Use of natural polymer modified by phenylboronic acid compound in preparing plant hollow capsule

Abstract

The application provides a use of a natural polymer modified by a phenyl boronic acid compound in preparation of a plant hollow capsule, and the natural polymer modified by the phenyl boronic acid compound is used as a gelling agent in preparation of the plant hollow capsule, and forms a dynamic borate ester bond with ortho dihydroxyl groups on a pullulan under weak alkaline conditions, so that a solution-gel transition occurs, the viscosity of a glue solution can be changed, film dipping is facilitated, the dynamic borate ester bond has a pH-sensitive reversible sol-gel transition performance, and the obtained plant hollow capsule has excellent sol-gel transition performance in a stomach acidic environment after being orally taken into the stomach, and is not affected by potassium ions. The application solves the problem that the plant hollow capsule using kappa-carrageenan as a gelling agent is inhibited by potassium ions or the plant hollow capsule using gellan gum as a gelling agent is inhibited by acidic conditions, so that the capsule is slowly disintegrated or cannot be effectively disintegrated, and drug dissolution is not facilitated.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of plant capsule, in particular to the use of a natural high molecule modified by a phenyl boronic acid compound in the preparation of a plant hollow capsule. BACKGROUND

[0002] Capsules are one of the important drug dosage forms, among which the medicinal hollow capsules have the advantages of covering the bad smell of drugs, high bioavailability, good targeting and stable performance, and have been widely used in the fields of food, medicine and health care products. Hollow capsules can be divided into gelatin capsules and plant capsules. With the development of the pharmaceutical industry, the defects of gelatin capsules and the safety problems of drugs have gradually emerged, such as easy softening at high temperature, easy brittleness at low temperature, which is not conducive to storage, easy to cross-link with drugs containing aldehyde groups, safety hidden dangers from animals, and not enough wide application. In order to improve the shortcomings of gelatin capsules, it has very important scientific significance and commercial value to research and develop non-gelatin capsules with stable performance, quality safety and low cost.

[0003] The foreign research technology of non-gelatin hollow capsules is more mature and professional. In the late 20th century, there were new non-gelatin hollow capsule materials and products. The United States Pharmacopoeia, European Pharmacopoeia and Japanese Pharmaceutical Bureau have clearly stipulated that non-gelatin materials are allowed to be used, which promotes the research and development of non-gelatin hollow capsules. The research and development of non-gelatin hard capsules in China started late, and most of them are still in the research and development stage. In addition, the level of production equipment is low, and there are fewer cases that can be successfully applied to industrial production.

[0004] Plant hollow capsules are made of natural high molecular polysaccharide as the main raw material, which meets the requirements of vegetarians and religiousists, and also eliminates the safety hazards of traditional gelatin hollow capsules. Moreover, plant hollow capsules are obviously superior to gelatin hollow capsules in terms of storage stability, chemical stability and other indicators. With the improvement of global residents' requirements for health, the pursuit of natural and healthy in medicines, health products and functional foods also promotes plant capsules to become a market trend, and the market demand is rising globally. With the continuous optimization of plant capsule production technology, the proportion of plant capsules in the capsule market will continue to increase.

[0005] There are many types of plant capsules on the current international and domestic market, including carboxypropyl methyl cellulose, pullulan, starch, algal polysaccharide, konjac gum and other types. Among them, the oxygen barrier rate, stability and safety of pullulan hollow capsules are significantly better than those of traditional animal gelatin capsules and plant hydroxypropyl methyl cellulose capsules, and it has been approved by the State Food and Drug Administration as a new type of capsule material, which is a potential substitute for gelatin capsules.

[0006] Gelling agent needs to be used in the preparation process of plant hollow capsules, and the addition of the gelling agent plays a crucial role in the preparation and performance of the plant hollow capsules. The gelling agent can make the glue solution form nodes between molecules under the bridging action of hydrogen bonds and then form a uniform semi-rigid solid gel with a space network structure, can change the rheological properties of the glue solution, is a key component for film formation of glue dipping, and directly affects the glue dipping process in the preparation process of capsules.

[0007] Currently commonly used gelling agents include carrageenan, gellan gum, guar gum, xanthan gum, acacia gum, locust bean gum, etc., among which carrageenan and gellan gum have become the main gelling agents for plant hollow capsules due to their excellent gel properties. However, it is found in actual production and application that the gel of kappa-carrageenan has poor transparency, and after freezing, it is prone to shrinkage and causes the rupture of capsules. Moreover, the disintegration and drug dissolution of plant hollow capsules using kappa-carrageenan or gellan gum as the gelling agent are greatly affected by pH, and the drug dissolution is inhibited in the presence of potassium ions or acid, which to some extent limits the wide application of plant capsules.

[0008] Therefore, developing a new type of gelling agent suitable for plant hollow capsules as a substitute for traditional gelling agents such as carrageenan and gellan gum is conducive to promoting the industrialized production and wide application of plant hollow capsules. SUMMARY

[0009] The present application aims to provide the use of phenylboronic acid-modified natural polymer in the preparation of plant hollow capsules, and the phenylboronic acid-modified natural polymer as a gelling agent in the preparation process of plant hollow capsules forms a dynamic borate ester bond with the ortho dihydroxyl groups on pullulan under weak alkaline conditions, thereby undergoing a solution-gel transition, changing the viscosity of the glue solution, facilitating film formation of glue dipping, and the dynamic borate ester bond has pH-sensitive reversible sol-gel transition performance. The obtained plant hollow capsules have excellent sol-gel transition performance in the acidic environment of the stomach after oral administration, and are not affected by potassium ions, which is conducive to improving the disintegration and drug dissolution performance of plant capsules in the presence of potassium ions or under acidic conditions.

[0010] The first aspect of the present application relates to the use of phenylboronic acid-modified natural polymer in the preparation of plant hollow capsules, wherein the phenylboronic acid compound has the structure of formula I,

[0011]

[0012] In formula I,

[0013] R1 and R2 are independently selected from -F, -Cl, -Br, -OMe, -NH2, -COOH, -NO2, -CHO or -H groups;

[0014] R3 is selected from -F, -Cl, -Br, -OMe, -NH2, -COOH, -NO2, -CHO, -H, -Ph or B(OH)2 group;

[0015] The natural polymer is a natural polymer containing 1,2-diol / phenol group, 1,3-diol / phenol group or polyol / phenol group;

[0016] The phenyl boronic acid compound with the structure of general formula I modifies the natural polymer through any one of the linking groups shown in general formula II,

[0017]

[0018] In the linking group shown in formula II, the A end is connected with the phenyl boronic acid compound shown in formula I by replacing any one of R1, R2 and R3 groups, and the B end is connected with the natural polymer.

[0019] In an optional embodiment, the natural polymer modified by the phenyl boronic acid compound is used as a gelling agent in the preparation of the plant hollow capsule.

[0020] In an optional embodiment, the modification degree of the natural polymer modified by the phenyl boronic acid compound is 1% to 70%.

[0021] Another aspect of the present application relates to a preparation method of a plant hollow capsule, comprising the following steps:

[0022] The plant hollow capsule is prepared by using pullulan as the main material of the plant hollow capsule, using the natural polymer modified by the phenyl boronic acid compound defined above as the gelling agent, forming a glue solution in deionized water, adjusting the glue solution to weak alkaline to form a sol, and then sequentially performing glue dipping, drying, shell pulling and repairing.

[0023] In the preparation method, the natural polymer modified by the phenyl boronic acid compound forms a dynamic borate ester bond with the ortho dihydroxy group on the pullulan under weak alkaline conditions, so that the glue solution forms a sol.

[0024] In an optional embodiment, the concentration of the pullulan is 10 to 20 wt.%, and the concentration of the natural polymer modified by the phenyl boronic acid compound is 1 to 5 wt.%.

[0025] In an optional embodiment, the mass ratio of the pullulan to the natural polymer modified by the phenyl boronic acid compound is (5:1) to (20:1).

[0026] In an optional embodiment, the molecular weight of the pullulan used is 20 to 2000 kDa, and the molecular weight of the natural polymer modified by the phenyl boronic acid compound used is 6.8 to 1600 kDa, and the modification degree is 1% to 70%.

[0027] In an alternative embodiment, the pH of the glue solution is adjusted to 8-10.

[0028] The present application also relates to a plant hollow capsule prepared by the aforementioned method.

[0029] In an alternative embodiment, the plant hollow capsule has excellent sol-gel transition performance under acidic conditions and is not affected by potassium ions, so that the disintegration and drug dissolution of the plant capsule are not inhibited in the presence of potassium ions or under acidic conditions.

[0030] The present application finds a new use of phenyl boronic acid-modified natural macromolecules, which can be used as a gelling agent for preparing a plant hollow capsule. The phenyl boronic acid-modified natural macromolecule can form a dynamic borate ester bond with an ortho dihydroxy group under weak alkaline conditions, thereby undergoing a solution-gel transition, changing the viscosity of the glue solution, promoting gelation at room temperature, facilitating film formation by glue dipping, and obtaining a plant hollow capsule.

[0031] The dynamic borate ester bond formed has a pH-sensitive reversible sol-gel transition performance. After oral administration, it has excellent sol-gel transition performance in the acidic environment of the stomach, rapidly disintegrates in the acidic environment, promotes drug dissolution, is not affected by acidic media and potassium ion media, and solves the problem of slow disintegration of plant hollow capsules using kappa-carrageenan or gellan gum as a gelling agent in potassium ion solution or acidic medium, which is not conducive to drug dissolution.

[0032] The present application also finds that the phenyl boronic acid-modified natural macromolecule has a plasticizing effect when used to prepare a plant hollow capsule, which can reduce the addition of other auxiliary materials such as plasticizers, thereby saving costs.

[0033] The use of phenyl boronic acid-modified natural macromolecules as a gelling agent for preparing a plant capsule can be carried out at room temperature, which is more energy-saving and more in line with the national energy-saving and emission-reduction policy compared with traditional preparation methods. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 is a schematic diagram of the glue formation principle of pullulan and phenyl boronic acid-modified hyaluronic acid under weak alkaline conditions.

[0035] Figure 2 is a synthesis line diagram of the phenyl boronic acid-modified hyaluronic acid derivative in Example 1 of the present application.

[0036] Figure 3 and Figure 4The NMR hydrogen spectrum of the benzene boronic acid modified hyaluronic acid of sample 1-1 and sample 1-2, respectively.

[0037] Figure 5 The morphology picture of the plant hollow capsule film obtained in Example 7.

[0038] Figure 6 The scanning scanning electron microscope picture (400x) of the plant hollow capsule shell obtained in Example 7.

[0039] Figure 7 The plant hollow capsule obtained in Example 7. DETAILED DESCRIPTION

[0040] In order to better understand the technical content of the present application, specific embodiments are described below with reference to the accompanying drawings.

[0041] Aspects of the present application are described in this disclosure with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. The embodiments of this disclosure need not necessarily include all aspects of the present application. It should be understood that various concepts and embodiments introduced above and those described in more detail below can be implemented in any of numerous ways.

[0042] In the "0921 Disintegration Time Limit Test Method" in the Chinese Pharmacopoeia 2020 Edition (Volume 4), the disintegration of capsules under specified conditions is required as follows:

[0043] The basket is suspended on the support through the upper end of the stainless steel shaft, immersed in a 1000 mL beaker, and the position of the basket is adjusted so that the mesh is 25 mm away from the bottom of the beaker when it is lowered to the low point, the beaker contains water with a temperature of 37℃±1℃, the water level is adjusted so that the mesh is at 15 mm below the water surface when the basket is raised to the high point, and the top of the basket cannot be immersed in the solution.

[0044] Hard or soft capsules, unless otherwise specified, take 6 test samples, and follow the device and method for tablet testing (for pharmaceutical capsules, if they float on the liquid surface, a baffle can be added; for traditional Chinese medicine capsules, a baffle is added). Hard capsules should disintegrate within 30 minutes; soft capsules should disintegrate within 1 hour; soft capsules with gelatin as the matrix can be tested in artificial gastric juice. If 1 capsule cannot completely disintegrate, another 6 capsules should be taken for retesting, and all should meet the requirements.

[0045] Among them, the disintegration liquid is: pure water (pH=7.0); artificial intestinal fluid: phosphate buffer solution (containing trypsin) (pH=6.8); acetic acid-sodium acetate buffer solution (pH=4.5); artificial gastric juice: hydrochloric acid and pepsin solution (pH=1.0).

[0046] The above disintegration medium with pH=6.8 is prepared from potassium dihydrogen phosphate, and the medium contains high concentration of potassium ions.

[0047] The current plant hollow capsule taking kappa-carrageenan as a gelling agent, the plant hollow capsule in the disintegration medium of pH=6.8, due to the inhibition of kappa-carrageenan by high concentration of potassium ions, the plant hollow capsule disintegrates slowly or cannot effectively disintegrate, which is not conducive to drug dissolution.

[0048] And the plant hollow capsule taking gellan gum as a gelling agent, the plant hollow capsule in the acid disintegration medium of pH=1.0, due to the inhibition of gellan gum by the acid medium, the plant hollow capsule disintegrates slowly or cannot effectively disintegrate, which is not conducive to drug dissolution.

[0049] The existence of the above two cases limits the wide application of the plant hollow capsule to a certain extent, therefore, the present application aims to develop a new type of gelling agent suitable for the plant hollow capsule, as a substitute for traditional gelling agents such as carrageenan, gellan gum, etc., to promote the industrialized production and wide application of the plant hollow capsule.

[0050] Boric acid or compounds containing boric acid structure can combine with compounds having 1,2-diol or 1,3-diol structure to form five-membered or six-membered ring borate. Borate bond is a kind of dynamic covalent bond with direction, which can be reversibly generated and broken by adjusting the pH value, pKa(acidity coefficient) or external environment of the system. Multifunctional materials prepared based on dynamic borate bond have been widely concerned due to their good application ability, and at present, borate is mainly applied to optical sensors for realizing clinical detection, self-repairable and recyclable glass polymers, green high-performance hydrogel capacitors and drug carrier hydrogels.

[0051] In the process of developing a new type of gelling agent suitable for the plant hollow capsule, the present application surprisingly found a new use of phenyl boronic acid compound modified natural high molecule, which can replace kappa-carrageenan or gellan gum as a gelling agent for the plant hollow capsule, which has good gelation performance in weak alkaline environment (pH 8-10), can change the viscosity of glue liquid, and is beneficial to film dipping; and has good sol-gel transition performance in acidic environment, and is not affected by potassium ions, which is beneficial to promote the disintegration and drug dissolution performance of the plant capsule in the presence of potassium ions or under acidic conditions.

[0052] Therefore, the present application relates to the use of phenyl boronic acid compound modified natural high molecule in the preparation of plant hollow capsules, wherein the phenyl boronic acid compound has the general formula I structure,

[0053]

[0054] In formula I,

[0055] R1and R2are independently selected from -F, -Cl, -Br, -OMe, -NH2, -COOH, -NO2, -CHO or -H group;

[0056] R3is selected from -F, -Cl, -Br, -OMe, -NH2, -COOH, -NO2, -CHO, -H, -Ph or B(OH)2group;

[0057] The natural polymer is a natural polymer containing 1,2-diol / phenol group, 1,3-diol / phenol group or polyol / phenol group;

[0058] The phenyl boronic acid compound with the structure of general formula I modifies the natural polymer through any one of the amide bond, ester bond, Schiff base bond shown in general formula II,

[0059]

[0060] In which, the A end of the connecting bond shown in formula II is connected with the phenyl boronic acid compound shown in formula I by replacing any one of R1, R2and R3groups, and the B end is connected with the natural polymer.

[0061] In another embodiment, the natural polymer is one or more of hyaluronic acid, sodium alginate, pullulan, starch, hydroxypropyl cellulose, chitosan and the like.

[0062] In an optional embodiment, the natural polymer modified by the phenyl boronic acid compound is used as a gelling agent in the preparation of the plant hollow capsule.

[0063] The natural polymer modified by the phenyl boronic acid compound can form a hydrogel derived polymer in an aqueous solution, when the concentration of the natural polymer modified by the phenyl boronic acid compound gelling agent in the aqueous solution is 1-5 wt.%, it is in a gel form at pH = 8-10, and in a solution form when the pH is lower than 7, and the transition of the sol-gel transition form is not interfered by potassium ions.

[0064] In an optional embodiment, the modification degree of the natural polymer modified by the phenyl boronic acid compound is 1%-70%.

[0065] In another embodiment of the present application, a preparation method of a plant hollow capsule is provided, comprising the following steps:

[0066] Taking pullulan as the main material of the hollow capsule, and the natural polymer modified by the phenyl boronic acid compound defined in the foregoing as the gelling agent, a glue solution is formed in deionized water, and the glue solution is adjusted to weak alkaline to form a sol, and then the glue dipping, drying, shell pulling and building are sequentially performed to obtain the plant hollow capsule.

[0067] The phenyl boronic acid compound modified natural polymer forms a dynamic borate ester bond with the ortho dihydroxyl groups on the pullulan under weak alkaline conditions, so that the glue solution forms a sol.

[0068] In an alternative embodiment, the concentration of the pullulan is 10-20 wt.%, and the concentration of the phenyl boronic acid compound modified natural polymer is 1-5 wt.%, so that the phenyl boronic acid compound modified natural polymer does not self-gel, and the amount of the plant gelling agent does not exceed one-tenth of the amount of the main material.

[0069] In an alternative embodiment, the mass ratio of the pullulan to the phenyl boronic acid compound modified natural polymer is (5:1)-(20:1).

[0070] In an alternative embodiment, the molecular weight of the pullulan used is 20-2000 kDa, and the molecular weight of the phenyl boronic acid compound modified natural polymer used is 6.8-1600 kDa, and the modification degree is 1%-70%.

[0071] In an alternative embodiment, the pH of the glue solution is adjusted to 8-10.

[0072] In an exemplary embodiment of the present application, a preparation method of a plant hollow capsule is provided, which comprises: dissolving a pullulan glue solution, adding a phenyl boronic acid compound modified natural polymer gelling agent, adjusting the pH of the glue solution to 8-10, dipping the glue to prepare a blank, drying, pulling out the shell, trimming, and obtaining a plant hollow capsule product.

[0073] The specific steps are as follows:

[0074] Sol: 10-20 wt.% pullulan is dissolved in deionized water, and 1-5 wt.% of the aforementioned phenyl boronic acid compound modified natural polymer is added as a gelling agent. The solution is stirred constantly until it is fully dissolved, and is left to stand at room temperature to remove bubbles and make the glue solution clear.

[0075] Adjusting the pH of the glue solution: the pH of the glue solution is adjusted to 8-10 using a sodium hydroxide solution.

[0076] Dipping the glue to prepare a blank: a capsule mold is used, and the mold rod is dipped into the glue solution to prepare a capsule blank. The appropriate size of the mold rod is selected and fixed on the mold plate, the upper end of the mold rod is dipped into the glue solution, the mold rod is slowly lifted away from the glue solution surface after 6-8 seconds, and the mold rod is turned over several times.

[0077] Drying: hot air is used for drying for 1 hour.

[0078] Pulling out the shell: the shell of the dried capsule is pulled out.

[0079] Trimming: trim off the damaged part with scissors to get a complete capsule shell.

[0080] It can be understood that, in the present application, through simple chemical reactions, phenylboronic acid can be connected to natural polymers through Schiff base bond, amide, hydrazide, ester bond and other bonding modes to directly synthesize natural polymer gelling agent modified by phenylboronic acid compounds; wherein the preparation of natural polymer modified by phenylboronic acid compounds can adopt the method common in the art, which is not limited further herein.

[0081] The prepared natural polymer modified by phenylboronic acid compounds can form a dynamic borate ester bond with the ortho dihydroxyl groups on pullulan under weak alkaline conditions (pH 8-10), thereby causing solution-gel transition, which can change the viscosity of the glue liquid and be beneficial to the film formation of the dipping glue; for example, the glue forming principle of hyaluronic acid modified by phenylboronic acid and pullulan under weak alkaline conditions is as shown in Figure 1 .

[0082] In another embodiment of the present application, a plant hollow capsule prepared by the foregoing method is also provided.

[0083] The plant hollow capsule has excellent sol-gel transition performance under acidic conditions and is not affected by potassium ions, so that the disintegration and drug dissolution of the plant capsule are not inhibited in the presence of potassium ions or under acidic conditions.

[0084] Compared with the existing gelatin capsules, the prepared pullulan plant hollow capsule has good stability under high temperature and high humidity conditions, is not denatured and does not become brittle. The pullulan plant hollow capsule does not contain amino groups and cannot chemically react with drug molecules containing aldehyde groups, thereby avoiding the reaction between the film and the drug; at the same time, the natural polymer gelling agent modified by phenylboronic acid compounds used to prepare the plant hollow capsule makes the disintegration of the capsule not limited by acidic environment or potassium ions, the storage conditions of the plant capsule are low, and various physical and chemical indicators can meet the requirements of Chinese Pharmacopoeia and national and industry standards.

[0085] The following specific examples are further described to illustrate the gelling agent and efficacy of the present application. These examples are only illustrative and are not intended to limit the scope of the present application in any way.

[0086] In the following examples, the experimental methods are described, which are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0087] Preparation of natural high molecular modified by phenyl boronic acid compounds

[0088]

Example 1

[0089] [Preparation of hyaluronic acid gelling agent modified by phenylboronic acid through amidation reaction]

[0090] The carboxyl group on hyaluronic acid (HA) and the amino group on 3-aminophenylboronic acid (3A-PBA) undergo an amidation reaction under EDC / NHS catalysis to prepare a phenylboronic acid-modified hyaluronic acid derivative (HA-PBA). The synthetic circuit diagram is shown below. Figure 2 As shown.

[0091] The specific experimental steps are as follows:

[0092] Following the reactant feeding method listed in Table 1, 2000.0 mg of hyaluronic acid (HA) was dissolved in 200 mL of 0.1 M MES buffer solution, and the pH of the solution was adjusted to 5.5 using 0.1 M HCl. Then, 1400.0 mg of EDC and 200.0 mg of NHS were added to the hyaluronic acid solution, and the reaction was activated for approximately 30 minutes. Subsequently, 3-aminophenylboronic acid was added to the above reaction mixture, and the reaction was carried out at room temperature in the dark for 12 hours. The resulting reaction solution was dialyzed (dialysis bag molecular weight cutoff: 3500 Da), and the pH of the solution was maintained at 5.5 during the purification process. After dialysis, the solution was freeze-dried to obtain hyaluronic acid derivatives (HA-PBA) with different grafting rates of phenylboronic acid groups.

[0093] through 1 After H-NMR characterization, taking samples 1-1 and 1-2 as examples, as follows: Figure 3 and Figure 4 As shown in Table 1, its structure can be verified and its phenylboronic acid grafting rate can be calculated.

[0094] Table 1. Synthesis feed ratio of phenylboronic acid modified hyaluronic acid gelling agents with different grafting rates

[0095]

[0096]

[0097]

Example 2

[0098] [Preparation of phenylboronic acid-modified chitosan gelling agent via amidation reaction]

[0099] The amino groups on chitosan (CS) and the carboxyl groups of 3-carboxyphenylboronic acid (3C-PBA) undergo an amidation reaction under the catalysis of EDC / NHS to prepare chitosan derivatives modified with phenylboronic acid groups.

[0100] The specific experimental steps are as follows:

[0101] Take 2000.0 mg of chitosan and dissolve it in 200 mL of 0.1 M MES buffer solution, and use 0.1 M HC1 to adjust the pH value of the solution to 5.5, then add 1198.0 mg of EDC and 719.3 mg of NHS to the hyaluronic acid solution, and react for about 30 minutes, then add 300.0 mg of 3-carboxyphenylboronic acid to the above reaction mixture and react at room temperature for 12 hours in the dark. The resulting reaction solution is dialyzed (dialysis bag molecular weight cutoff: 3500 Da), and the pH value of the solution is maintained at 5.5 during purification. After dialysis, freeze-drying is performed to obtain a chitosan derivative functionalized with a phenylboronic acid group.

[0102] [Example 3]

[0103] [Preparation of a phenylboronic acid-modified chitosan gelling agent by Schiff base reaction]

[0104] The Schiff base reaction of the amino group on chitosan (CS) and the aldehyde group of 2-aldehyde phenylboronic acid (2F-PBA) occurs at room temperature to prepare a chitosan derivative modified with a phenylboronic acid group.

[0105] The specific experimental steps are as follows:

[0106] Take 2000.0 mg of chitosan and dissolve it in 200 mL of deionized water, and after complete dissolution, add 937.0 mg of 2-aldehyde phenylboronic acid and react for 0.5 hours. After the reaction is complete, dialyze against deionized water for three days, and freeze-dry to obtain a chitosan derivative functionalized with a phenylboronic acid group.

[0107] [Example 4]

[0108] [Preparation of a phenylboronic acid-modified sodium alginate gelling agent by Schiff base reaction]

[0109] The Schiff base reaction of the aldehyde group on aldehyde-modified sodium alginate (Alg) and the amino group on 2-amino phenylboronic acid (3A-PBA) occurs at room temperature to prepare a sodium alginate derivative modified with a phenylboronic acid group.

[0110] The specific experimental steps are as follows: Take 2000.0 mg of aldehyde-modified sodium alginate and dissolve it in 200 mL of deionized water, and after complete dissolution, add 595.5 mg of 2-amino phenylboronic acid and react for 0.5 hours. After the reaction is complete, dialyze against deionized water for three days, and freeze-dry to obtain a sodium alginate derivative functionalized with a phenylboronic acid group.

[0111] [Example 5]

[0112] [Preparation of a phenylboronic acid-modified pullulan gelling agent by esterification reaction]

[0113] The hydroxyl group of pullulan (P) and the carboxyl group of 4-carboxyphenylboronic acid (4C-PBA) are esterified under the catalysis of DCC / DMAP to prepare a pullulan derivative modified with a phenylboronic acid group.

[0114] The specific experimental steps are as follows:

[0115] 2000.0 mg of pullulan is dissolved in 200 mL of deionized water, and after complete dissolution, 773.4 mg of condensing agent DCC and 458.0 mg of DMAP are added. After 0.5 hours of activation, 623.0 mg of 4-carboxyphenylboronic acid is added, and the reaction is carried out at room temperature for 24 hours. After the reaction is completed, the obtained reaction solution is dialyzed (dialysis bag molecular weight cut-off: 3500 Da), and in the purification process, 100 mM sodium chloride solution is used for dialysis for 36 hours, and then deionized water is used for dialysis for 48 hours, to obtain a pullulan derivative functionalized with a phenylboronic acid group.

[0116]

Example 6

[0117] [Preparation of a phenylboronic acid-modified hyaluronic acid gelling agent by esterification reaction]

[0118] The carboxyl group of hyaluronic acid (HA) and the hydroxyl group of o-hydroxyphenylboronic acid (3O-PBA) are esterified under the catalysis of DCC / DMAP to prepare a hyaluronic acid derivative modified with a phenylboronic acid group. The specific experimental steps are as follows: 2000.0 mg of hyaluronic acid with a molecular weight of 370 K Da is dissolved in 200 mL of deionized water, and after complete dissolution, 1022.4 mg of condensing agent DCC and 605.6 mg of DMAP are added. After 0.5 hours of reaction, 684.7 mg of o-hydroxyphenylboronic acid is added, and the reaction is carried out at room temperature for 24 hours. After the reaction is completed, the obtained reaction solution is dialyzed (dialysis bag molecular weight cut-off: 3500 Da), and in the purification process, 100 mM sodium chloride solution is used for dialysis for 36 hours, and then deionized water is used for dialysis for 48 hours, to obtain a hyaluronic acid derivative functionalized with a phenylboronic acid group.

[0119] Preparation of pullulan-based plant capsules

[0120]

Example 7

[0121] A pullulan (molecular weight: 40 K Da) is used as a hollow capsule main material, and a phenylboronic acid-modified hyaluronic acid (samples 1-2) is used as a gelling agent, and the specific components and preparation methods are as follows:

[0122] Sol: 20.0 g of pullulan is dissolved in 100.0 mL of deionized water, and a phenylboronic acid-modified hyaluronic acid is added as a gelling agent. Stir constantly to dissolve thoroughly, and let stand at room temperature to remove bubbles, so that the glue liquid is clear.

[0123] Adjusting pH: Adjust the pH of the glue solution to about 9 using 0.1 mol / L sodium hydroxide.

[0124] Dipping glue to make embryo: Use the capsule mold to dip the mold rod into the glue solution to prepare the capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Dip the upper end of the mold rod into the glue solution. After the glue solution completely covers the mold rod for 10.0-20.0 s, slowly lift the mold rod away from the glue solution surface. Then turn the mold rod over and turn it three times.

[0125] Drying: Dry using flowing hot air for 1 hour.

[0126] Shell pulling: Pull out the dried capsule shell.

[0127] Pruning: Prune the damaged parts with scissors to obtain a complete capsule shell.

[0128] The variables in the above process are shown in Table 2.

[0129] Table 2

[0130]

[0131]

Example 8

[0132] Use pullulan (molecular weight: 40 KDa) as the hollow capsule main material and benzene boronic acid modified chitosan (obtained in Example 2) as the gelling agent. The specific components and preparation method are as follows:

[0133] Sol: Weigh 20.0 g of pullulan and dissolve it in 100.0 mL of deionized water. Add 1.0 g of benzene boronic acid modified chitosan as the gelling agent. Stir constantly until it is fully dissolved. Let it stand at room temperature to remove bubbles and make the glue solution clear.

[0134] Adjusting pH: Adjust the pH of the glue solution to about 9 using 0.1 mol / L sodium hydroxide.

[0135] Dipping glue to make embryo: Use the capsule mold to dip the mold rod into the glue solution to prepare the capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Dip the upper end of the mold rod into the glue solution. After the glue solution completely covers the mold rod for 10.0 s, slowly lift the mold rod away from the glue solution surface. Then turn the mold rod over and turn it three times.

[0136] Drying: Dry using flowing hot air for 1 hour.

[0137] Shell pulling: Pull out the dried capsule shell.

[0138] Pruning: Prune the damaged parts with scissors to obtain a complete capsule shell.

[0139]

Example 9

[0140] Purified pullulan (40KDa) as the main material of the capsule, and the benzene boronic acid modified chitosan (obtained in Example 3) as the gelling agent. The specific components and preparation method are as follows:

[0141] Sol: 20.0 g of purified pullulan was dissolved in 100.0 mL of deionized water, 1.0 g of benzene boronic acid modified chitosan was added as the gelling agent, and it was continuously stirred until it was fully dissolved. The bubbles were removed at room temperature to make the glue liquid clear.

[0142] Adjusting pH: 0.1 mol / L of sodium hydroxide was used to adjust the pH of the glue liquid to about 9.

[0143] Dipping glue to make embryo: using the capsule mold, the mold rod was dipped into the glue liquid to prepare the capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Then, immerse the upper end of the mold rod into the glue liquid. After 10.0 s, slowly lift the mold rod away from the glue liquid surface. Then, turn the mold rod over and turn it 3 times.

[0144] Drying: dry for 1 hour using flowing hot air.

[0145] Pulling out the shell: the dried capsule shell was pulled out.

[0146] Pruning: use scissors to trim the damaged parts to get the complete capsule shell.

[0147]

Example 10

[0148] Purified pullulan (40KDa) as the main material of the capsule, and the benzene boronic acid modified chitosan (obtained in Example 3) as the gelling agent. The specific components and preparation method are as follows:

[0149] Sol: 20.0 g of purified pullulan was dissolved in 100.0 mL of deionized water, 1.0 g of benzene boronic acid modified chitosan was added as the gelling agent, and it was continuously stirred until it was fully dissolved. The bubbles were removed at room temperature to make the glue liquid clear.

[0150] Adjusting pH: 0.1 mol / L of sodium hydroxide was used to adjust the pH of the glue liquid to about 9.

[0151] Dipping glue to make embryo: using the capsule mold, the mold rod was dipped into the glue liquid to prepare the capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Then, immerse the upper end of the mold rod into the glue liquid. After 10.0 s, slowly lift the mold rod away from the glue liquid surface. Then, turn the mold rod over and turn it 3 times.

[0152] Drying: dry for 1 hour using flowing hot air.

[0153] Pulling out the shell: the dried capsule shell was pulled out.

[0154] Trimming: trim off the damaged part with scissors to get the intact capsule shell.

[0155] Example 11

[0156] Purified water was used as the solvent, and the specific components and preparation methods are as follows:

[0157] Sol: 20.0 g of pullulan was dissolved in 100.0 mL of deionized water, 1.0 g of benzene boronic acid modified pullulan was added as the gelling agent, and it was continuously stirred until it was fully dissolved. It was left to stand at room temperature to remove bubbles and make the glue liquid clear.

[0158] Adjusting pH: the pH of the glue liquid was adjusted to about 9 using 0.1 mol / L sodium hydroxide.

[0159] Dipping glue embryo: using the capsule mold, the mold rod was dipped into the glue liquid to prepare the capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Dip the upper end of the mold rod into the glue liquid, and when the glue liquid completely covers the mold rod, 10.0 s later, slowly lift the mold rod away from the glue liquid surface, and then turn the mold rod over, turning it 3 times.

[0160] Drying: dry using flowing hot air for 1 hour.

[0161] Pulling out the shell: the dried capsule shell was pulled out.

[0162] Trimming: trim off the damaged part with scissors to get the intact capsule shell.

[0163] Example 12

[0164] Purified water was used as the solvent, and the specific components and preparation methods are as follows:

[0165] Sol: 20.0 g of pullulan was dissolved in 100.0 mL of deionized water, 1.0 g of benzene boronic acid modified pullulan was added as the gelling agent, and it was continuously stirred until it was fully dissolved. It was left to stand at room temperature to remove bubbles and make the glue liquid clear.

[0166] Adjusting pH: the pH of the glue liquid was adjusted to about 9 using 0.1 mol / L sodium hydroxide.

[0167] Dipping embryo: using capsule mold, the mold rod is dipped into the glue solution to prepare capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Then, dip the upper end of the mold rod into the glue solution. After 10.0 seconds, slowly lift the mold rod away from the glue solution surface. Then, turn the mold rod over and turn it three times.

[0168] Drying: dry using flowing hot air for 1 hour.

[0169] Shell pulling: pull out the dried capsule shell.

[0170] Pruning: trim the damaged part with scissors to obtain a complete capsule shell.

[0171] Comparative Example 1

[0172] The preparation process of the plant capsule is the same as that of Example 7

[0173] Sol→add gelling agent→dipping embryo→drying→shell pulling→product.

[0174] Sol: weigh 20.0 g of pullulan (molecular weight: 40 KDa) and add it to 100.0 mL of deionized water. After fully dissolving, add 1.0 g of kappa-carrageenan and continuously stir to fully dissolve. Let it stand at room temperature to remove bubbles and make the glue solution clear.

[0175] Dipping embryo: using capsule mold, the mold rod is dipped into the glue solution to prepare capsule embryo. First, select the appropriate size of the mold rod and fix it on the mold plate. Then, dip the upper end of the mold rod into the glue solution. After 10.0 seconds, slowly lift the mold rod away from the glue solution surface. Then, turn the mold rod over and turn it three times.

[0176] Drying: dry using flowing hot air for 1 hour.

[0177] Shell pulling: pull out the dried capsule shell.

[0178] Pruning: trim the damaged part with scissors to obtain a complete capsule shell

[0179] Comparative Example 2

[0180] The preparation process of the plant capsule is the same as that of Example 7

[0181] Sol→add gelling agent→dipping embryo→drying→shell pulling→product.

[0182] Sol: weigh 20.0 g of pullulan (molecular weight: 40 KDa) and add it to 100.0 mL of deionized water. After fully dissolving, add 1.0 g of kappa-carrageenan and continuously stir to fully dissolve. Let it stand at room temperature to remove bubbles and make the glue solution clear.

[0183] Dipping capsule embryo: using a capsule mold, dipping the mold rod into the glue solution to prepare a capsule embryo, first select the appropriate size of the mold rod and fix it on the mold plate, immerse the upper end of the mold rod into the glue solution, wait for the glue solution to completely immerse the mold rod for 10.0s, then slowly lift the mold rod away from the glue solution surface, and then turn the mold rod over, turn it over 3 times.

[0184] Drying: drying for 1 hour using flowing hot air.

[0185] Pulling out the shell: pulling out the capsule shell after drying.

[0186] Trimming: trimming the damaged part with scissors to obtain a complete capsule shell

[0187] Determination of properties and disintegration of plant hollow capsules

[0188] [Testing of the plant hollow capsule of the invention]

[0189] According to the hard capsule standard of the Chinese Pharmacopoeia 2020 edition, the appearance, tightness, drying loss, disintegration performance at 37℃ and friability of the plant hollow capsule obtained in Example 7 were determined, and the specific results are shown as follows:

[0190] In combination with the results shown in Figure 5 , Figure 6 and Figure 7 , it can be seen that the thickness of the capsule prepared in Example 7 is 0.130mm-0.140mm, the appearance is neat, and there is no bonding, deformation or rupture phenomenon.

[0191] The capsule tightness was determined, there was no powder leakage phenomenon, and no rupture; the drying loss was 8.30%.

[0192] The disintegration performance showed that the prepared plant capsule appeared obvious damage within 30-60s and completed drug release, and within 5-10min, it was completely disintegrated and was not affected by the pH of the solution, and randomly selected 50 capsules for friability test, none were broken.

[0193] The above data show that the plant hollow capsule can be successfully prepared according to the invention, and the quality of the obtained plant hollow capsule completely meets the requirements of the pharmacopoeia.

[0194] [Comparative test]

[0195] According to the standard of the Chinese Pharmacopoeia (2020 edition), the yield, friability, drying loss, tightness and disintegration performance of the capsule product prepared in Example 7 of the invention and the capsule products prepared in Comparative Example 1 and Comparative Example 2 were compared, and the results are shown in Table 3.

[0196] Table 3

[0197]

[0198]

[0199] The above experimental results prove that the plant hollow capsules obtained by using the natural polymer modified by the phenyl boronic acid compound as a gelling agent meet the standards of the Chinese Pharmacopoeia, and the disintegration performance is obviously not affected by the acid medium and potassium ions.

[0200] Although the present application has been disclosed with reference to preferred embodiments, it is not intended to limit the application. Those skilled in the art who are familiar with the technical field of the present application can make various modifications and improvements without departing from the spirit and scope of the present application. Therefore, the protection scope of the present application shall be subject to the scope defined by the claims.

Claims

1. The use of natural polymers modified with phenylboronic acid compounds in the preparation of plant-based empty capsules, among which, The natural polymer modified with phenylboronic acid compounds is phenylboronic acid linked to hyaluronic acid via amide or ester bonds, and the main material of the plant-based hollow capsule is pullulan polysaccharide; the natural polymer modified with phenylboronic acid compounds forms dynamic borate ester bonds with the ortho-dihydroxy groups on pullulan polysaccharide under weakly alkaline conditions.

2. The use according to claim 1, characterized in that, Natural polymers modified with phenylboronic acid compounds are used as gelling agents in the preparation of plant-based hollow capsules.

3. The use according to claim 1, characterized in that, The degree of modification of natural polymers modified with phenylboronic acid compounds ranges from 1% to 70%.

4. A method for preparing plant-based empty capsules, characterized in that, Includes the following steps: Pullulan polysaccharide is used as the main material for plant hollow capsules. Natural polymers modified with phenylboronic acid compounds as described in claims 1-3 are used as gelling agents to form a gel in deionized water. The gel is then adjusted to a weakly alkaline state to form a sol. The process of dipping the capsule in the gel, drying, shelling, and trimming is carried out sequentially to obtain the plant hollow capsules. Among them, the natural polymer modified with phenylboronic acid compounds forms a dynamic borate bond with the ortho-dihydroxy groups on pullulan polysaccharide under weakly alkaline conditions, causing the adhesive to form a sol.

5. The method for preparing plant-based empty capsules according to claim 4, characterized in that, In the adhesive, the concentration of pullulan polysaccharide is 10-20 wt.%, and the concentration of natural polymers modified with phenylboronic acid compounds is 1-5 wt.%.

6. The method for preparing plant-based empty capsules according to claim 4, characterized in that, The mass ratio of pullulan polysaccharide and phenylboronic acid compounds modified natural polymers is (5:1) to (20:1).

7. The method for preparing plant-based empty capsules according to claim 4, characterized in that, The pullulan polysaccharide used has a molecular weight of 20 to 2000 kDa; the natural polymer modified with phenylboronic acid compounds has a molecular weight of 6.8 to 1600 kDa and a degree of modification of 1% to 70%.

8. The method for preparing plant-based empty capsules according to claim 4, characterized in that, Adjust the pH of the adhesive solution to 8-10.

9. A plant-based empty capsule prepared by the method according to any one of claims 4-8.

10. The plant-based empty capsule according to claim 9, characterized in that, This plant-based hollow capsule exhibits sol-gel transition properties under acidic conditions and is unaffected by potassium ions, ensuring that the disintegration and drug dissolution of the plant capsule are not inhibited in the presence of potassium ions or under acidic conditions.

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