WO2017107627A1 - Chitosan oligosaccharide tablet and preparation method therefor - Google Patents

Abstract

A chitosan oligosaccharide tablet and preparation method therefor. The tablet comprises a chitosan oligosaccharide tablet core and a coating.

Description

Chitooligosaccharide tablet and preparation method thereof Technical field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a chitosan oligosaccharide tablet and a preparation method thereof.

Background technique

Chitosan oligosaccharides are oligosaccharides obtained by degrading chitin or chitosan, which are formed by linking 2-10 glucosamines through glycosidic bonds. They are the only basic aminopolysaccharides present in natural sugars, and have good water solubility. It is easily absorbed by the human body, safe and non-toxic, and has good biocompatibility. Its physiological activity and functional properties are significantly improved compared with chitin or chitosan. With its unique functional properties, chitooligosaccharides can be used in wastewater treatment, food industry, textile, chemical, household chemicals, agriculture, bioengineering and medicine.

Glucosamine and acetylglycine are two essential substances in the human body. The lack of these two substances can lead to a decline in human autoimmune function, leading to diseases such as hypertension, cardiovascular and cerebrovascular diseases, and cancer. Chitosan oligosaccharides are decomposed in the human body to produce these two substances. Therefore, the medical community refers to chitosan oligosaccharides as elements that keep the body alkaline after fat, protein, sugar, minerals and vitamins. Chitooligosaccharides are called The sixth element of life. Modern pharmacological research proves that chitosan oligosaccharide can improve immunity, inhibit the growth of cancer cells, promote the formation of liver and spleen antibodies, promote the absorption of calcium and minerals, proliferate bifidobacteria, lactic acid bacteria and other beneficial human flora, lower blood fat, lower blood pressure, It can be used in medicine, functional foods and other fields to lower blood sugar, regulate cholesterol, lose weight, and prevent adult diseases. The chitosan oligosaccharide has a low molecular weight and is highly hygroscopic. The solution has strong reducibility and is susceptible to oxidation reaction when exposed to air. Therefore, the stability of the tablet is low and the shelf life is short. Therefore, it is necessary to develop a stable chitosan oligosaccharide tablet to ensure the stable performance of its efficacy.

Summary of the invention

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a chitosan oligosaccharide tablet comprising a shell oligosaccharide tablet core and a coating film, wherein the shell oligosaccharide tablet core shell has a high oligosaccharide content, and the coating film It has good moisture, light, air and oxidation resistance. The chitosan oligosaccharide tablet provided by the invention has a smooth appearance, and the difference in tablet weight, hardness and friability are in compliance with the relevant regulations of the Chinese Pharmacopoeia, and the medicinal active ingredient content is high, and the dissolution property is good, which is beneficial to the absorption of the drug by the human body. It can reduce the dosage and the number of medications, and has stable physical and chemical properties and long shelf life.

In order to achieve the above object, the technical solution of the present invention is as follows:

A chitosan oligosaccharide tablet consisting of a shell oligosaccharide tablet core and a coating film composed of the following weight percentage components: chitosan oligosaccharide 85-89%, crospovidone 3 to 6%, 2 to 5% of calcium hydrogen phosphate, 3 to 8% of microcrystalline cellulose, 0.3 to 1% of magnesium stearate, and 1 to 5% of povidone K30 solution; package for use of the coating film The coating liquid is prepared from the following raw materials in parts by weight: 8 to 12 parts of pullulan, 4 to 8 parts of sodium alginate, 1 to 3 parts of polyethylene glycol, and 0.5 to 2 parts of titanium dioxide.

Further, the povidone K30 solution has a concentration of 1 to 5%, and is prepared from an ethanol solution having a volume fraction of 94 to 98%; further, the concentration of the povidone K30 solution is 3%.

Further, the content of the chitosan oligosaccharide tablet core of the chitosan oligosaccharide tablet is 95 to 98%; and the content of the coating film is 2 to 5%.

As a preferred embodiment of the present invention, the shell oligosaccharide tablet core is composed of the following components by weight: chitosan oligosaccharide 85.5%, crospovidone 4%, calcium hydrogen phosphate 4%, microcrystalline cellulose 4 %, magnesium stearate 0.5% and concentration of 3% povidone K30 solution 2%; the coating liquid used for the coating film is prepared from the following parts by weight of raw materials: 10 parts of pullulan, seaweed 6 parts of sodium, 2 parts of polyethylene glycol and 1 part of titanium dioxide.

Most of the tablet excipients are polysaccharides, which may affect the content of chitosan oligosaccharides by UV spectrophotometry. Therefore, the screening of core excipients of the present invention mainly adopts the principle of not determining the content of chitosan oligosaccharides. At the same time, under the premise that the relevant indicators meet the requirements of the Chinese Pharmacopoeia, the content of the auxiliary materials is optimized, and the content of the main drug chitosan oligosaccharide is increased. In the present invention, microcrystalline cellulose (MCC) having a small hygroscopicity is selected as a filler, and the problem of strong hygroscopicity of chitosan oligosaccharide can be solved, and the tablet core has good compressibility and moldability. Since the adhesion of chitosan oligosaccharide is relatively large, it will have a relatively large effect on the disintegration of the tablet. Therefore, calcium hydrogen phosphate (CaHPO ₄ ) which can be used as a filler or a disintegrating agent is selected as the chitosan oligosaccharide of the present invention. Another filler for tablets, in addition to CaHPO _4, can also increase the hardness of chitosan oligosaccharide tablets and improve their stability.

Pullulan is an extracellular water-soluble mucopolysaccharide similar to dextran and xanthan gum produced by fermentation of Aureobasidium pullulans. It has strong film-forming, gas barrier and plasticity, and is easily soluble. It is widely used in medicine, food, light industry, chemical industry and petroleum, etc. in water, non-toxic, harmless, colorless and tasteless. Sodium alginate, also known as sodium alginate, kelp gum, alginate, alginate, is a natural polysaccharide compound extracted from kelp or seaweed. It has good biocompatibility, stability, solubility and viscosity, and toxicity. Low and safe, it is widely used in food, medicine, textile, printing and dyeing, paper making, daily chemical and other products, as a thickener, Emulsifiers, stabilizers, binders, sizing agents, etc. In the pharmaceutical industry, sodium alginate is mainly used as a binder, a disintegrant, and a sustained release material. Polyethylene glycol is a commonly used water-soluble plasticizer, and titanium dioxide is a commonly used sunscreen for coating films. The coating film of the chitosan oligosaccharide tablet of the invention is compounded by pullulan, sodium alginate, polyethylene glycol and titanium dioxide, and can be uniformly, continuously and densely wrapped on the surface of the shell oligosaccharide tablet core, and has antioxidant capacity. It has high bulk density and high mechanical strength, and has good moisture, light and air isolation effects. It solves the problem that shell oligosaccharides are easy to absorb moisture and easily oxidize, greatly improving the stability of chitosan oligosaccharide tablets, and is beneficial to shells. Preservation of oligosaccharide tablets.

The invention also provides a preparation method of the above chitosan oligosaccharide tablet, comprising the following steps:

S1, respectively, dried chitosan oligosaccharide, crospovidone, calcium hydrogen phosphate, microcrystalline cellulose, magnesium stearate, povidone K30, pullulan, sodium alginate and titanium dioxide, finely ground, over 100 Mesh screening

S2, taking pullulan and sodium alginate, mixed with 5 to 8 times the amount of water, stirring, completely dissolved, adding polyethylene glycol and titanium dioxide, stirring uniformly, to obtain a coating liquid;

S3, the povidone K30 is dissolved in an ethanol solution, stirred, and the povidone K30 is completely dissolved to prepare a povidone K30 solution;

S4, the chitosan oligosaccharide is mixed with crospovidone, calcium hydrogen phosphate and microcrystalline cellulose by equal amount addition method, and the soft material is prepared by adding povidone K30 solution under stirring, granulating, passing through 20 mesh sieve, 38 Dry at ~42 °C, sieving, sizing, adding magnesium stearate, mixing evenly, and pressing the tablet to obtain the shell of oligosaccharide tablets;

S5, the pressed shell oligosaccharide tablet core is removed from the fine powder and placed in a coating pot for preheating, the inlet air temperature is 28-35 ° C, preheating for 25-35 min, and the coating pan speed is slowly increased to 15 rpm. The coating liquid is slowly sprayed on the surface of the rotating core; in the early stage of spraying, the hot air drying and the spraying are alternately performed, the inlet air temperature is controlled at 25 to 35 ° C, the coating pan speed is 15 rpm, and the coating process is performed. The temperature of the bed is kept constant. After the surface of the coating film is formed, continuous spraying is carried out until the film is weighted to the specified weight. After the spraying, the film is further dried by hot air for 8 to 12 minutes, then cooled to room temperature, and the cloth is wrapped. The tablets were dried in an oven at 40 ° C for 1 h to obtain chitosan oligosaccharide tablets.

Therefore, the advantages of the present invention over the prior art are:

(1) The chitosan oligosaccharide tablet provided by the invention has a smooth appearance, and the indexes of tablet weight difference, hardness and friability are in compliance with the relevant regulations of the Chinese Pharmacopoeia; at the same time, the pharmaceutical active ingredient is high, the dissolution property is good, and the physical and chemical properties are stable. On the one hand, it can increase the bioavailability of chitosan oligosaccharides, reduce the amount of drug used and the number of drugs used, and on the other hand, extend the shelf life of tablets.

(2) The chitosan oligosaccharide tablet of the invention has simple formula and easy availability of raw materials, and has simple preparation method, stable process and can be popularized and applied.

detailed description

The invention is further described below by way of specific embodiments, but the invention is not limited to the following examples. It is obvious to those skilled in the art that the chitosan oligosaccharide tablets of the present invention are suitably modified and replaced with the same efficacy within the scope of the present invention or without departing from the scope, spirit and scope of the present invention. They are all considered to be included in the scope of the present invention.

The inventive examples 1 to 4 of the chitosan oligosaccharide tablets are composed of the components in the following table by weight percentage:

Preparation method of the shell oligosaccharide tablets of the embodiments 1 to 4 of the present invention:

S1, respectively, dried chitosan oligosaccharide, crospovidone, calcium hydrogen phosphate, microcrystalline cellulose, magnesium stearate, povidone K30, pullulan, sodium alginate and titanium dioxide, finely ground, over 100 Mesh screening

S2, taking pullulan and sodium alginate, mixed with 6 times the weight of water, stirring, completely dissolved, adding polyethylene glycol and titanium dioxide, stirring uniformly, to obtain a coating liquid;

S3, the povidone K30 is dissolved in an ethanol solution, stirred, and the povidone K30 is completely dissolved to prepare a povidone K30 solution;

S4, the chitosan oligosaccharide is mixed with crospovidone, calcium hydrogen phosphate and microcrystalline cellulose by equal amount addition method, and the soft material is prepared by adding povidone K30 solution under stirring, granulating, passing through 20 mesh sieve, 40 Dry at °C, sieving, granulating, adding magnesium stearate, mixing evenly, and tableting to obtain the shell of oligosaccharide tablets;

S5, the pressed shell oligosaccharide tablet core is removed from the fine powder and placed in a coating pan for preheating, the inlet air temperature is 30 ° C, preheating for 30 min, the coating pan speed is slowly increased to 15 rpm, with the The coating liquid is slowly sprayed on the rotation The core surface of the core; in the early stage of spraying, hot air drying and spraying alternately, the inlet air temperature is controlled at 30 ° C, the coating pan speed is 15 rpm, and the film bed temperature is kept constant during the coating process, after the surface forms a coating film, Continuous spraying until the film weight gain to the specified weight, after the spraying, continue to dry with hot air for 10 minutes, then cooled to room temperature, and the coated tablets were placed in an oven at 40 ° C for 1 h to obtain a shell. Oligosaccharide tablets.

Comparative example one

This comparative formula: the tablet core consists of the following weight percentage components: chitosan oligosaccharide 85.5%, crospovidone 4%, microcrystalline cellulose 8%, magnesium stearate 0.5%, povidone K30 solution 2%; coating film formulation is the same as in Example 1.

This comparative example preparation method is referred to the production method of Example 1 of the present invention.

Comparative example two

The formulation of the comparative example: the core of the formulation is the same as that of the embodiment 1; the coating film is prepared from the following raw materials by weight: 10 parts of hydroxypropyl methylcellulose, 6 parts of sodium alginate, 2 parts of polyethylene glycol and 1 part of titanium dioxide.

This comparative example preparation method is referred to the production method of Example 1 of the present invention.

Test Example 1 Determination of Dissolution of Chitosan Oligosaccharide Tablets of the Present Invention

1. Test materials: The shell oligosaccharide tablets prepared in Example 1 of the present invention, the inventive examples 1-4, and Comparative Examples 1 and 2.

2. Test method: Take 6 tablets of chitosan oligosaccharide tablets, according to the test method of the second method (plasma method) of the XC dissolution test method of the Chinese Pharmacopoeia (2010 edition), with 900 mL vacuum degassed water as dissolution. Medium, test temperature 37 °C ± 0.5 °C, rotation speed 50r / min, 5,10,15,20,30,45,60,90min, sample 5mL, filter with 0.45μm microporous membrane, add after each sample, etc. Amount of dissolution medium. The absorbance of the filtrate was measured by the phenol sulfuric acid method, and the cumulative release percentage of chitosan oligosaccharides was calculated.

3. Test results: See Table 1.

Table 1 Results of dissolution measurement of chitosan oligosaccharide tablets of the present invention

Time/min	0	5	10	15	20	30	45	60	90
Example 1 core	0	66%	84%	91%	98%	99%	99.9%	99.9%	99.9%
Example 1	0	52%	66%	83%	90%	99%	99.9%	99.9%	99.9%
Example 2	0	48%	61%	79%	87%	94%	99.9%	99.9%	99.9%
Example 3	0	32%	58%	74%	87%	90%	99.9%	99.9%	99.9%
Example 4	0	36%	64%	78%	90%	97%	99.9%	99.9%	99.9%
Comparative example 1	0	twenty one%	42%	51%	66%	81%	92%	96%	98%
Comparative example 2	0	17%	31%	45%	59%	67%	78%	85%	93%

From the results of Table 1, it can be seen that the shell oligosaccharide tablets prepared in Examples 1 to 4 of the present invention have a dissolution rate of 85% at or above 20 minutes, and almost completely dissolved in 45 minutes, and the shell oligosaccharide has good dissolution performance. The dissolution time of the chitosan oligosaccharide tablets prepared in Comparative Example 1 and Comparative Example 2 was significantly prolonged, indicating that the composition and ratio of the core and coating liquid of the chitosan oligosaccharide tablet of the present invention are reasonable, and contribute to chitosan oligosaccharide. Dissolution.

Test Example 2: Performance test of the chitosan oligosaccharide tablet of the present invention

1. Test materials: the core tablets of the inventive example 1, the inventive examples 1-4, and the chitosan oligosaccharides prepared by the comparative examples 1 and 2.

2, detection method:

According to the relevant test methods and regulations of the Chinese Pharmacopoeia (2010 edition), the appearance properties, sheet weight difference, hardness and friability of the test materials were tested and judged.

3. Test results: See Table 2.

Table 2 Performance test results of the chitosan oligosaccharide tablets of the present invention

	Exterior	Slice weight difference	hardness	Brittleness
Film core of Example 1	+	+	>100N	+
Example 1	+	+	>100N	+
Example 2	+	+	>100N	+
Example 3	+	+	>100N	+
Example 4	+	+	>80N	+
Comparative example 1	Sticky	+	>50N	+
Comparative example 2	+	+	>70N	+

Note: “+” means qualified; “—” means unqualified.

It can be seen from the results of Table 2 that the appearance traits, the difference in tablet weight, the hardness and the friability of the chitosan oligosaccharide tablets prepared in Examples 1-4 of the present invention are in compliance with the relevant provisions of the Chinese Pharmacopoeia (2010 edition), and Comparative Example 1 The prepared chitosan oligosaccharide tablets have a sticking phenomenon, and the hardness thereof is small, indicating that the composition and ratio of the excipients of the chitosan oligosaccharide tablet core of the invention are reasonable.

Test Example 3: Stability test of the chitosan oligosaccharide tablet of the present invention

Refer to the Chinese Pharmacopoeia (2010 edition) two appendix XIXC drug substance and pharmaceutical preparation stability test guidelines, the core of the invention 1st, the inventive examples 1-4 and the comparative example 2 shell Oligosaccharide tablets were subjected to accelerated tests and stability tests. The investigation items included appearance traits, chitosan oligosaccharide content, related substances and hardness. All the inspection items were in compliance with the Pharmacopoeia regulations and were considered as passing. If one or more items did not meet the requirements of the Pharmacopoeia, they were deemed to have failed. The results are shown in Tables 3 and 4.

Table 3 Accelerated test results of the chitosan oligosaccharide tablets of the present invention

Note: “+” means qualified; “—” means unqualified.

Table 4 Long-term test results of the chitosan oligosaccharide tablets of the present invention

Note: “+” means qualified; “—” means unqualified.

According to this test example:

The physicochemical properties of the chitosan oligosaccharide tablets of Examples 1 to 4 of the present invention are stable and have a long shelf life. The tablet core of Example 1 was compared with the tablet stability test result of Example 1, and the results showed that the stability of the tablet after coating was clear. It is superior to the tablet core; the chitosan oligosaccharide tablet prepared by the comparative example 2 is compared with the chitosan oligosaccharide tablet prepared by the inventive examples 1-4, and the stability of the chitosan oligosaccharide tablet prepared by the invention is stable. The property is superior to the comparative example, and the shelf life is longer, indicating that the composition and ratio of the coating film of the invention are reasonable, and the stability of the chitosan oligosaccharide tablet can be effectively improved.

Claims (7)

1. A chitosan oligosaccharide tablet characterized by comprising a shell oligosaccharide tablet core and a coating film, the shell oligosaccharide tablet core being composed of the following weight percentage components: chitosan oligosaccharide 85 to 89%, 3 to 6% of vidoketone, 2 to 5% of calcium hydrogen phosphate, 3 to 8% of microcrystalline cellulose, 0.3 to 1% of magnesium stearate, and 1 to 5% of povidone K30 solution; The coating liquid used for the film is mainly prepared from the following raw materials by weight: 8 to 12 parts of pullulan, 4 to 8 parts of sodium alginate, 1 to 3 parts of polyethylene glycol, and 0.5 to 2 parts of titanium dioxide.
2. The chitosan oligosaccharide tablet according to claim 1, wherein the shell oligosaccharide tablet core is composed of the following components by weight: chitosan oligosaccharide 85.5%, crospovidone 4%, calcium hydrogen phosphate 4%, microcrystalline cellulose 4%, magnesium stearate 0.5% and povidone K30 solution 2%.
3. The chitosan oligosaccharide tablet according to claim 2, wherein the povidone K30 solution has a concentration of from 1 to 5% and is prepared from an ethanol solution having a volume fraction of 94 to 98%.
4. The chitosan oligosaccharide tablet according to claim 3, wherein the povidone K30 solution has a concentration of 3%.
5. The chitosan oligosaccharide tablet according to claim 1, wherein the coating liquid used for the coating film is prepared from the following raw materials by weight: 10 parts of pullulan, 6 parts of sodium alginate, and poly 2 parts of ethylene glycol and 1 part of titanium dioxide.
6. The chitosan oligosaccharide tablet according to any one of claims 1 to 5, wherein the content of the chitosan oligosaccharide tablet core of the chitosan oligosaccharide tablet is 95 to 98%; and the content of the coating film is 2 to 5%.
7. A method of preparing a chitosan oligosaccharide tablet according to claim 1, comprising the steps of:

   S1, respectively, dried chitosan oligosaccharide, crospovidone, calcium hydrogen phosphate, microcrystalline cellulose, magnesium stearate, povidone K30, pullulan, sodium alginate and titanium dioxide, finely ground, over 100 Mesh screening

   S2, taking pullulan and sodium alginate, mixed with 4-6 times the weight of water, stirring, completely dissolved, adding polyethylene glycol and titanium dioxide, stirring uniformly, to obtain a coating liquid;

   S3, the povidone K30 is dissolved in an ethanol solution, stirred, and the povidone K30 is completely dissolved to prepare a povidone K30 solution;

   S4, the chitosan oligosaccharide is mixed with crospovidone, calcium hydrogen phosphate and microcrystalline cellulose by equal amount addition method, and the soft material is prepared by adding povidone K30 solution under stirring, granulating, passing through 20 mesh sieve, 38 Dry at ~42 °C, sieving, sizing, adding magnesium stearate, mixing evenly, and pressing the tablet to obtain the shell of oligosaccharide tablets;

   S5, the pressed shell oligosaccharide tablet core is removed from the fine powder and placed in a coating pot for preheating, the inlet air temperature is 28-35 ° C, preheating for 25-35 min, and the coating pan speed is slowly increased to 15 rpm. The coating liquid is slowly sprayed on the surface of the rotating core; in the early stage of spraying, the hot air drying and the spraying are alternately performed, the inlet air temperature is controlled at 25 to 35 ° C, the coating pan speed is 15 rpm, and the coating process is performed. The temperature of the bed is kept constant. After the surface of the coating film is formed, continuous spraying is carried out until the film is weighted to the specified weight. After the spraying, the film is further dried by hot air for 8 to 12 minutes, then cooled to room temperature, and the cloth is wrapped. The tablets were dried in an oven at 40 ° C for 1 h to obtain chitosan oligosaccharide tablets.