preparation of pullulan hollow capsules.

[0062] In this example, the pullulan polysaccharide used was the cyclized pullulan polysaccharide prepared in Example 1. The component dosages and preparation method were the same as those in Example 2, and pullulan empty capsules 3 (referred to as empty capsules 3 for short) were obtained.

[0063] Example 5

[0064] This example also involves the preparation of a pullulan polysaccharide empty capsule.

[0065] In this example, the pullulan polysaccharide used was the cyclized pullulan polysaccharide prepared in Example 1, and its conductivity was controlled. The component dosages and preparation method were the same as those in Example 2, and pullulan empty capsules 4 (referred to as empty capsules 4 for short) were obtained.

[0066] In this example, the conductivity of the pullulan polysaccharide used was also 0.4 ms / cm, and the control method of its conductivity was the same as that in Example 3.

[0067] Example 6

[0068] This example examines the surface smoothness of the empty capsules 1 - 4 prepared in Examples 2 - 5. To verify the effects of the molecular weight, conductivity, and molecular configuration of pullulan polysaccharide on the surface smoothness of the prepared capsule shells, the following comparative examples were also set up in this example:

[0069] Comparative Example 1: Except that the molecular weight of the pullulan polysaccharide was 771,200 daltons, the component dosages and preparation method were the same as those in Example 2, and comparative pullulan empty capsules 1 (referred to as comparative capsules 1 for short) were obtained.

[0070] Comparative Example 2: Pullulan polysaccharide with a molecular weight of 7,712,000,000 daltons was used as the raw material, and its conductivity was controlled to 0.4 ms / cm. The component dosages and preparation method were the same as those in Example 2, and pullulan empty capsules 2 (referred to as comparative capsules 2 for short) were obtained.

[0071] Comparative Example 3: Pullulan polysaccharide with a molecular weight of 7,712,000,000 daltons was used as the raw material, and it was treated using the cyclization method in Example 1. The specific treatment method was also the same as that in Example 1. The dosages of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, and pullulan empty capsules 3 (referred to as comparative capsules 3 for short) were obtained.

[0072] Comparative Example 4: Pullulan polysaccharide with a molecular weight of 7,712,000,000 daltons was used as the raw material, and it was treated using the cyclization method in Example 1. The specific treatment method was also the same as that in Example 1, and its conductivity was controlled to 0.4 ms / cm. The dosages of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, and pullulan empty capsules 4 (referred to as comparative capsules 4 for short) were obtained.

[0073] Comparative Example 5: Pullulan with a molecular weight of 100,000 Daltons was used as the raw material, and the component dosage and preparation method were the same as those in Example 2, obtaining Comparative Pullulan Empty Capsule 5 (abbreviated as Comparative Capsule 5).

[0074] Comparative Example 6: Pullulan with a molecular weight of 100,000 Daltons was used as the raw material and was treated by the cyclization method in Example 1. The specific treatment method was also the same as that in Example 1. The dosage of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, obtaining Pullulan Empty Capsule 6 (abbreviated as Comparative Capsule 6).

[0075] Comparative Example 7: The components and dosage were the same as those in Example 3, except that the conductivity of pullulan was controlled at 0.05 ms / cm. The dosage of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, obtaining Pullulan Empty Capsule 7 (abbreviated as Comparative Capsule 7).

[0076] Comparative Example 8: The components and dosage were the same as those in Example 3, except that the conductivity of pullulan was controlled at 1.2 ms / cm. The dosage of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, obtaining Pullulan Empty Capsule 8 (abbreviated as Comparative Capsule 8).

[0077] Comparative Example 9: The components and dosage were the same as those in Example 5, except that the conductivity of pullulan was controlled at 0.05 ms / cm. The dosage of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, obtaining Pullulan Empty Capsule 9 (abbreviated as Comparative Capsule 9).

[0078] Comparative Example 10: The components and dosage were the same as those in Example 5, except that the conductivity of pullulan was controlled at 1.2 ms / cm. The dosage of the remaining components for preparing the capsule shell and the preparation method were the same as those in Example 2, obtaining Pullulan Empty Capsule 10 (abbreviated as Comparative Capsule 10). In this example, the surface friction, surface smoothness, and mechanical properties of the prepared capsule shell were used as the investigation indexes. Among them:

[0079] The detection method of the surface body friction of the capsule shell was carried out according to the method disclosed in the patent CN108548478B applied by our company before. The smoothness was expressed by the friction coefficient; the smaller the friction coefficient, the better the smoothness.

[0080] The mechanical properties of the capsule shell were directly expressed by the friability. The detection method was tested with reference to the pharmacopoeia method. The friability standard: <10%.

[0081] The performance detection results of each capsule shell are shown in Table 1.

[0082] Table 1. Performance detection results of each capsule shell

[0083]

[0084] The results in Table 1 show that the best smoothness is achieved when the molecular weight of pullulan is controlled within 100,000 - 600,000 Daltons. Among them, the smoothness of the hollow capsule 4 (controlled molecular weight + controlled conductivity + cyclization) is the best and the capsule has no risk of brittleness.

[0085] Example 7

[0086] This example examines the effects of the dosage of the joint composition and reaction conditions on the properties of the prepared cyclized pullulan. Based on the hollow capsule 4 prepared in Example 5, in the capsule shells of each sample under investigation, except for the different cyclized pullulans used, the other components and the capsule preparation methods are the same as those in Example 5. The cyclized pullulans of each hollow capsule are shown in Table 2.

[0087] Table 2. Cyclized pullulan used for each capsule shell

[0088]

[0089] Prepare pullulan polysaccharide capsule samples 1 - 12 (Product 1 is the hollow capsule 4 prepared in Example 5) from the above cyclized pullulans 1 - 12 according to the method in Example 2, and then detect and evaluate the smoothness and mechanical properties of each sample according to the method in Example 6. In this example, the surface friction, surface smoothness of the capsule shell, and the brittleness of the capsule shell are also used as the investigation indicators. The test results are shown in Table 3.

[0090] Table 3. Performance test results of each hollow capsule sample

[0091]

[0092] The results in Table 3 show that when the dosage of sodium periodate is 0.05 - 0.1%, both the smoothness and brittleness are better; at the same time, when the pH is controlled at 5.0 - 5.5, the reaction temperature is 0 - 8 °C, and the reaction time is 16 h, both the smoothness and brittleness are better.

[0093] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above - mentioned exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non - restrictive. In addition, it should be understood that although this specification is described according to the embodiments, it does not only contain one technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in the embodiments can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A pullulan hollow capsule with high smoothness, characterized in that: The conductivity of the pullulan polysaccharide used in the hollow capsule is controlled within the range of 0.1 ms / cm to 0.8 ms / cm; and the pullulan polysaccharide is a pullulan polysaccharide with a cyclized structure formed by treatment with a cyclization linker composition; the cyclization linker composition consists of sodium periodate, cystine and diaminopolyethylene glycol, wherein: the dosage of sodium periodate is 0.01% to 0.1% of the weight of the pullulan polysaccharide; the dosage of cystine is 1% to 5% of the weight of the pullulan polysaccharide; the dosage of diaminopolyethylene glycol is 5% to 10% of the weight of the pullulan polysaccharide.

2. The highly smooth pullulan hollow capsule according to claim 1, wherein: The hollow capsule is prepared from the following components by mass fraction: pullulan polysaccharide 75 to 90 wt%, gelling agent 0.5 to 5 wt%, humectant 0.01 to 0.15 wt%, lubricant 0.1 to 1 wt%, the balance being pure water.

3. The high-smoothness pullulan hollow capsule according to claim 2, wherein: The molecular weight of the pullulan polysaccharide is controlled within 10,000 to 600,000 daltons, and the proportion of pullulan polysaccharide below 100,000 daltons and above 500,000 daltons does not exceed 20%, and the average molecular weight is 250,000 to 350,000 daltons.

4. The highly smooth pullulan hollow capsule according to claim 1, wherein: In the cyclization linker composition, the dosage of sodium periodate is 0.01% to 0.05% of the weight of the pullulan polysaccharide; the molecular weight of the diaminopolyethylene glycol is 5k to 10k daltons.

5. The highly smooth pullulan hollow capsule according to claim 2, wherein: the gelling agent is gellan gum, including one or a mixture of several of gellan gum, carrageenan, locust bean gum, pectin, xanthan gum, konjac gum; the humectant is one or a mixture of several of glycerol, sorbitol, mannitol, triethyl citrate, sodium dioctyl sulfosuccinate; the lubricant is one or a mixture of several of sodium stearyl fumarate, sucrose ester, corn starch, colloidal silicon dioxide, magnesium stearate, poloxamer, copovidone, glyceryl palmitostearate.

6. A method for improving the smoothness of pullulan hollow capsules, characterized in that: It includes the following process steps: 1) Preparation of pullulan polysaccharide: Prepare or directly weigh pullulan polysaccharide with a molecular weight range of 10,000 to 600,000 daltons, wherein the proportion of pullulan polysaccharide below 100,000 daltons and above 500,000 daltons does not exceed 20%, and the average molecular weight is 250,000 to 350,000 daltons; use sodium periodate, cystine and diaminopolyethylene glycol as a linker composition to treat pullulan polysaccharide to form a cyclized structure; and detect its conductivity, and control it within the range of 0.1 ms / cm to 0.8 ms / cm; 2) Material ratio: Weigh 75 to 90 wt% of the cyclized pullulan polysaccharide, 0.5 to 5 wt% of the gelling agent, 0.01 to 0.15 wt% of the humectant, 0.1 to 1 wt% of the lubricant, and the balance being cold pure water, totaling 100 parts by mass fraction; 3) Preparation of the glue solution: Add the gelling agent to cold pure water and stir, and raise the temperature to above 90 °C and incubate for 30 to 90 min until completely dissolved, then add the humectant and the lubricant and continue to stir until completely dissolved, and finally add the cyclized pullulan polysaccharide and incubate and stir until completely dissolved to form a glue solution, and keep it warm and stable at 50 to 60 °C for standby; 4) Dipping and forming: Dip the well-stabilized glue solution into a mold for forming, and quickly dry it in an oven at 40-45 °C for 20-60 min to obtain a capsule cap body glue blank. Then, use a demolder for demolding, cutting, and nesting to obtain a pullulan hollow capsule with high smoothness.

7. The method for improving the smoothness of pullulan hollow capsules according to claim 6, characterized in that: In step 1), the process of forming a cyclic structure by treating pullulan with sodium periodate, cystine, and diaminopolyethylene glycol as the linker composition is as follows: 1-1) Dissolve pullulan in distilled water, add sodium periodate at 0.01%-0.1% of the weight of pullulan, control the reaction temperature at 0-8 °C, the pH value at 5.0-5.5, and carry out the reaction for 6-20 hours under light-shielded conditions. After the reaction, remove the unreacted sodium periodate to obtain an oxidized pullulan solution; 1-2) Add cystine at 1%-5% of the weight of pullulan to the oxidized pullulan solution, keep the pH environment unchanged, and carry out a condensation reaction at room temperature for 4-8 hours to form a condensed pullulan solution; 1-3) Then add diaminopolyethylene glycol at 5%-10% of the weight of pullulan to the condensed pullulan solution and react for 2-6 hours to obtain a pullulan polysaccharide molecule with weak head-to-tail connections; 1-4) Purify the cyclic pullulan polysaccharide and detect that the purity of the product reaches 99% or above for standby.

8. The method for improving the smoothness of pullulan hollow capsules according to claim 6, wherein: In step 3), the specific process of preparing the glue solution is as follows: 3-1) Add the gelling agent to cold pure water and stir until dissolved at a stirring speed of 60-120 r / min. Then, heat the solution to above 90 °C and incubate for 1 h; 3-2) Add the humectant and lubricant and stir until completely dissolved at a stirring speed of 60-120 r / min; 3-3) Add the cyclized pullulan polysaccharide, stir evenly, and incubate for 4-5 hours, stirring once per hour at a stirring speed of 60-120 r / min; 3-4) After the pullulan polysaccharide is completely dissolved, keep it warm and stable at 50-60 °C for 2-3 h for dip forming.

9. The method for improving the smoothness of pullulan hollow capsules according to claim 8, wherein: In step 3-1), the temperature for dissolving and incubating the gelling agent is 90-98 °C.

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