CN105477341B - Liquid adhesive bandage and preparation method thereof - Google Patents

Abstract

The invention discloses a bletilla striata gum, wherein the mass percentage of bletilla striata polysaccharide is 60-70%, and the average molecular weight is 320-560 kDa. The invention also provides a liquid adhesive bandage and a preparation method thereof. The preparation is prepared from the following raw and auxiliary materials in parts by weight: 200-500 parts by weight of bletilla gum, 4-20 parts by volume of glycerol, 1-5 parts by volume of isopropyl myristate, 200-1000 parts by volume of ethanol, 2-10 parts by volume of p-hydroxybenzoate, 1-4 parts by volume of peppermint oil and 5-15 parts by volume of laurocapram, wherein the corresponding relation of parts by weight/parts by volume is as follows: g/mL. The bletilla striata gum is used as a film forming material, and the effects of hemostasis and antibiosis of the bletilla striata gum are utilized, so that the bletilla striata gum is particularly suitable for patients with large wounds and more bleeding, and has good clinical application prospect.

Description

Liquid adhesive bandage and preparation method thereof

Technical Field

The invention relates to a liquid adhesive bandage and a preparation method thereof, belonging to the field of medicines.

Background

The common Bletilla gum is an extract of common Bletilla medicinal materials, wherein the important component common Bletilla gum is glucomannan which is formed by polymerizing glucose and mannose by β glycosidic bonds, has biological activities of resisting inflammation, promoting blood coagulation and the like, can be used as a natural polymer material, and has the characteristics of self degradability, no irritation, no toxic or side effect, rich resources, low cost, easy obtainment and the like.

At present, the average molecular weight of bletilla striata polysaccharide in bletilla striata gum commonly used in the field of medicine is 65000-150000 kDa, the bletilla striata polysaccharide can be used as a film forming material in a pharmaceutical preparation, and although the bletilla striata polysaccharide has the advantage of good flexibility, the film forming property is poor, and the toughness is insufficient, so the bletilla striata gum is often required to be mixed with other film forming materials for use (Zhaoyongwei. research progress of bletilla striata polysaccharide [ J ] in Chinese traditional medicine science and technology, 2015, 22 (4): 51-53), which greatly limits the application of the bletilla striata gum.

In addition, the traditional adhesive bandage for wound care at present has obvious defects in the using process: the air permeability is poor; the adhesive bandage is fixed on a wound through an adhesive layer, the sealing performance is poor, microorganisms or water easily permeate into the wound, and the wound is infected and scars are too large; the wound dressings are all of a certain size, and are inconvenient to use for certain specific wound positions.

Aiming at the defects and problems existing in the use of the traditional wound plaster, a novel liquid wound plaster appears in recent years. The liquid woundplast is solvent filled in a small bottle and belongs to biomembrane forming type disinfectant. Compared with the traditional band-aid, the liquid band-aid has the advantages that: 1. applying the medicine in a smearing or spraying mode to form a protective film on the wound; 2. the waterproof and air permeability are good; 3. the traditional band-aid is difficult to use on irregular wounds, while the liquid band-aid is convenient to use, has no shape limitation and only needs to be directly smeared on the wounds; 4. the paste is not greasy when being smeared on the affected surface, does not stick to clothes and mattresses, can move freely, and is clean and dry. At present, most of film-forming materials of the liquid band-aid are artificially synthesized high-molecular polymers, and the materials have obvious advantages in the aspects of film-forming performance, toughness and the like, but have the defect of incapability of degrading. For example, CN 1561966a discloses a liquid wound plaster, which uses polyvinyl acetal as a film forming material and nano-silver as a bactericide to achieve water-proof and bacteriostatic effects. CN 102258804A provides another liquid wound plaster, the film-forming substance in the formula is polyvinyl alcohol, and in addition, bacteriostatic agent Callicarpa nudiflora is added. Except for using a high molecular polymer which is difficult to degrade, special bactericides are required to be added into the two liquid wound plasters.

In the prior art, natural high molecular compounds, such as bletilla gum, are also reported to be used as film-forming materials for preparing liquid bandages. However, since the film-forming property is poor as described above, it is necessary to use a mixture with other film-forming materials. For example, CN 104056301a discloses a liquid bandage, which comprises bletilla striata gum and poloxamer 740 as main ingredients, and through the synergistic effect of the two, the liquid bandage is endowed with the characteristics of quick hemostasis, good bactericidal effect and quick film forming.

Aiming at the defects in the prior art, the liquid adhesive bandage with good hemostatic and bactericidal effects, degradable raw materials and no side effect is developed, which is a problem to be solved urgently.

Disclosure of Invention

The invention aims to provide a bletilla striata pharmaceutical composition, which solves the problem that special bactericides are required to be added in products of the same type except for film-forming materials, and avoids the use of artificially synthesized high-molecular polymers. The invention also aims to provide a preparation method and application of the bletilla striata pharmaceutical composition.

The invention provides a bletilla striata gum, wherein the mass percentage of bletilla striata polysaccharide is 60-70%, and the average molecular weight is 320-560 kDa.

The invention provides a preparation method of the bletilla striata gum, which comprises the following steps:

a. crushing rhizoma bletillae, adding an ethanol water solution according to a material-liquid ratio of 1: 2-1: 8(w/v, g/mL), refluxing and degreasing, filtering, collecting filter residues, adding petroleum ether according to a material-liquid ratio of 1: 2-1: 8(w/v, g/mL), refluxing and degreasing, filtering, and collecting filter residues;

b. according to the common bletilla pseudobulb medicinal materials: adding water into the mixture according to the water feed-liquid ratio of 1: 40-1: 60(w/v, g/mL), stirring and extracting at the extraction temperature of 60-80 ℃, and collecting an extracting solution;

c. concentrating the extracting solution obtained according to the step b, removing protein, adding an ethanol water solution until the alcohol content reaches 40-80% (v/v) for alcohol precipitation, and collecting precipitates to obtain the bletilla gum.

Preferably, the concentration of the ethanol water solution in the step a is 95% (v/v), the material-liquid ratio is 1:5(w/v, g/mL), the reflux degreasing temperature after adding ethanol is 60 ℃, the boiling point of petroleum ether is 60-90 ℃, and the material-liquid ratio is 1:5(w/v, g/mL); b, adding water with a feed-liquid ratio of 1:50(w/v, g/mL) into the step b, and extracting at the temperature of 70 ℃; and c, deproteinizing by adopting a Sevage method, adding 95% (v/v) ethanol water solution until the alcohol content reaches 60% (v/v), and precipitating by alcohol.

The invention provides a bletilla striata gum pharmaceutical composition, which is an external preparation prepared from the bletilla striata gum and pharmaceutically acceptable auxiliary materials or auxiliary components.

Further, the bletilla rubber pharmaceutical composition is a preparation prepared from the following raw and auxiliary materials in proportion:

200-500 parts by weight of bletilla gum, 4-20 parts by volume of glycerol, 1-5 parts by volume of isopropyl myristate, 200-1000 parts by volume of ethanol, 2-10 parts by volume of p-hydroxybenzoate, 1-4 parts by volume of peppermint oil and 5-15 parts by volume of laurocapram, wherein,

the corresponding relation of the parts by weight/volume is as follows: g/mL.

Preferably, the bletilla rubber pharmaceutical composition is a preparation prepared from the following raw and auxiliary materials in parts by weight:

400 parts by weight of bletilla gum, 10 parts by volume of glycerol, 4 parts by volume of isopropyl myristate, 1000 parts by volume of ethanol, 4 parts by volume of p-hydroxybenzoate, 2 parts by volume of peppermint oil and 10 parts by volume of laurocapram, wherein,

the corresponding relation of the parts by weight/volume is as follows: g/mL.

Wherein the p-hydroxybenzoate ester is a mixture of methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate in a ratio of 1:1 (v/v).

Preferably, the preparation is a film agent, a coating agent or a spraying agent.

Further preferably, the preparation is a liquid wound plaster.

The invention provides a preparation method of the bletilla striata pharmaceutical composition, which comprises the following steps:

a. taking raw and auxiliary materials in each proportion;

b. dissolving common bletilla gum in ethanol to obtain ethanol solution;

c. and c, adding laurocapram, isopropyl myristate, glycerol, p-hydroxybenzoate and peppermint oil into the ethanol solution obtained in the step b, stirring, and uniformly mixing to obtain the composition.

Further, the step b is carried out in a thermostatic water bath at 50 ℃ while heating and stirring; the stirring speed of the step c is 300-400 rpm.

The invention provides a bletilla striata gum pharmaceutical composition, wherein the raw materials have the following functions:

the common bletilla gum is a natural film forming material, can quickly form a film to protect the wound surface, and simultaneously plays the roles of astringing to stop bleeding, reducing swelling and promoting tissue regeneration.

The ethanol is used as a dispersion medium of the film forming material, so that the film forming material is in a colloidal solution state and has a certain anticorrosion effect.

The glycerol is a plasticizer, increases the flexibility and the stretchability of the film, and has the effects of moistening the skin and preventing the skin from cracking.

Isopropyl myristate has good lubricity, and can improve the affinity of the product with skin and promote penetration.

Laurocapram is a transdermal enhancer, and can promote permeation and absorption of antibacterial and hemostatic effects in rhizoma Bletillae gum, and soften membrane to some extent.

The p-hydroxybenzoate ester is antibacterial antiseptic, and can avoid microbial contamination, and is beneficial for storage and preservation.

The peppermint oil is an aromatic, so that the product has a cool feeling and can relieve pain, and is easy to accept by patients.

The invention uses the common bletilla gum as a film forming material and utilizes the hemostatic and antibacterial effects; avoids the use of synthetic polymers, can promote the healing of wounds, reduces the generation of scars, and is non-toxic and non-irritant. The liquid adhesive bandage has good film forming property and air permeability, has no irritation, can relieve pain, and is suitable for injured skin; meanwhile, the liquid wound plaster has a remarkable hemostatic effect, is more suitable for patients with large wounds and more bleeding, and has a good clinical application prospect.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a character diagram of the bletilla gum of the present invention;

FIG. 2 is a graph of a full thickness circular wound resulting from a full skin resection of the back of a mouse;

FIG. 3 is a graph of wound healing in mice.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

Detection method

(1) Method for measuring relative molecular mass of bletilla polysaccharide

The relative molecular mass of the white and polysaccharide was determined by High Performance Gel Permeation Chromatography (HPGPC). A chromatographic column: TSK-gel G4000PWXL (7.8 mm. times.300 mm), mobile phase pure water, column temperature 30 ℃, flow rate 0.5mL/min, sample injection 20. mu.L, differential refractometer. Firstly, sequentially injecting samples of glucan series reference substances according to relative molecular masses (5, 50, 150, 410kDa and Glc) from small to large, injecting samples, drawing a standard curve by lgMw (logarithm of molecular mass) to tR (retention time) for determining retention time to obtain a linear regression equation, and calculating a determination result.

(2) Determination of bletilla gum polysaccharide content

Preparation of a test solution:

placing 1g of defatted rhizoma Bletillae powder in a 100ml conical flask, adding a certain amount of water, stirring and extracting at a certain temperature for a certain time, centrifuging the extracting solution at 1500r/min for 10min, taking 1ml of supernatant, diluting by 100 times, and preparing to obtain rhizoma Bletillae polysaccharide test solution.

Preparation of control solutions:

accurately weighing 10.55mg of anhydrous glucose dried to constant weight at 105 ℃, placing the anhydrous glucose in a 10mL volumetric flask, adding water to dissolve and dilute the anhydrous glucose to a scale, shaking up the anhydrous glucose, accurately weighing 1mL of the anhydrous glucose, placing the anhydrous glucose in the 10mL volumetric flask, adding water to dilute the anhydrous glucose to the scale, and shaking up the anhydrous glucose to obtain the anhydrous glucose-containing measuring instrument, wherein each 1mL of the anhydrous glucose-containing measuring instrument contains 105.5 mu g of the anhydrous glucose.

Preparation of 5% phenol reagent:

weighing 5.2359g of redistilled phenol, placing the redistilled phenol in a 100ml measuring flask, adding water to dissolve the redistilled phenol, fixing the volume to a scale, and shaking up to obtain the finished product.

Selection of detection wavelength:

placing 1ml of the reference solution in a test tube with a plug, adding 1ml of 5% phenol-sulfuric acid reagent in an ice-water bath, boiling the water bath for 10min, cooling to room temperature, scanning within the wavelength range of 400-600 nm, and selecting 490nm as the detection wavelength because the 490nm has the maximum absorption.

And (3) preparing a standard curve:

the measurement was performed by a sulfuric acid-phenol method, and control solutions 0.0mL, 0.6mL, 0.8mL, 1mL, 1.2mL, 1.4mL, 1.6mL, and 1.8mL were precisely measured and placed in test tubes with stoppers, diluted to 2mL, and 1mL of a 5% phenol solution was added, followed by mixing, 5mL of sulfuric acid was added rapidly, shaking was performed, cooling was performed in a cold water bath for 10min, then the absorbance (microplate reader) was measured at a wavelength of 490nm with the first portion as a blank, and a standard curve was drawn with the absorbance as ordinate and the concentration as abscissa, and y is 34.133x-0.0636(R2 is 0.9991), indicating that glucose has a good linear relationship with absorbance in the range of 63.3 μ g to 189.9 μ g.

Determination of the content of bletilla striata gum polysaccharide:

dissolving a polysaccharide sample solution in 1mL of a test tube of 10mL, adding water to 2.0mL, sequentially adding 1.0mL of 5% phenol and 5.0mL of concentrated sulfuric acid, shaking up, placing in boiling water for water bath for 10min, taking out from the ice bath for 10min, placing to room temperature, measuring absorbance at 490nm, and measuring and calculating the mass percentage of the bletilla polysaccharide.

EXAMPLE 1 preparation of a pharmaceutical composition of the invention

1. Extracting bletilla striata gum:

taking 100g of rhizoma bletillae, crushing, sieving by a No. 3 sieve, adding 500mL of 95% (v/v) ethanol water solution, carrying out reflux degreasing for 2 times at 60 ℃ for 1-2h each time, filtering, collecting filter residues, adding 500mL of petroleum ether (boiling point: 60-90 ℃) for reflux degreasing for 2h, filtering, and collecting filter residues;

adding 5000mL of water into the filter residue, stirring and extracting at 70 deg.C for 2 times (each for 2 hr), filtering, and mixing filtrates;

deproteinization using the Sevage method: putting the filtrate into a separating funnel by utilizing the characteristic that protein is denatured in organic solvents such as trichloroethane and the like, adding a mixed solution of Sevage reagent (trichloromethane: n-butanol (5:1)) with the volume of 1/3, shaking for 20min, centrifuging (1500r/min), allowing denatured protein to be located at the junction of an extracting solution and the Sevage reagent to form a layer, removing protein in the middle part, repeating for multiple times until no protein is separated out, collecting an organic layer, and concentrating;

adding 95% v/v ethanol aqueous solution until the alcohol content reaches 60% (v/v), precipitating with ethanol, collecting precipitate, sequentially washing the precipitate with anhydrous ethanol, acetone, and diethyl ether for 3 times, and removing residual organic solvent to obtain rhizoma bletilla gum 41.7 g.

Detecting three batches of rhizoma bletilla gum according to the detection methods (1) and (2), wherein the mass percentages of rhizoma bletilla polysaccharide are respectively 60%, 66.30% and 70%, and the average molecular weights are respectively 320kDa, 480kDa and 560 kDa. The properties of the bletilla striata gum are shown in figure 1.

The common bletilla gum with the mass percentage of 66.30 percent and the average molecular weight of 480kDa is used in the following all.

2. Prescription:

20g of common bletilla gum, 0.5ml of glycerol, 0.2ml of isopropyl myristate, 50ml of ethanol, 0.1ml of methyl p-hydroxybenzoate, 0.1ml of ethyl p-hydroxybenzoate, 0.1ml of peppermint oil and 0.5ml of laurocapram.

3. The preparation method comprises the following steps:

dissolving bletilla striata gum in 70% v/v ethanol water solution, heating and stirring in a constant-temperature water bath at 50 ℃, adding laurocapram, isopropyl myristate, glycerol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and peppermint oil after dissolving, stirring at the speed of 300-400rpm, and uniformly mixing to obtain the liquid wound plaster.

EXAMPLE 2 preparation of pharmaceutical compositions of the invention

The extraction of bletilla gum was the same as in example 1.

Prescription: 10g of common bletilla gum, 0.5ml of glycerol, 0.2ml of isopropyl myristate, 50ml of ethanol, 0.1ml of methyl p-hydroxybenzoate, 0.1ml of ethyl p-hydroxybenzoate, 0.1ml of peppermint oil and 0.5ml of laurocapram.

The preparation method comprises the following steps: dissolving bletilla striata gum in 70% v/v ethanol water solution, heating and stirring in a constant-temperature water bath at 50 ℃, adding laurocapram, isopropyl myristate, glycerol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and peppermint oil after dissolving, stirring at the speed of 300-400rpm, and uniformly mixing to obtain the liquid wound plaster in the example 2.

EXAMPLE 3 preparation of a pharmaceutical composition of the invention

The extraction of bletilla gum was the same as in example 1.

Prescription: 25g of common bletilla gum, 0.5ml of glycerol, 0.2ml of isopropyl myristate, 50ml of ethanol, 0.1ml of methyl p-hydroxybenzoate, 0.1ml of ethyl p-hydroxybenzoate, 0.1ml of peppermint oil and 0.5ml of laurocapram.

The preparation method comprises the following steps: dissolving bletilla striata gum in 70% v/v ethanol water solution, heating and stirring in a constant-temperature water bath at 50 ℃, adding laurocapram, isopropyl myristate, glycerol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and peppermint oil after dissolving, stirring at the speed of 300-400rpm, and uniformly mixing to obtain the liquid wound plaster in the embodiment 3.

The beneficial effects of the invention are proved by comparative examples and pharmacodynamic experiments.

Comparative example 1 preparation of liquid wound dressing by adding other film-forming materials

The preparation method of rhizoma bletilla gum is the same as example 1.

Prescription: 12g of common bletilla gum, 3g of chitosan, 0.5ml of glycerol, 0.2ml of isopropyl myristate, 50ml of ethanol, 0.1ml of methyl p-hydroxybenzoate, 0.1ml of ethyl p-hydroxybenzoate, 0.1ml of peppermint oil and 0.5ml of laurocapram.

The preparation method comprises the following steps: dissolving chitosan and bletilla hyacinthine gum in 70% v/v ethanol water solution, heating in a constant-temperature water bath at 50 ℃ while stirring, adding laurocapram, isopropyl myristate, glycerol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and peppermint oil after dissolving, stirring at 300-400rpm, and uniformly mixing to obtain the liquid wound plaster in the comparative example 1.

Experimental example 1 measurement experiment of film Forming speed

Measurement method

0.5g of the adhesive bandages prepared in example 1 and comparative examples 1-3 were applied to the skin surface and wound surface, and the time for curing and film forming was observed.

Results of the experiment

Example 1: the liquid wound plaster is applied to an affected part for 30-90 s to form a colorless transparent film.

Example 2: the liquid wound plaster is coated on the surface of the skin wound for 18 minutes to form a transparent film.

Example 3: the liquid wound plaster is coated on the surface of the skin wound for 60s to form a transparent film.

Comparative example 1: the liquid wound plaster is applied to an affected part for 30-90 s to form a colorless transparent film.

The above experiments show that: the liquid adhesive bandage can form a film on the surface of a wound in a short time, and particularly the film forming time of the liquid adhesive bandage prepared according to the embodiment 1 is only 30-90 s. The addition of other film forming materials, such as chitosan, did not significantly increase the film forming rate of the liquid wound dressing.

Experimental example 2 skin irritation test

The liquid wound dressings prepared in example 1 and comparative example 1 were applied to the arms of 20 volunteers, and the presence of redness and swelling and other abnormalities were observed at 2h, 4h, 8h, 12h, and 24h, respectively.

The experimental results are as follows: example 1 subjects with liquid wound dressings had a zero skin irritation response score; comparative example 1 subjects with liquid wound dressings occasionally experienced redness or redness.

The above experiments show that: the liquid wound plaster has no irritation, and the skin irritation of the product can be increased after other film-forming materials such as chitosan are added.

Experimental example 3 drug efficacy experiment

10 male mice with similar body weight were anesthetized with 10% chloral hydrate (dose: 0.5mL/100g) in the abdominal cavity, shaved at the back, and the back of the mice was subjected to a full-thickness excision with a 1cm biopsy punch to form a full-thickness circular wound, as shown in FIG. 2, which was divided into ① and ② groups, ① groups were applied with the liquid wound patch of example 1, and ② groups were applied with the liquid wound patch of comparative example 1. the wound healing was observed and the wound healing time was recorded at 1 day, 2 days, 5 days, and 7 days.

The results of the experiment show that ① group wounds healed first and the swelling subsided a day, ② group wounds scab 24 hours later than ① group wounds, and the comparison of the parallel experiments shows that the liquid wound plaster in example 1 has the effects of obviously shortening the treatment time, stopping bleeding and promoting wound healing, and is shown in figure 3.

The above experiments show that: the liquid wound plaster has no wound infection, and has obvious effects of stopping bleeding and promoting wound healing.

In conclusion, the liquid adhesive bandage has good film forming property and air permeability, is nonirritating, can relieve pain, and is suitable for injured skin; meanwhile, the product has obvious hemostatic effect, is more suitable for patients with larger wound and more bleeding, and has good clinical application prospect.

Claims (6)

1. The utility model provides a bletilla gum for liquid adhesive bandage, characterized by: wherein the mass percentage of the bletilla polysaccharide is 60-70%, and the average molecular weight is 320-560 kDa;

the preparation method of the bletilla striata gum comprises the following steps:

a. crushing rhizoma bletillae, adding 95% ethanol water solution according to the material-liquid ratio of 1:5 w/v and g/mL, performing reflux degreasing at 60 ℃, filtering, collecting filter residues, adding petroleum ether with the boiling point of 60-90 ℃ according to the material-liquid ratio of 1:5 w/v and g/mL, performing reflux degreasing, filtering, and collecting the filter residues;

b. according to the common bletilla pseudobulb medicinal materials: adding water into the mixture according to the water feed-liquid ratio of 1:50 w/v and g/mL, stirring and extracting at the extraction temperature of 70 ℃, and collecting an extracting solution;

c. and c, concentrating the extracting solution obtained in the step b, deproteinizing by adopting a Sevage method, adding 95% ethanol water solution until the alcohol content reaches 60% v/v, precipitating with ethanol, and collecting precipitates to obtain the bletilla striata gum.

2. A bletilla striata glue pharmaceutical composition, which is characterized in that: the bletilla striata gel is an external preparation prepared by the bletilla striata gel of claim 1 and pharmaceutically acceptable auxiliary materials or auxiliary components;

the external preparation is prepared from the following raw and auxiliary materials in proportion: 400 parts by weight of common bletilla gum, 10 parts by volume of glycerol, 4 parts by volume of isopropyl myristate, 1000 parts by volume of ethanol, 4 parts by volume of p-hydroxybenzoate, 2 parts by volume of peppermint oil and 10 parts by volume of laurocapram, wherein the corresponding relation of parts by weight/parts by volume is as follows: g/mL.

3. The pharmaceutical composition of a white gelatin as claimed in claim 2, wherein: the p-hydroxybenzoate ester is a mixture of methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate at a ratio of 1:1 v/v.

4. The pharmaceutical composition of a white gelatin as claimed in claim 2, wherein: the external preparation is a liquid wound plaster.

5. A preparation method of the bletilla striata pharmaceutical composition as claimed in any one of claims 2 to 4, which is characterized by comprising the following steps: the method comprises the following steps:

a. taking raw and auxiliary materials in each proportion;

b. dissolving common bletilla gum in ethanol to obtain ethanol solution;

c. and c, adding laurocapram, isopropyl myristate, glycerol, p-hydroxybenzoate and peppermint oil into the ethanol solution obtained in the step b, stirring, and uniformly mixing to obtain the composition.

6. The method of claim 5, wherein: b, heating in a constant-temperature water bath at 50 ℃ while stirring; the stirring speed of the step c is 300-400 rpm.

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