CN100379763C - Crosslinked Poria cocos polysaccharide and its preparation method and application - Google Patents

Abstract

The invention relates to cross-linked pachyrhythmic polysaccharide and its preparation method and application. The cross-linked polysaccharide is prepared by the following method: the polysaccharide is mixed with water or alcohol 2-5 times the mass of the polysaccharide to obtain a mixed solution, the pH value is adjusted between 9 and 11, and 0.1%-0.5% of the mass of the polysaccharide is added Epichlorohydrin, cross-linking reaction at 35-45 DEG C for 6-10 hours, and then neutralizing, filtering, washing, and freeze-drying to obtain cross-linked pachyrhin. The cross-linked poria cocos polysaccharide of the invention has good fluidity, strong water absorption, high bulk density and expansibility, and can be used as an excellent high-efficiency disintegrant. The cross-linked polysaccharide is evenly dispersed in powder form during the disintegration process, which increases the disintegration ability of the tablet and improves the disintegration efficiency of the tablet.

Description

Crosslinked Poria cocos polysaccharide and its preparation method and application

Technical field:

The invention relates to cross-linked pachyrhythmic polysaccharide and its preparation method and application.

Background technique:

Pharmaceutical excipients are the material basis for the existence of pharmaceutical preparations and the necessary materials for the production of pharmaceutical preparations. Therefore, all countries in the world attach great importance to the development of new pharmaceutical excipients.

Tablets are the most widely used oral solid preparations. To improve the quality of tablets, choosing good excipients is the key. Fillers and disintegrants are the most important excipients in ordinary tablets, and the selection of these excipients directly affects the internal quality of the tablet and the curative effect of the drug. At present, the commonly used auxiliary materials mainly include starch, cellulose, alginic acid, clay, PVP, gum and so on.

With the development of pharmaceutical preparations in the direction of "three effects" (high-efficiency, quick-acting, long-acting) and "three small" (low toxicity, small side effects, small dose), new excipients, especially those with good sustained-release and controlled-release The development of natural pharmaceutical excipients with different effects is more meaningful, and the research on the development of natural polymer polysaccharides is particularly eye-catching and has broad prospects.

Poria cocos is the dried sclerotia of Polyporaceae plant Poria cocos (Schw.) Wolf. Its structure is a kind of glucan whose main chain is connected by linear β(1→3) glycosidic bonds, and the branch chain is connected by 9 to 10 outer glucose residues through β(1→6) glycosidic bonds. It has a starch-like polymer polysaccharide structure. Poria cocos is a traditional Chinese medicine. Many scholars have conducted extensive research on it, but a large number of experiments have proved that the pharmacological effect of Poria cocos polysaccharide as an anti-tumor drug is not obvious. Therefore, trying to develop Poria cocos polysaccharide as a natural polymer excipient has great feasibility, innovation and broad application prospects.

Invention content:

The object of the present invention is to provide a kind of cross-linked pachymans and its preparation method and application. The obtained cross-linked pachyrans is used as tablet disintegrating agent, and it is evenly dispersed in powder form during the disintegration process, which can increase the disintegration of tablets. Disintegration ability, improve tablet disintegration efficiency.

The technical solution provided by the present invention is: cross-linked polysaccharide, which is obtained by the following method: mix polysaccharide with water or alcohol 2-5 times the quality of polysaccharide to obtain a mixed solution, adjust the pH value between 9 and 11, and add the quality of polysaccharide 0.1%-0.5% epichlorohydrin, cross-linking reaction at 35-45 ° C for 6-10 hours, then neutralize, filter, wash, and freeze-dry to obtain cross-linked pachyrhin; or, grind Poria cocos sclerotia into 60 -200 mesh powder, dissolved in 0.5-5wt% sodium hydroxide or potassium hydroxide solution, the temperature is controlled at 0°C-5°C, stirred until thick, left for 10-20 hours, filtered to obtain the filtrate, adjust the pH value Between 9 and 11, add 0.05%-0.25% epichlorohydrin based on the mass of Poria cocos sclerotia powder, conduct a cross-linking reaction at 35-45°C for 6-10 hours, then neutralize, filter, wash, and freeze-dry to obtain cross-linking Poria cocos polysaccharide.

The cross-linked Poria cocos polysaccharide in the new polymer pharmaceutical excipient described in the present invention is a derivative of Poria cocos with β (1 → 3) glycosidic bonds as the main chain and β (1 → 6) glycosidic bonds as branched chains. It can be used as a tablet disintegrant.

The method for measuring the degree of cross-linking of the cross-linked pachyranan prepared by the present invention adopts the sedimentation method. For specific methods, refer to Zhang Yousong, Handbook of Production and Application of Modified Starch [M], Beijing: China Light Industry Press, 1999.

The present invention studies its application performance by investigating different aspects of the prepared cross-linked pachyrhin:

1. Investigate the swelling property of cross-linked pachymansin.

2. The fluidity of the prepared cross-linked pachyranan was investigated by the fixed cone bottom method.

3. Investigate the bulk density of the prepared cross-linked pachyrhin by the free fall method of the fixed frame.

4. The prepared cross-linked pachymane was applied to the disintegrant of calcium sulfate blank tablet, and its disintegration characteristics were investigated.

Cross-linked pachyranan can be used in wet granulation in tablets, or it can be added to dry granules. The external addition method can be adopted for tablets that are difficult to disintegrate hydrophobic drugs; the internal addition method can be used for tablets that are difficult to form;

The above experimental research shows that the cross-linked polysaccharide has good fluidity and can meet the basic needs of tablet production. In addition, the cross-linked Poria cocos polysaccharide has strong water absorption, high bulk density and expansibility, and is evenly dispersed in powder form during the disintegration process, which increases the disintegration ability of the tablet and improves the disintegration efficiency of the tablet. Therefore, the novel high molecular pharmaceutical excipient cross-linked polysaccharide of the present invention is an excellent high-efficiency disintegrant.

Detailed ways:

The following examples further illustrate the invention.

Example 1: Preparation of Crosslinked Pachyranan 1

1. Preparation of Poria cocos polysaccharide

Grind commercially available fresh Poria cocos sclerotium into powder, pass through a 60-mesh sieve, take 600 g and dissolve in 0.5 wt% NaOH solution (the mass ratio of Poria cocos powder to NaOH solution is 1:100), and the temperature is controlled at 0°C to 5°C. ℃, stirred until thick, left overnight, filtered with suction to obtain the filtrate, then neutralized the filtrate with 10% acetic acid, placed overnight at 0°C to 5°C, filtered with suction to obtain a white precipitate, washed the precipitate with water, ethanol, and acetone ethyl ether in sequence, at 20°C Dried at ~50°C to obtain pachyphyllin.

2. Preparation of Cross-linked Pachyranan 1

Add 2 times of the quality of pachyrhynch in 30g of pachyrhiza, after stirring evenly, add 5% aqueous sodium hydroxide solution to make the pH of the whole system be 9, stir mechanically, add 0.1% of the mass of pachycarp when the reaction temperature reaches 35°C Epichlorohydrin, cross-linking reaction for 6 hours, and then use 1mol/L dilute sulfuric acid to neutralize the reaction product to a pH value of 5-6, filter, wash, and freeze-dry to obtain a sedimentation volume of 7.1 mL of cross-linked pachyrhin 1.

Embodiment two: the preparation of cross-linked pachymansin 2

Grind commercially available fresh Poria cocos sclerotium into powder, pass through a 60-mesh sieve, take 60g and dissolve in 2wt% sodium hydroxide solution (the mass ratio of Poria cocos powder to NaOH solution is 1: 100), and the temperature is controlled at 0° C. 5°C, stirred until thick, left overnight, suction filtered to obtain the filtrate, adjusted the pH value to 10, mechanically stirred, when the reaction temperature reached 35°C, added 0.03 g of epichlorohydrin, cross-linked for 8 hours, and then used 1mol/ 1 L of dilute sulfuric acid neutralized the reaction product to a pH value of 5-6, filtered, washed, and freeze-dried to obtain cross-linked pachyan 2 with a sedimentation volume of 6.9 mL.

Embodiment 3: Preparation of cross-linked pachymansin 3

Add 5 times the quality of pachyrhizan in 30g pachyrhizan (commercially available), after stirring evenly, add 5% sodium hydroxide aqueous solution, make the pH of the whole system be 11, stir mechanically, add pachyrhin when the reaction temperature reaches 45°C 0.1% epichlorohydrin by mass, cross-linking reaction for 10 hours, and then neutralize the reaction product with 1mol/L dilute sulfuric acid to a pH value of 5-6, filter, wash, freeze-dry to obtain a sedimentation volume of 6.7mL Cross-linked pachymansin3.

Embodiment 4: Preparation of cross-linked pachymansin 4

Add 5 times the alcohol of pachyrhizan quality in 30g pachyrhiza (preparation of pachyrhin is the same as in Example 1), after stirring evenly, add 5% aqueous sodium hydroxide solution to make the pH value of the whole system 10, mechanically stir, and the reaction temperature reaches At 35°C, add 0.2% epichlorohydrin based on the mass of the polysaccharide, cross-link for 10 hours, then use 1mol/L dilute sulfuric acid to neutralize the reaction product to a pH value of 5-6, filter, wash, and freeze-dry to obtain The sedimentation volume was 6.6 mL of cross-linked pachyranan 4.

Embodiment 5: Preparation of cross-linked pachymansin 5

Add alcohol with 2 times the quality of pachyrhiza in 30g of pachyrhizan (commercially available), stir evenly, add 5% sodium hydroxide aqueous solution, make the pH of the whole system be 11, stir mechanically, add pachyrhin when the reaction temperature reaches 40°C 0.2% epichlorohydrin by mass, cross-linking reaction for 6 hours, then neutralize the reaction product with 1mol/L dilute sulfuric acid to a pH value of 5-6, filter, wash, freeze-dry to obtain a sedimentation volume of 6.5mL Cross-linked pachyranan 5.

Embodiment 6: Preparation of cross-linked pachymansin 6

Add water or alcohol with 2 times the quality of pachyphyllin (commercially available) in 30g pachyphyllum, after stirring evenly, add a certain volume of 5% sodium hydroxide aqueous solution to make the pH value of the whole system 9, mechanically stir, and the reaction temperature reaches 45 Add 0.2% epichlorohydrin of the mass of pachyphyllin at ℃, cross-linking reaction for 8 hours, then neutralize the reaction product with 1mol/L dilute sulfuric acid to a pH value of 5-6, filter, wash, and freeze-dry to obtain sedimentation Cross-linked pachyranan 6 with a volume of 6.3 mL.

Embodiment 7: Preparation of cross-linked pachymansin 7

1. The preparation of Poria cocos polysaccharide: commercially available fresh Poria cocos sclerotium is ground into powder, crosses 200 mesh sieves, gets 600g to be dissolved in the KOH solution of 5wt% (the consumption mass ratio of Poria cocos powder and KOH solution is 1: 200), temperature Control the temperature at 0°C to 5°C, stir until thick, leave overnight, and obtain the filtrate by suction filtration, then neutralize the filtrate with 10% acetic acid, place it at 0°C to 5°C overnight, and obtain white precipitate by suction filtration, followed by water, ethanol, acetone The precipitate was washed with ether, and dried at 20°C to 50°C to obtain pachyrhin.

2. Preparation of Crosslinked Pachyranan 7

Add 5 times the alcohol of the quality of the polysaccharide in 30g of the polysaccharide, after stirring evenly, add 5% sodium hydroxide aqueous solution, make the pH value of the whole system be 11, stir mechanically, add 0.5% of the quality of the polysaccharide when the reaction temperature reaches 35°C Epichlorohydrin, cross-linking reaction for 8 hours, and then use 1mol/L dilute sulfuric acid to neutralize the reaction product to a pH value of 5-6, filter, wash, and freeze-dry to obtain a sedimentation volume of 6.1 mL of cross-linked pachyrhin 7.

Embodiment 8: Preparation of cross-linked pachymansin 8

Grind commercially available fresh Poria cocos sclerotium into powder, pass through a 200 mesh sieve, take 60g and dissolve in 5wt% potassium hydroxide solution (the mass ratio of Poria cocos powder to KOH solution is 1:200), and the temperature is controlled at 0°C- 5°C, stirred until thick, left overnight, suction filtered to obtain the filtrate, adjusted the pH to 9, mechanically stirred, when the reaction temperature reached 45°C, added 0.15 g of epichlorohydrin, cross-linked for 10 hours, and then used 1mol/ The reaction product was neutralized with 1 L of dilute sulfuric acid to a pH value of 5-6, filtered, washed, and freeze-dried to obtain cross-linked pachyan 8 with a sedimentation volume of 5.9 mL.

Embodiment 9: Preparation of cross-linked pachymansin 9

Add 3 times the water or alcohol of the quality of the polysaccharide in 30g of the polysaccharide (the preparation of the polysaccharide is the same as in Example 8), after stirring evenly, add 5% aqueous sodium hydroxide solution to make the pH value of the whole system 10, mechanically stir, and react When the temperature reaches 45°C, add 0.5% epichlorohydrin based on the mass of the polysaccharide, cross-link for 6 hours, then neutralize the reaction product with 1mol/L dilute sulfuric acid to a pH value of 5-6, filter, wash, and freeze Dry to obtain cross-linked pachymane 9 with a sedimentation volume of 6.0 mL.

Study on Swellability of Crosslinked Poria Cocos Polysaccharide

The inventor added 1 g of the cross-linked pachyrhin sample to a 50 ml measuring cylinder, added 50 ml of distilled water, and vibrated vigorously to completely suspend the powder in the water, repeat the vibration once after an interval of 10 min, and remove the supernatant after standing for 48 h to measure the sample after water absorption. volume of. The swelling property of cross-linked pachymansin was characterized by the volume data (average value of 5 identical experiments) of 1 g sample after fully absorbing water.

Table 1 Comparison of fluidity of several disintegrants

Sample name Volume after water absorption (mL)

PVPP 7.5

CMS-Na 19.5

L-HPC 9.5

Starch No significant swelling

Cross-linked pachymansin 1 28.0

Cross-linked pachyranan 2 32.8

Cross-linked pachymansin 3 30.1

Cross-linked pachymansin 4 20.2

Cross-linked pachyan 5 29.0

Cross-linked pachyranan 6 24.5

Cross-linked pachymansin 7 23.8

Cross-linked pachymansin 8 19.7

Cross-linked pachymansin 9 21.5

Study on Fluidity of Crosslinked Poria Cocos Polysaccharide

The inventor adopts the fixed conical bottom method, the diameter of the bottom is 3.5cm, the diameter of the funnel outlet is 1.3cm, the length of the outlet pipe is 5.8cm, and the height between the pipe end and the bottom is 4.5cm. The fluidity of several different disintegrants was compared, and the results are shown in Table 2.

Table 2 Comparison of fluidity of several disintegrants

Sample name Angle of repose (degrees)

PVPP 29.7

CMS-Na 34.6

L-HPC 61.7

Starch 50.8

Cross-linked Poria cocos polysaccharide series (1～9) 29.7～31.3

Study on Bulk Density of Crosslinked Poria Cocos Polysaccharide

The inventor adopts a 100ml measuring cylinder, takes 30g of each sample, and the drop height is 15.1cm, and vibrates 5 times in a free fall mode in a fixed frame for relative comparison. (Data is the average of 3 times)

Table 2 Comparison of bulk density of several disintegrants

Sample Name Volume (ml) ³ Bulk Density (g/ml)

PVPP 83.0 0.36

CMS-Na 53.3 0.56

L-HPC 68.1 0.44

Starch 53.0 0.57

Cross-linked Poria cocos polysaccharide series (1～9) 59～66 0.45～0.51

Study on Disintegration Characteristics of Blank Tablets with Crosslinked Poria Cocos Polysaccharide

The inventors used calcium sulfate to prepare blank model sheets. The consumption of disintegrating agent is all 5%, adopts the method for internally adding disintegrating agent and equal amount 3% HPMC slurry wet granulation, adds 0.5% magnesium stearate, is compressed into the plain tablet of diameter 10mm with single-punch tablet machine. Several different disintegrants were compared, and the results are shown in Table 3.

Table 3 Comparison of disintegration time of several disintegrants

Disintegrant Hardness (kg) Disintegration time (s±SD)

Calcium sulfate blank 4.50 ＞1800

PVPP 4.49 193±34.5

CMS-Na 4.06 155±19.9

L-HPC 5.96 393±22.8

Starch 5.01 444±56.7

Cross-linked polysaccharide 1 5.17 77±12.8

Cross-linked pachyranan 2 4.36 76±8.6

Cross-linked pachymansin 3 4.22 98±13.3

Cross-linked polysaccharide 4 4.58 33±6.4

Cross-linked pachyranan 5 4.50 29±2.8

Cross-linked pachyranan 6 4.70 61±3.4

Cross-linked pachymansin 7 5.32 52±7.7

Cross-linked polysaccharide 8 5.30 121±25.2

Cross-linked pachymansin 9 5.93 49±3.7

The cross-linked pachyrhin has good fluidity and can meet the basic needs of tablet production. In addition, the cross-linked Poria cocos polysaccharide has strong water absorption, high bulk density and expansibility, and is evenly dispersed in powder form during the disintegration process, which increases the disintegration ability of the tablet and improves the disintegration efficiency of the tablet.

Claims (4)

1. cross-linked pachyman, made by laxative remedy: the water of Pachymose and 2-5 times of Pachymose quality or alcohol mix and obtain mixed solution, between the adjust pH 9～11, the epoxy chloropropane that adds the 0.1%-0.5% of Pachymose quality, at 35-45 ℃ of crosslinking reaction 6-10 hour, neutralize then, filter, washing, lyophilize obtain cross-linked pachyman; Perhaps, poria cocos sclerotium is worn into 60-200 order powder, be dissolved in the sodium hydroxide or potassium hydroxide solution of 0.5-5wt%, temperature is controlled at 0 ℃～5 ℃, is stirred to thick shape, placed 10-20 hour, suction filtration obtains filtrate, between the adjust pH 9～11, adds the epoxy chloropropane of the 0.05%-0.25% of poria cocos sclerotium powder quality, at 35-45 ℃ of crosslinking reaction 6-10 hour, neutralize then, filter, washing, lyophilize obtain cross-linked pachyman.

2. the preparation method of the described cross-linked pachyman of claim 1, it is characterized in that: the water of Pachymose and 2-5 times of Pachymose quality or alcohol mix and obtain mixed solution, the epoxy chloropropane that adds the 0.1%-0.5% of Pachymose quality in the mixed solution, between pH value 9～11,35-45 ℃ crosslinking reaction 6-10 hour, neutralize then, filter, washing, lyophilize obtain cross-linked pachyman.

3. the preparation method of the described cross-linked pachyman of claim 1, it is characterized in that: poria cocos sclerotium is worn into 60-200 order powder, be dissolved in the sodium hydroxide or potassium hydroxide solution of 0.5-5wt%, temperature is controlled at 0 ℃～5 ℃, be stirred to thick shape, placed 10-20 hour, suction filtration obtains filtrate, between the adjust pH 9～11, the epoxy chloropropane that adds the 0.05%-0.25% of poria cocos sclerotium powder quality, at 35-45 ℃ of crosslinking reaction 6-10 hour, neutralize then, filter, washing, lyophilize obtain cross-linked pachyman.

4. the described cross-linked pachyman of claim 1 is as the application of disintegrating agent in the preparation medicinal tablet.