CN105255173B - A kind of preparation method for being crosslinked polyglutamic acid hydrogel - Google Patents

Abstract

Polyglutamic acid hydrogel and preparation method thereof is crosslinked the present invention relates to a kind of dispersed low concentration of stabilization.Comprise the following steps：γ polyglutamic acid blob of viscoses are first prepared using high concentration cross-linked formulation, then add aqueous solution homogenate and are crushed, the stabilization of crosslinking polyglutamic acid, dispersed low concentration of water gel is obtained.The stable and uniform of the present invention disperses the preparation method that low concentration is crosslinked polyglutamic acid hydrogel, and step is few and product characteristics are stable, suitable for industrialized production and application；The concentration of crosslinking polyglutamic acid in product is controlled, the series of products of viscosity raising, the easy aquation of product can be obtained and be able to uniformly smear and disperse in skin surface, in skin surface without sticky or phenomenon of flaking.

Description

A kind of preparation method of cross-linked polyglutamic acid hydrogel

technical field

The invention relates to a cross-linked polyglutamic acid hydrogel, in particular to a stable low-concentration cross-linked polyglutamic acid hydrogel in a uniform dispersion state and a preparation method thereof.

Background technique

γ-polyglutamic acid hydrogel is a polymer network that cross-links γ-polyglutamic acid (hereinafter referred to as polyglutamic acid) molecules and can maintain a large amount of water without dissolving after swelling in water. Wang Jingxin et al. (Progress in research and application of γ-polyglutamic acid hydrogel, Microbiology Bulletin, 2014) introduced that the cross-linking preparation methods of polyglutamic acid hydrogel include radiation and chemical cross-linking methods. Compared with radiation crosslinking, chemically crosslinked polyglutamic acid hydrogels have better performance and wider application. Due to its good water absorption and water retention, cross-linked polyglutamic acid can be used as a pharmaceutical carrier, wound dressing and soil water retention agent.

Zhuang Huahong et al. (Preparation, properties and application of γ-polyglutamic acid hydrogel, Applied Chemistry, 2014), systematically introduced the preparation method of polyglutamic acid hydrogel, that is, using glycidyl ether as a crosslinking agent Preparation method of polyglutamic acid hydrogel. Specifically, in the method of cross-linking with ethylene glycol glycidyl ether, the reaction at 60°C is selected for 44-48h; in the method of cross-linking of polyethylene glycol glycidyl ether, the reaction is selected at 60°C for about 40h; In the method of alcohol diglycidyl ether cross-linking, a 60°C water bath shaker was used to react for 48 hours. This type of method does not require activation and organic solvents, and polyglutamic acid hydrogels with different water absorption rates can be prepared. However, the heating and holding time is relatively long, about 40 hours, and the energy consumption is relatively large.

CN 201010206161.8 uses polyglutamic acid as the main raw material, ethylene glycol diglycidyl ether as the crosslinking agent, and adjusts the pH value of the system at regular intervals during the reaction process to prepare hydrogel. The pH adjustment process is specifically to adjust the pH environment of the entire system to 3-5 after adding ethylene glycol diglycidyl ether and stir evenly, and react at a constant temperature, and then adjust the pH of the system back to the initial value every 1-2 hours. The reaction is carried out in aqueous solution, which is beneficial to environmental protection; the preparation time is short, and the obtained hydrogel has high water absorption rate, fast swelling rate and biodegradability. However, this method requires pH adjustment, which increases the process steps and increases the cost.

The crosslinking agent used in CN200410004665.6 is polyglycidyl ether or a mixture of polyglycidyl ether and glycerol diglycidyl ether, and the amount of the crosslinking agent is 0.02% to 20% of the total weight of the related substrate containing γ-polyglutamic acid %. In CN200510114908.6, the dosage of crosslinking agents such as polyglycerol polyglycidyl ether and sorbitol polyglycidyl ether is 0.01% to 20% of the weight of various forms of γ-polyglutamic acid. These two methods have a wide range of cross-linking agent dosage.

Due to the water-absorbing but water-insoluble properties of cross-linked polyglutamic acid, when a sufficient amount of water exists, a solid-liquid two-phase distribution state in which the cross-linked polyglutamic acid hydrogel water-absorbing body and free flowing water coexist is formed. After the cross-linked polyglutamic acid hydrogel is generally crushed, the particle size can be reduced, and the suspension capacity is increased to form a suspension, but it is still easy to settle and stratify after proper standing treatment. This unstable suspension brings many inconveniences in industrial production, such as uneven distribution, inaccurate dosage, and the need to mix again before use.

The present invention will provide a polyglutamic acid cross-linking method that shortens the cross-linking incubation time, does not require pH adjustment and reduces the dosage range of the cross-linking agent, and makes the prepared cross-linked polyglutamic acid hydrogel broken to form a stable uniform gel. Disperse the suspension.

Contents of the invention

The purpose of the present invention is to provide a preparation method of cross-linked polyglutamic acid hydrogel, by which a stable, uniformly dispersed and low-concentration cross-linked polyglutamic acid hydrogel is prepared.

Another object of the present invention is to provide a cross-linked polyglutamic acid hydrogel, which has the characteristics of stable uniform dispersion and low concentration, can make the state of the hydrogel stable without sedimentation, and has the characteristics of increased viscosity , and the characteristics of rapid hydration when applied to the skin surface.

A preparation method of cross-linked polyglutamic acid hydrogel, comprising the steps of:

(1) Polyglutamic acid and cross-linking agent are cross-linked in an aqueous solution to prepare high-concentration cross-linked polyglutamic acid gel blocks;

(2) Take an appropriate amount of the cross-linked polyglutamic acid gel block obtained in step (1), add an appropriate amount of aqueous solution, and homogenize the mixture until it is in a uniform fluid state to obtain a cross-linked polyglutamic acid hydrogel.

In the preparation method of the present invention, the polyglutamic acid is polyglutamic acid H type, polyglutamic acid salt type, or a mixture thereof, preferably polyglutamic acid sodium salt.

In the preparation method of the present invention, the average molecular weight of the polyglutamic acid ranges from 700,000 to 2.5 million, preferably 800,000 to 1.5 million.

In the preparation method of the present invention, the crosslinking agent is glycidyl ether, selected from ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, and 1,4-butanediol diglycidyl ether one or a mixture of more than one.

In the preparation method of the present invention, the aqueous solution is deionized water or an aqueous solution containing 0.02% to 0.50% (w/v) preservative, and the preservative is selected from methylparaben, ethylparaben, Propylparaben, Butylparaben, Phenoxyethanol, Alkyl imidazolidinyl urea, Diazolidinyl urea, Iodopropynyl n-butylcarbamate, Chlorinated [cis 1-(3- One or more mixtures of chloropropane)-3,5,7-triazol-1-azonium-adamantane and propylene glycol.

In the preparation method of the present invention, the polyglutamic acid content in the step (1) is 10%-30% (w/v), preferably 16%-28% (w/v).

In the preparation method of the present invention, the amount of the crosslinking agent in the step (1) is 3% to 20% (v/w) of the mass of polyglutamic acid, preferably 3% to 10% of the mass of polyglutamic acid. % (v/w).

In the preparation method of the present invention, the cross-linking in the step (1) is carried out at 40-121° C. for 0.5-24 hours.

In the preparation method of the present invention, the heat preservation range in the step (1) is preferably 45-65°C.

In the preparation method of the present invention, the heat preservation time in the step (1) is preferably 4-10 hours.

Preparation method of the present invention, the calculation formula of aqueous solution addition in described step (2) is:

In the formula, V: the added volume of the aqueous solution, L or mL; W: the weight of the high-concentration cross-linked polyglutamic acid gel, kg or g; A: the polyglutamic acid in the high-concentration cross-linked polyglutamic acid gel Acid percentage concentration (w/v); B: Cross-linked polyglutamic acid percentage concentration (w/v) in the cross-linked polyglutamic acid hydrogel product.

According to the preparation method of the present invention, a kind of cross-linked polyglutamic acid hydrogel prepared, the cross-linked polyglutamic acid concentration is 0.20%～0.43% (w/v), preferably 0.20%～0.41% (w /v).

Beneficial effects of the present invention: the method of the present invention can prepare a stable uniformly dispersed cross-linked polyglutamic acid hydrogel, and its uniform dispersion property can make the content of the components in the hydrogel stable and consistent, which is convenient for packaging, transportation and use. The viscosity of the crosslinked polyglutamic acid hydrogel is increased compared with the same concentration of uncrosslinked polyglutamic acid, and a series of hydrogel fluids with different viscosities can be prepared. The cross-linked polyglutamic acid hydrogel within the set concentration range can be evenly dispersed and applied on the skin surface. When the hydrogel with a higher concentration is used, there will be no shelling phenomenon that forms a white film after drying. When the concentration of hydrogel is low, there will be no phenomenon that the water sample cannot quickly moisturize the dry skin. The cross-linked polyglutamic acid hydrogel is easy to spread on the skin surface, and the skin is moist and refreshing when applied on the spot without sticky feeling. The series of cosmetics developed from this with such a comfortable skin feel are more likely to be accepted by consumers. accept.

detailed description

Example Preparation of a stable homogeneously dispersed low-concentration cross-linked polyglutamic acid hydrogel

According to Table 1, high-concentration cross-linked polyglutamic acid gum blocks were prepared respectively.

Table 1 Preparation of high-concentration cross-linked polyglutamic acid gel blocks

Preparation method of high-concentration cross-linked polyglutamic acid gel blocks: According to the data in Table 1, a certain amount of sodium polyglutamate and cross-linking agent were dissolved in deionized water, stirred and mixed, and kept in a water bath for a period of time to obtain a non-flowing High-concentration cross-linked polyglutamic acid gel blocks.

According to Table 2, stable uniformly dispersed low-concentration cross-linked polyglutamic acid hydrogels were prepared respectively.

Table 2 Stable uniformly dispersed low-concentration cross-linked polyglutamic acid hydrogel

Stable uniformly dispersed low-concentration cross-linked polyglutamic acid hydrogel preparation method: According to the data in Table 2, weigh a certain mass of high-concentration cross-linked polyglutamic acid gel block, add the added amount calculated according to the designed hydrogel concentration. Liquid volume (can be deionized water, or an aqueous solution containing preservatives), homogenized in a crushing homogenizer to a uniform fluid state, to obtain a stable and uniformly dispersed low-concentration cross-linked polyglutamic acid hydrogel.

Experimental example

1. Stability test: the cross-linked polyglutamic acid hydrogel was left standing for 10 months

Insufficient or excessive cross-linking will affect the formation of the final stable cross-linked polyglutamic acid hydrogel. The following will use Experimental Example 1 and Experimental Example 2 to represent the insufficient and excessive crosslinking degree respectively, and at the same time compare with the prepared crosslinked polyglutamic acid hydrogel example to observe the apparent stability of the sample.

Experimental Example 1 Dissolve 4.0 g of sodium polyglutamate with an average molecular weight of 1.2 million and 40 μL of 1,4-butanediol diglycidyl ether in 50 mL of deionized water, stir and mix, and keep warm in a water bath at 60 ° C for 4 hours to obtain a fluid State cross-linked polyglutamic acid (polyglutamic acid content 8%, 1,4-butanediol diglycidyl ether accounts for 1% by weight of polyglutamic acid). Inhomogeneous precipitates can be seen when stirred, and dark yellow precipitates are deposited at the bottom after a long period of storage. After stirring and mixing, absorb 4.2376g of the glue, in order to obtain a cross-linked polyglutamic acid hydrogel with a cross-linked polyglutamic acid content of 0.21%, calculate and add 161mL of deionized water, and homogenize in a crushing homogenizer, A dispersed cross-linked polyglutamic acid hydrogel was obtained.

Experimental Example 2 Dissolve 1.86 g of sodium polyglutamate with an average molecular weight of 1.2 million and 205 μL of 1,4-butanediol diglycidyl ether in 6 mL of deionized water, stir and mix, and keep warm in a water bath at 60 ° C for 4 hours to obtain a non-flowing The cross-linked polyglutamic acid rubber block (the content of polyglutamic acid is 31%, and 1,4-butanediol diglycidyl ether accounts for 11% of the weight of polyglutamic acid). Segment and weigh 1.1346 g of the glue block, in order to obtain a cross-linked polyglutamic acid hydrogel with a cross-linked polyglutamic acid content of 0.21%, calculate and add 167 mL of deionized water, and homogenize in a crushing homogenizer to obtain Dispersed cross-linked polyglutamic acid hydrogels.

Put Experimental Example 1, Experimental Example 2, and the cross-linked polyglutamic acid hydrogel in the preparation example of cross-linked polyglutamic acid hydrogel respectively in the Erlenmeyer flask, sealed and stored at 4°C for 10 months . Regularly observe and record the apparent state, mainly to see whether it is delaminated and sticky description, etc., see Table 3. When observing the viscosity of the cross-linked polyglutamic acid hydrogel, shake the triangular flask by hand, and the fluid moves synchronously with the shaking amplitude. The qualitative description of the fluid collision produces fine bubbles and recovers quickly is "thin"; when the fluid is not easy to follow the shaking Amplitude synchronous motion, fluid collisions may produce sparse larger bubbles, and the qualitative description of the stable suspension in the fluid is "viscous".

Table 3 Visual observation results of cross-linked polyglutamic acid hydrogel standing for 10 months

^* Note: Bubbles are the gas that is filled into the hydrogel during the homogenization process, and gradually rises and escapes from the liquid phase after standing still, which has no effect on the uniform dispersion of the hydrogel.

The results show that under the conditions of sodium polyglutamate content of 8% and crosslinking agent 1% (experimental example 1, the degree of crosslinking is insufficient), the crosslinked fluid containing precipitation is produced, which not only affects the sampling consistency of subsequent operations, It also causes turbidity and precipitation in the final hydrogel; and under the conditions of 31% sodium polyglutamate content and 11% cross-linking agent (experimental example 2, excessive cross-linking), a uniform cross-linked polyglutamic acid gel was obtained. block, but because the cross-linked network is too tight, dense hydrogel particles are obtained after homogenization, which cannot be suspended stably, and a large amount of sedimentation occurs after long-term storage, resulting in stratification. In the parameter range disclosed in the present invention, a uniform cross-linked product can be prepared, and a cross-linked polyglutamic acid hydrogel that is uniformly dispersed and has no sedimentation and stratification can be further prepared. No matter its viscosity is low or high, its hydrogel The stable state can be maintained for at least 10 months.

2. Viscosity of cross-linked polyglutamic acid hydrogel

Within the concentration range of the cross-linked polyglutamic acid disclosed in the present invention, in order to show the thickening effect of a series of treatments such as cross-linking on the polyglutamic acid aqueous solution, the concentration of 0.05% to 1.32% prepared in Table 2 is taken. % series of cross-linked polyglutamic acid hydrogels, take sodium polyglutamate with an average molecular weight of 1.3 million to make a series of 0.05% to 1.32% uncrosslinked polyglutamic acid aqueous solutions (experimental examples 3 to 11) in parallel , and a deionized aqueous solution was used as a control solution (experimental example 12). Viscosity was detected by a Brookfield RVDVE230 viscometer, a rotor with a suitable range was selected, the rotation speed was 100r/min, and the fluid temperature was about 24°C. The results are shown in Table 4.

Table 4 Viscosity comparison of crosslinked polyglutamic acid hydrogel and uncrosslinked polyglutamic acid aqueous solution

*Cross-linked polyglutamic acid sodium, sodium polyglutamate concentration/%: For cross-linked polyglutamic acid hydrogel, it refers to the cross-linked polyglutamic acid sodium concentration; for uncross-linked polyglutamic acid aqueous solution, it is Refers to the concentration of sodium polyglutamate.

It can be seen from Table 4 that within the concentration range of 0.05% to 1.32% cross-linked sodium polyglutamate and sodium polyglutamate, the viscosity of cross-linked polyglutamic acid hydrogel at the same concentration is higher than that of uncross-linked polyglutamic acid hydrogel. The viscosity of the aqueous acid solution has a viscosity ratio > 1; and the viscosity increase phenomenon is more obvious in the preferred range of 0.075% to 0.41%, and the viscosity ratio is ≥ 5. Although the viscosity of Example 21 is 99 times that of Experimental Example 4, homogenization is difficult due to the high viscosity, which belongs to the general hydrogel range.

3. Smear test of cross-linked polyglutamic acid hydrogel

Take about 0.05mL of the samples of Examples and Experimental Examples in Table 4 and smear the skin on the back of the palm of the test subject, and see Table 5 for the smear test results.

Table 5 Cross-linked polyglutamic acid hydrogel smear test

*Here, qualitative viscosity is used to describe the skin feel of cross-linked polyglutamic acid hydrogel.

**Hydration refers to how smoothly the cross-linked polyglutamic acid hydrogel transforms from semi-solid to liquid after contacting the skin surface.

The appearance of this type of gel is colorless and transparent, and it shows a series of viscosities due to different concentrations (see Table 4). In the concentration range of 0.05% to 1.32% cross-linked sodium polyglutamate, when the cross-linked polysodium glutamate hydrogel is applied on the skin surface, it will transform into a low-viscosity fluid. It can be seen from Table 5 that the hydration The obvious degree of sexuality is positively correlated with its own stickiness. The 0.075%-0.43% cross-linked sodium polyglutamate hydrogel has obvious hydration and is comfortable to use, but the 0.43% sample is classified as a general hydrogel due to the long time-consuming homogenization step during preparation, which is preferred The concentration range of the cross-linked sodium polyglutamate hydrogel is 0.075%-0.41%.

The hydration mechanism of cross-linked polyglutamic acid hydrogel is related to its own ion sensitivity. As it is gradually spread on the skin surface, the contact with salt ions in sweat increases, and its viscosity-reducing hydration degree intensifies. Therefore, the cross-linked polyglutamic acid hydrogel series samples are easy to spread on the skin surface, presenting a moist and refreshing skin feeling without sticky feeling.

In contrast, a 1.32% aqueous solution of sodium polyglutamate (experimental example 3) has a certain viscosity but does not exhibit hydration, so it will appear sticky and greasy after being applied to the skin surface, and will form a white color after it is completely dried. Shell-like diaphragm. The deionized aqueous solution without polyglutamic acid (experimental example 12) has low viscosity itself, no viscosity reduction, no stickiness in the process of being applied, and poor spreadability.

Therefore, according to the different viscosity states, the cross-linked polyglutamic acid hydrogel can be developed into a series of products such as gel, gel, and lotion with good skin feeling.

Claims (12)

1. a preparation method of cross-linked polyglutamic acid hydrogel, comprising the steps of: (1) Polyglutamic acid and cross-linking agent are cross-linked in an aqueous solution to prepare high-concentration cross-linked polyglutamic acid gel blocks; It is characterized in that (2) taking an appropriate amount of the cross-linked polyglutamic acid gel block obtained in step (1), adding an appropriate amount of aqueous solution, and homogenizing the mixture until it is in a uniform fluid state to obtain the cross-linked polyglutamic acid hydrogel; Wherein, in the step (1), the polyglutamic acid content is 10% to 30% (w/v), and the amount of the crosslinking agent is 3% to 20% (v/w) of the polyglutamic acid mass; Wherein, the cross-linking in the step (1) is carried out at 40-121° C. for 0.5-24 hours; Wherein, the percentage concentration of the cross-linked polyglutamic acid in the cross-linked polyglutamic acid hydrogel in the step (2) is 0.20%-0.43% (w/v). 2. preparation method as claimed in claim 1, is characterized in that, described linking agent is glycidyl ether, is selected from ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4- One or more mixtures of butanediol diglycidyl ether. 3. preparation method as claimed in claim 1 is characterized in that, described aqueous solution is deionized water or contains the aqueous solution of 0.02%～0.50% (w/v) preservative, and preservative is selected from methylparaben , ethylparaben, propylparaben, butylparaben, phenoxyethanol, alkyl imidazole urea, bis-imidazolidinyl urea, iodopropynyl n-butyl carbamate, chlorinated [ One or more of cis-1-(3-chloropropane)-3,5,7-triazol-1-azonium-adamantane and propylene glycol. 4. The preparation method according to claim 1, characterized in that the polyglutamic acid content in the step (1) is 16%-28% (w/v). 5. The preparation method according to claim 1, characterized in that the amount of the cross-linking agent in the step (1) accounts for 3%-10% (v/w) of the mass of polyglutamic acid. 6. The preparation method according to claim 1, characterized in that, in the step (1), the cross-linking action, the heat preservation range is 45-65°C. 7. The preparation method according to claim 1, characterized in that, in the step (1), the cross-linking action takes a holding time of 4 to 10 hours. 8. preparation method as claimed in claim 1 is characterized in that, the computing formula of aqueous solution addition in described step (2) is: <mrow> <mi>V</mi> <mo>=</mo> <mfrac> <mrow> <mi>W</mi> <mo>&amp;times;</mo> <mi>A</mi> </mrow> <mi>B</mi> </mfrac> <mo>,</mo> </mrow> In the formula, V: the added volume of the aqueous solution, L or mL; W: the weight of the high-concentration cross-linked polyglutamic acid gel, kg or g; A: the polyglutamic acid in the high-concentration cross-linked polyglutamic acid gel Acid percentage concentration (w/v); B: Cross-linked polyglutamic acid percentage concentration (w/v) in the cross-linked polyglutamic acid hydrogel product. 9. The preparation method according to claim 1, characterized in that, said polyglutamic acid is polyglutamic acid H type, polyglutamic acid salt type, or a mixture thereof. 10. The preparation method according to claim 1, characterized in that the average molecular weight of the polyglutamic acid ranges from 700,000 to 2,500,000. 11. The preparation method according to claim 1, characterized in that, the percentage concentration of cross-linked polyglutamic acid in the cross-linked polyglutamic acid hydrogel is 0.20%～0.41% (w/v) . 12. A cross-linked polyglutamic acid hydrogel prepared by the method of claim 1.