Low-browning chitosan oligosaccharide tablets and preparation method thereof

Abstract

The present invention discloses a low-browning chitosan oligosaccharide tablet and a preparation method thereof, and belongs to the field of drug preparation technology. The low-browning chitosan oligosaccharide tablet of the present invention contains the following components by mass: 65-80 parts of chitosan oligosaccharide, 0-30 parts of D-mannitol, 5-12 parts of microcrystalline cellulose, 0.5-2 parts of sodium carboxymethyl starch, 2-5 parts of pyrroloquinoline quinone disodium salt, 0.01-0.02 parts of sodium metabisulfite, 0.5-2 parts of magnesium stearate, 0.1-3 parts of citric acid, and 0.01-0.5 parts of aspartame. The chitosan oligosaccharide tablet prepared by the above-mentioned components of the present invention has good adhesion, a smooth surface, no edge knocking or fragmentation, light product color, good stability, and almost no browning.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a low-browning chitosan oligosaccharide tablet and a preparation method thereof. Background Art

[0002] Chitosan oligosaccharides are degradation products of chitosan. Compared to chitosan, chitosan oligosaccharides not only possess rich biological activity but also overcome chitosan's poor solubility, leading to widespread applications in functional foods and pharmaceuticals. However, chitosan oligosaccharides contain amino groups, making them charged sugars. During preparation and storage, they are susceptible to Maillard reactions, causing non-enzymatic browning. This browning leads to a darker color and reduced water solubility. It also reduces thermal stability, severely impacting product purity, bioactivity, and safety, significantly hindering its application in functional foods and pharmaceuticals. Current research on the browning of chitosan oligosaccharides is limited to liquid formulations, with a lack of research on the browning of chitosan oligosaccharides in solid dosage forms. When chitosan oligosaccharides are used as active pharmaceutical ingredients (APIs), tablets are typically produced using a wet granulation process. However, wet granulation results in a darker product color and a certain degree of browning. Summary of the Invention

[0003] The invention aims to solve the problems of browning and attenuation of chitosan oligosaccharide tablet products during shelf life.

[0004] The technical solutions of the present invention are as follows:

[0005] The present invention provides a low-browning chitosan oligosaccharide tablet comprising the following components in parts by weight:

[0006] 65-80 parts of chitosan oligosaccharide, 0-30 parts of D-mannitol, 5-12 parts of microcrystalline cellulose, 0.5-2 parts of sodium carboxymethyl starch, 2-5 parts of disodium pyrroloquinoline quinone, 0.01-0.02 parts of sodium metabisulfite, 0.5-2 parts of magnesium stearate, 0.1-3 parts of citric acid, and 0.01-0.5 parts of aspartame.

[0007] In a specific embodiment, the chitosan oligosaccharide tablets of the present invention contain the following components in parts by weight:

[0008] 65 parts of chitosan oligosaccharide, 22 parts of D-mannitol, 7 parts of microcrystalline cellulose, 1.4 parts of sodium carboxymethyl starch, 2 parts of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0009] In a specific embodiment, the chitosan oligosaccharide tablets of the present invention contain the following components in parts by weight:

[0010] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 3.5 parts of disodium pyrroloquinoline quinone, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame

[0011] In a specific embodiment, the chitosan oligosaccharide tablets of the present invention contain the following components in parts by weight:

[0012] 80 parts of chitosan oligosaccharide, 0 part of D-mannitol, 11.6 parts of microcrystalline cellulose, 0.8 part of sodium carboxymethyl starch, 5 parts of disodium pyrroloquinoline quinone, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0013] The chitosan oligosaccharide tablets can be prepared by tableting according to conventional processes.

[0014] Specifically, the chitosan oligosaccharide tablets can be prepared by the following method:

[0015] The ambient temperature is controlled at 18-25°C and the humidity is controlled below 30Rh%. The API, filler, binder, disintegrant, browning inhibitor, lubricant, and flavoring are mixed. The process parameters of the mixing equipment are set to: speed 8 r / min, time 20 min; the rotary tableting equipment is adjusted to a load of 600±30 mg, a pressure of 80-150 kN, and a speed of 15-30 r / min for compression molding; the blast temperature is adjusted to 45-65°C, the speed is adjusted to 1-15 r / min, and the atomization pressure is adjusted to 4-5 kg / cm 2 , increase the weight by 2-4%, and perform coating. After the coating is completed, the slices are air-dried to obtain chitosan oligosaccharide tablets.

[0016] In the above preparation method, the coating liquid used for coating is: 35 parts of polyvinyl alcohol, 22 parts of ethyl cellulose, 21 parts of polyacrylic acid resin, 14 parts of triethyl citrate and 8 parts of polysorbate 80 are dissolved in 95% alcohol (v / v) to prepare a 3% solution.

[0017] In the present invention, the raw material is chitosan oligosaccharide; the filler is D-mannitol; the binder is microcrystalline cellulose or hydroxypropyl cellulose; the disintegrant is sodium carboxymethyl starch; the browning inhibitor is pyrroloquinoline quinone disodium salt and sodium metabisulfite; the lubricant is magnesium stearate, and the flavoring agents are citric acid and aspartame.

[0018] The invention provides a new application of pyrroloquinoline quinone disodium salt, namely, application of pyrroloquinoline quinone disodium salt in inhibiting the browning of chitosan oligosaccharides.

[0019] The present invention also provides the use of pyrroloquinoline quinone disodium salt in the preparation of low-browning chitosan oligosaccharide tablets.

[0020] The present invention also provides the use of pyrroloquinoline quinone disodium salt and sodium metabisulfite in the preparation of low-browning chitosan oligosaccharide tablets.

[0021] The invention also provides the use of pyrroloquinoline quinone disodium salt and sodium pyrosulfite in reducing the loss of chitosan oligosaccharide content in chitosan oligosaccharide tablets.

[0022] The beneficial effects of the present invention are:

[0023] The browning inhibitor of the present invention comprises pyrroloquinoline quinone disodium salt and sodium metabisulfite. The composition can effectively prevent the browning reaction of chitosan oligosaccharides and can significantly inhibit the browning and decay of chitosan oligosaccharides. Pyrroloquinoline quinone disodium salt itself is an ingredient with multiple physiologically active functions. The chitosan oligosaccharide tablets prepared based on this composition have both a stable shelf life and multiple health benefits. In addition, the chitosan oligosaccharide tablets prepared using the above-mentioned components of the present invention have good adhesion, a smooth surface, no edge chipping or fragmentation, a light product color, good stability, and almost no browning. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the color diagram of chitosan oligosaccharide tablets in the accelerated test. DETAILED DESCRIPTION

[0025] In the present invention, the API is chitosan oligosaccharide; the filler is D-mannitol; the binder is microcrystalline cellulose; the disintegrant is sodium carboxymethyl starch; the browning inhibitors are pyrroloquinoline quinone disodium salt and sodium metabisulfite; the lubricant is magnesium stearate, and the flavorings are citric acid and aspartame. The CAS number of the browning inhibitor, pyrroloquinoline quinone disodium salt, is 122628-50-6.

[0026] The other materials used in the present invention, unless otherwise stated, can be obtained through commercial channels. Unless otherwise specified, other terms used in the present invention generally have the meanings commonly understood by those of ordinary skill in the art. The present invention will be further described in detail below with reference to specific examples and data. The following examples are merely for illustration of the present invention and are not intended to limit the scope of the present invention in any way.

[0027] The preparation method of chitosan oligosaccharide tablets comprises the following steps:

[0028] The ambient temperature was controlled at 20°C and the humidity was controlled below 30%RH; the API, filler, binder, disintegrant, browning inhibitor, lubricant, and flavoring were mixed, and the process parameters of the mixing equipment were set to: speed 8 r / min, time 20 min; the rotary tableting equipment was adjusted to a load of 600±30 mg, a pressure of 100 kN, and a speed of 25 r / min for compression molding; the blast temperature was adjusted to 50°C, a speed of 10 r / min, and an atomization pressure of 4 kg / cm 2, increase weight by 3%, and coat, and dry the slices after coating to obtain chitosan oligosaccharide slices. The chitosan oligosaccharide slices are placed in HDPE bottles, 2g of desiccant is placed in each bottle, and sealed with aluminum foil gaskets for standby use.

[0029] In the above preparation method, the coating liquid used for coating is: 35 parts of polyvinyl alcohol, 22 parts of ethyl cellulose, 21 parts of polyacrylic acid resin, 14 parts of triethyl citrate, and 8 parts of polysorbate 80 are dissolved in 95% alcohol (v / v) to prepare a 3% solution.

[0030] The following examples were prepared according to the above method:

[0031] Example 1

[0032] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0033] 65 parts of chitosan oligosaccharide, 22 parts of D-mannitol, 7 parts of microcrystalline cellulose, 1.4 parts of sodium carboxymethyl starch, 2 parts of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0034] Example 2

[0035] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0036] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 3.5 parts of disodium pyrroloquinoline quinone, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame

[0037] Example 3

[0038] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0039] 80 parts of chitosan oligosaccharide, 0 part of D-mannitol, 11.6 parts of microcrystalline cellulose, 0.8 part of sodium carboxymethyl starch, 5 parts of disodium pyrroloquinoline quinone, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0040] Comparative Example 1

[0041] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0042] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0043] Comparative Example 2

[0044] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0045] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0046] Comparative Example 3

[0047] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0048] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 3 parts of sodium ascorbate, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0049] Comparative Example 4

[0050] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0051] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 0.02 parts of butylated hydroxyanisole (BHA), 0.01 parts of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 parts of aspartame.

[0052] Comparative Example 5

[0053] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0054] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 1 part of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0055] Comparative Example 6

[0056] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0057] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 6 parts of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

[0058] Comparative Example 7

[0059] The ingredients and mass fractions of chitosan oligosaccharide tablets are as follows:

[0060] 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 3.5 parts of disodium pyrroloquinoline quinone, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 parts of aspartame

[0061] (1) Accelerated test

[0062] Keep the ambient temperature at 37±2°C and the relative humidity at 75±5%, away from direct sunlight, for three months. Then, take an appropriate amount of sample and observe its appearance, color, and condition under natural light. Smell it, rinse your mouth with warm water, and taste it.

[0063] The test results are shown in the table Figure 1 As shown in Table 1:

[0064] Figure 1 The color diagram of chitosan oligosaccharide tablets in the accelerated test. Figure 1 It can be seen that the chitosan oligosaccharide tablets of Examples 1 to 3 showed almost no browning after being placed for 3 months, and the color was well maintained. However, in the absence of a browning inhibitor, as shown in Comparative Examples 1 and 2, the chitosan oligosaccharide tablets were severely browned. After replacing pyrroloquinoline quinone disodium salt with other browning inhibitors, as shown in Comparative Examples 3 and 4, the chitosan oligosaccharide tablets showed a certain degree of browning, which shows that the browning inhibition effect of pyrroloquinoline quinone disodium salt is relatively excellent. When the amount of pyrroloquinoline quinone disodium salt used is reduced, as shown in Comparative Example 5, the chitosan oligosaccharide tablets showed a certain degree of browning. In the absence of sodium metabisulfite and retaining pyrroloquinoline quinone disodium salt, as shown in Comparative Example 7, the browning phenomenon is not obvious, which also proves the excellent effect of pyrroloquinoline quinone disodium salt in inhibiting browning.

[0065] Table 1

[0066]

[0067]

[0068] (2) Chitosan oligosaccharide content detection

[0069] 1. Instruments and reagents

[0070] The instruments and reagents used are: spectrophotometer; water bath; volumetric flask; stoppered test tube; concentrated sulfuric acid; 10 mol / L NaOH solution: 20 g NaOH dissolved in 50 ml distilled water; standard: glucosamine hydrochloride (≥99%); 3,5-dinitrosalicylic acid (DNS) reagent: dissolve 185 g potassium sodium tartrate in 500 mL distilled water, heat, add 6.3 g 3,5-dinitrosalicylic acid, 21 g sodium hydroxide, 5 g recrystallized phenol, and 5 g sodium sulfite to the hot water in sequence, stir to dissolve, cool, add distilled water to make up to 1000 mL, and store in a brown bottle for later use.

[0071] 2. Glucosamine hydrochloride standard solution

[0072] Accurately prepare 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, and 0.6 mg / mL glucosamine hydrochloride standard solutions.

[0073] 3. Standard curve drawing

[0074] Take 2 mL of glucosamine hydrochloride standard solution and add 1.5 mL of DNS reagent. Heat in a boiling water bath for 5 min. After cooling, dilute to 25 mL. Measure the absorbance at 540 nm and draw a standard curve with the absorbance as the ordinate and the solution concentration as the abscissa.

[0075] 4. Sample determination

[0076] Place 10-50 mg of sample in a stoppered test tube and add 2 mL of distilled water to dissolve. Then, slowly add 4 mL of concentrated sulfuric acid to the tube in an ice-water bath, cover and shake well. Hydrolyze in a 90°C water bath for 2 hours. Remove from the ice water and cool rapidly. Transfer the degradation solution to a 100 mL volumetric flask and neutralize with 10 mol / L NaOH solution in an ice-water bath until neutral. Add distilled water to the mark and shake well to prepare the test solution. Add 2 mL of the hydrolyzate to 1.5 mL of DNS reagent and heat in a boiling water bath for 5 minutes. After cooling, dilute to 25 mL and measure the absorbance at 540 nm. (The measured value should be within the range of the standard curve. If it is not within the range of the standard curve, the sample solution should be diluted accordingly and re-measured according to the method specified in this article).

[0077] 5. Result calculation

[0078]

[0079] Where:

[0080] X is the content of chitosan oligosaccharide in the sample (calculated as glucosamine hydrochloride), g / 100g; 0.994 is the conversion coefficient; m is the mass of glucosamine hydrochloride found in the standard curve, mg; f is the sample dilution factor; M is the dry weight of the sample, mg.

[0081] The test result of the permissible error shall be based on the arithmetic mean of the parallel determination results. The absolute difference between two independent determination results obtained under repeatability conditions shall not exceed 5% of the arithmetic mean.

[0082] The test results are shown in Table 2:

[0083] Table 2

[0084]

[0085] As shown in Table 2, in the absence of browning inhibitors, as shown in Comparative Examples 1 and 2, the chitosan content decreased significantly after 3 months of storage. After replacing pyrroloquinoline quinone disodium salt with other browning inhibitors, or reducing the amount of pyrroloquinoline quinone disodium salt used, as shown in Comparative Examples 3 and 4, the chitosan content decreased to a certain extent. Figure 1 The results are basically consistent with those shown in Table 1. However, when only pyrroloquinoline quinone disodium salt is used as the browning inhibitor, as shown in Comparative Example 7, the chitosan content is significantly reduced compared to when both browning inhibitors are used (Example). Therefore, from the perspective of browning inhibition alone, pyrroloquinoline quinone disodium salt is sufficiently excellent, but if the loss of chitosan content is taken into account, the effect of using pyrroloquinoline quinone disodium salt and sodium metabisulfite at the same time will be better, which can not only significantly inhibit the browning of chitosan oligosaccharide tablets, but also inhibit the attenuation of chitosan oligosaccharide.

[0086] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other manner. Any person skilled in the art may utilize the above-disclosed technical content to modify or modify the present invention into equivalent embodiments. However, any simple modifications, equivalent variations, and modifications to the above embodiments that do not depart from the technical content of the present invention and are based on the technical essence of the present invention remain within the scope of protection of the present invention.

Claims

1. A low-browning chitosan oligosaccharide tablet, characterized in that: Contains the following ingredients in parts by mass: 65-80 parts of chitosan oligosaccharide, 0-30 parts of D-mannitol, 5-12 parts of microcrystalline cellulose, 0.5-2 parts of sodium carboxymethyl starch, 2-5 parts of disodium pyrroloquinoline quinone, 0.01-0.02 parts of sodium metabisulfite, 0.5-2 parts of magnesium stearate, 0.1-3 parts of citric acid, and 0.01-0.5 parts of aspartame.

2. The chitosan oligosaccharide tablet according to claim 1, wherein The chitosan oligosaccharide tablets contain the following components in parts by mass: 65 parts of chitosan oligosaccharide, 22 parts of D-mannitol, 7 parts of microcrystalline cellulose, 1.4 parts of sodium carboxymethyl starch, 2 parts of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

3. The chitosan oligosaccharide tablet according to claim 1, wherein The chitosan oligosaccharide tablets contain the following components in parts by mass: 72 parts of chitosan oligosaccharide, 10.9 parts of D-mannitol, 10 parts of microcrystalline cellulose, 1 part of sodium carboxymethyl starch, 3.5 parts of pyrroloquinoline quinone disodium salt, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

4. The chitosan oligosaccharide tablet according to claim 1, characterized in that The chitosan oligosaccharide tablets contain the following components in parts by mass: 80 parts of chitosan oligosaccharide, 0 part of D-mannitol, 11.6 parts of microcrystalline cellulose, 0.8 part of sodium carboxymethyl starch, 5 parts of disodium pyrroloquinoline quinone, 0.01 part of sodium metabisulfite, 1 part of magnesium stearate, 1.55 parts of citric acid, and 0.04 part of aspartame.

5. The method for preparing the chitosan oligosaccharide tablet according to any one of claims 1 to 4, characterized in that: Here are the steps: The ambient temperature was controlled at 18-25°C and the humidity was controlled below 30%RH. The API, filler, binder, disintegrant, browning inhibitor, lubricant, and flavoring were mixed. The process parameters of the mixing equipment were set to: speed 8 r / min, time 20 min. The rotary tableting equipment was adjusted to a load of 600±30 mg, a pressure of 80-150 kN, and a speed of 15-30 r / min for compression molding. The blast temperature was adjusted to 45-65°C, a speed of 1-15 r / min, and an atomization pressure of 4-5 kg / cm 2 , increase weight by 2~4%, and perform coating. After coating, the slices are air-dried to obtain chitosan oligosaccharide tablets.

6. The preparation method according to claim 5, characterized in that The coating solution used for coating is: 35 parts of polyvinyl alcohol, 22 parts of ethyl cellulose, 21 parts of polyacrylic acid resin, 14 parts of triethyl citrate, and 8 parts of polysorbate 80 are dissolved in 95% alcohol (v / v) to prepare a 3% solution.

7. Application of pyrroloquinoline quinone disodium salt and sodium metabisulfite in the preparation of low-browning chitosan oligosaccharide tablets.

8. Application of pyrroloquinoline quinone disodium salt and sodium metabisulfite in reducing the loss of chitosan oligosaccharide content in chitosan oligosaccharide tablets.

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