CN106317427B - A kind of polyurethane/guar gum complex microsphere and preparation method thereof - Google Patents

Abstract

The invention provides a preparation method of polyurethane/guar gum composite microspheres, comprising: (1) adding polyether alcohol and acetone into a container, heating and stirring and steaming out water; (3) then reduce the system temperature to 45-65°C, add a chain extender to carry out the chain extension reaction, then lower the system temperature and speed up the stirring speed, and drop triethylamine to carry out the neutralization reaction; ( 4) heating up and steaming out excess acetone in the reaction system, adding water, and vigorously stirring to obtain an aqueous solution of polyurethane; The solution was dropped into the CaCl ₂ aqueous solution to finally obtain polyurethane/guar gum composite microspheres. The invention prepares the polyurethane/guar gum composite microspheres through a phase separation method, can give full play to the advantages of the two materials, and has certain potential application value.

Description

A kind of polyurethane/guar gum composite microsphere and preparation method thereof

technical field

The invention relates to the field of polymer materials, in particular to a composite microsphere, in particular to a polyurethane/guar gum composite microsphere used as a drug carrier and a preparation method thereof.

Background technique

Polyurethane (PU) is a synthetic polymer material, because its structure is easy to design and process, so it has been developed rapidly in the field of synthetic polymer materials. The chemical structural characteristics of polyurethane are composed of soft segments with a glass transition temperature lower than room temperature and hard segments with a glass transition temperature higher than room temperature. Therefore, polyurethane has good mechanical properties, high elasticity, wear resistance, lubricity, and fatigue resistance It is widely used in various fields due to its uniqueness, biocompatibility, biostability, mechanical strength, and processability.

CN2601168Y discloses a polyurethane composite protective pad, which is widely used in The field of home improvement.

CN2658519Y discloses a reinforced polyurethane elastic hose, which is composed of a polyurethane elastomer inner tube, a steel wire mesh and a polyurethane elastomer outer tube. Due to the existence of the polyurethane elastomer isolation layer, the friction between the steel wire mesh is eliminated, and the polyurethane has Good abrasion resistance, thus enhancing the service life of polyurethane elastomer hoses.

Among them, it is worth noting that polyurethane is also widely used in the field of medical biomaterials, such as artificial heart valves, artificial lungs, artificial skin, artificial blood vessels, etc. In the field of drug carriers, pure polyurethane materials have good mechanical properties and biocompatibility, but their degradation rate is slow.

Contents of the invention

In view of the above problems, the inventors of the present application found that there is a natural polysaccharide substance—guar gum, which has good water solubility and degradation performance, and can be used in conjunction with polyurethane to prepare drug-loaded microspheres with excellent performance. .

First aspect, subject of the present invention is a kind of preparation method of polyurethane/guar gum composite microsphere, it is characterized in that, comprises:

Step 1: Add polyether alcohol and acetone 1-5 times its mass in the container, heat and stir and steam out the water;

Step 2: Add metered isocyanate dropwise to ensure that the NCO/OH value is (1-6): 1, and perform pre-polymerization at 75-95°C to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then reduce the system temperature to 45-65°C, add a chain extender of 1%-8% of the mass of isocyanate to carry out the chain extension reaction, then lower the system temperature and increase the stirring speed, and drop triethyl ether into the reaction system The amine carries out neutralization reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add water with monomer content, and stir vigorously to obtain a certain concentration of polyurethane aqueous solution;

Step 5: preparing an aqueous solution of guar gum with a mass percentage of 5-20%, compounding the aqueous solution of polyurethane and guar gum according to the mass ratio (0.1 to 1): 3, standing for defoaming to obtain a composite solution, and then The composite solution is dropped into the CaCl ₂ aqueous solution with a mass percentage of 5-10%, and the polyurethane/guar gum composite microspheres are finally obtained.

In a preferred embodiment of the present invention, the guar gum is any one of guar collagen powder, esterified modified guar gum or etherified modified guar gum.

The polyether alcohol is any one of polytetrahydrofuran glycol (PTMG) and polyethylene glycol (PEG).

The isocyanate is any one of toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), isophorone diisocyanate (IPDI) and isopropyl isocyanate (HDI).

The chain extender is any one of 2,2-dimethylolpropionic acid (DMPA) and 2,2-dimethylolbutyric acid (DMBA).

Preferably, in the step 1, the amount of acetone added is 1-2 times that of polyether alcohol; the container is a three-necked flask equipped with a stirrer and a reflux condenser.

In the step 2, the NCO/OH value is (2-4):1.

In the step 3, the added amount of the chain extender is 1%-2% of the mass of the isocyanate.

In described step 5, the mass ratio of the aqueous solution of described polyurethane, guar gum is (0.5～1): 1; Described CaCl The mass percent of _aqueous solution is 8%; The mass percent of described guar gum aqueous solution is 10% -15%.

On the other hand, the subject of the present invention is a polyurethane/guar gum composite microsphere obtained by any one of the above-mentioned preparation methods.

In another aspect, the subject of the present invention is the application of the polyurethane/guar gum composite microspheres described above in the field of drug carriers.

The invention relates to a polyurethane/guar gum composite microsphere and a preparation method thereof. Polyurethane has good mechanical properties, processability and biocompatibility, and is an ideal drug carrier material. However, due to the difficult degradation of polyurethane, its application range is limited. As guar gum is a natural polymer material, polyurethane/guar gum composite microspheres can be prepared by phase separation method, which can give full play to the advantages of the two materials and has certain potential application value.

Description of drawings

Fig. 1 is the graph of performance test result of embodiment 1-4 and comparative example.

Detailed ways

For the technical scheme of the present invention, namely:

A preparation method of polyurethane/guar gum composite microspheres, characterized in that, comprising:

Step 1: Add polyether alcohol and acetone 1-5 times its mass in the container, heat and stir and steam out the water;

Step 2: Add metered isocyanate dropwise to ensure that the NCO/OH value is (1-6): 1, and perform pre-polymerization at 75-95°C to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then lower the temperature of the system to 45-65°C, add a chain extender of 1% to 8% of the mass of isocyanate to carry out the chain extension reaction, then lower the temperature of the system and increase the stirring speed, and add triethyl ether dropwise to the reaction system The amine carries out neutralization reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add water with monomer content, and stir vigorously to obtain a certain concentration of polyurethane aqueous solution;

Step 5: prepare the guar gum aqueous solution, compound the aqueous solution of polyurethane and guar gum according to the mass ratio (0.1～1): 3, let it stand for defoaming, and obtain the composite solution, then drop the composite solution to a mass percentage of In 5-10% CaCl ₂ aqueous solution, finally obtain polyurethane/guar gum composite microsphere;

In a preferred embodiment of the present invention, the guar gum is any one of guar collagen powder, esterified modified guar gum or etherified modified guar gum; the polyether alcohol is polytetrahydrofuran Any one in diol (PTMG) and polyethylene glycol (PEG); Described isocyanate is toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), isophorone diisocyanate (IPDI) and Any one of isopropyl isocyanate (HDI); the chain extender is any one of 2,2-dimethylolpropionic acid (DMPA) and 2,2-dimethylolbutyric acid (DMBA) Kind; Preferably, in the step 1, the amount of acetone added is 1-2 times that of polyether alcohol; the container is a three-necked flask equipped with a stirrer and a reflux condenser; in the step 2, NCO/OH Value is (2～4): 1; In described step 3, the addition amount of described chain extender is 1%～2% of isocyanate quality; In described step 5, the aqueous solution of described polyurethane, guar gum The mass ratio is (0.5～1): 1; the mass percentage of the CaCl _aqueous solution is 8%; the mass percentage of the guar gum aqueous solution is 10-15%;

A polyurethane/guar gum composite microsphere obtained by any one of the above-mentioned preparation methods; and

Another application of the polyurethane/guar gum composite microspheres described above in the field of drug carriers.

The above-mentioned technical solution of the present invention will be further described below through specific embodiments and in conjunction with the accompanying drawings, but the present invention is not limited.

Example 1

Step 1: Add 5.0g PEG-400 and 10g acetone into a three-neck flask equipped with a stirrer and a reflux condenser, heat and stir and evaporate the water;

Step 2: Add 7.8 g of toluene diisocyanate dropwise, and perform prepolymerization at 75-95° C. to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then lower the temperature of the system to 45-65°C, add 0.2g of dimethylolpropionic acid to carry out the chain extension reaction, then lower the temperature of the system and increase the stirring speed, and add triethylamine dropwise to the reaction system for neutralization Reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add distilled water with monomer content, stir vigorously, and obtain a polyurethane aqueous solution with a certain concentration;

Step 5: the preparation mass fraction is 10% guar gum aqueous solution, the quality such as the aqueous solution of polyurethane, guar gum is compounded, stand defoaming, obtain composite solution, then use syringe to drop composite solution into 8% In CaCl ₂ aqueous solution, polyurethane/guar gum composite microspheres were finally obtained.

Example 2

Step 1: Add 7.5g PEG-600 and 10g acetone into a three-necked flask equipped with a stirrer and a reflux condenser, heat and stir and evaporate the water;

Step 2: Add 10.9 g of diphenylmethane diisocyanate dropwise, and perform prepolymerization at 75-95° C. to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then lower the temperature of the system to 45-65°C, add 0.2g of dimethylolpropionic acid to carry out the chain extension reaction, then lower the temperature of the system and increase the stirring speed, and add triethylamine dropwise to the reaction system for neutralization Reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add distilled water with monomer content, stir vigorously, and obtain a polyurethane aqueous solution with a certain concentration;

Step 5: Prepare a phosphoric acid-modified guar gum aqueous solution with a mass fraction of 15%, compound the aqueous solution of polyurethane and guar gum according to the mass ratio of 3:4, let it stand for defoaming, and obtain a composite solution, and then use a syringe to compound The solution was dropped into 8% CaCl ₂ aqueous solution to finally obtain polyurethane/guar gum composite microspheres.

Example 3

Step 1: Add 5.0g PEG-200 and 10g acetone into a three-necked flask equipped with a stirrer and a reflux condenser, heat and stir and evaporate the water;

Step 2: Add 19.4 g of isophorone diisocyanate dropwise, and perform prepolymerization at 75-95° C. to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then lower the system temperature to 45-65°C, add 0.2g of dimethylol butyric acid for chain extension reaction, then lower the system temperature and increase the stirring speed, and drop triethylamine into the reaction system for neutralization Reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add distilled water with monomer content, stir vigorously, and obtain a polyurethane aqueous solution with a certain concentration;

Step 5: Prepare a phosphoric acid-modified guar gum aqueous solution with a mass fraction of 15%, compound the aqueous solution of polyurethane and guar gum according to the mass ratio of 3:5, let stand for defoaming, and obtain a composite solution, and then use a syringe to compound The solution was dropped into 8% CaCl ₂ aqueous solution to finally obtain polyurethane/guar gum composite microspheres.

Example 4

Step 1: Add 5.0g of PTMG-650 and 10g of acetone into a three-neck flask equipped with a stirrer and a reflux condenser, heat and stir and evaporate the water;

Step 2: Add 4.7 g of toluene diisocyanate dropwise, and perform prepolymerization at 75-95° C. to obtain an acetone solution of polyurethane prepolymer;

Step 3: Then lower the temperature of the system to 45-65°C, add 0.2g of dimethylolbutyric acid for chain extension reaction, then lower the temperature of the system and increase the stirring speed, and drop triethylamine into the reaction system for neutralization Reaction, obtains the acetone solution of polyurethane;

Step 4: Elevate the temperature to steam out excess acetone in the reaction system, add distilled water with monomer content, stir vigorously, and obtain a polyurethane aqueous solution with a certain concentration;

Step 5: Prepare a phosphoric acid-modified guar gum aqueous solution with a mass fraction of 15%, compound the aqueous solution of polyurethane and guar gum according to the mass ratio of 3:4, let it stand for defoaming, and obtain a composite solution, and then use a syringe to compound The solution was dropped into 8% CaCl ₂ aqueous solution to finally obtain polyurethane/guar gum composite microspheres.

comparative example

Polyurethane-starch microspheres were prepared as a comparative sample. The preparation method was referred to in Example 1, and the same amount of starch was used to replace the guar gum, and other conditions remained unchanged.

Performance Testing

Tetracycline hydrochloride was used as a model drug to determine the drug loading rate. The specific method is as follows: during the preparation of the microspheres, the tetracycline hydrochloride is dissolved in the guar gum aqueous solution. After the preparation of microspheres is completed, a certain mass of microspheres is soaked in 50 mL of PBS solution at 37.2°C, and shaken in a constant temperature water bath. 3mL samples were taken out at different time points, and an equal amount of PBS solution was added at the same time. After the sample taken out was centrifuged for 2 min, the drug concentration in the sample was determined by absorbance photometry.

Finally, the obtained microsphere drug release index is shown in Figure 1, and the microsphere drug loading data is shown in Table 1. It can be seen from Figure 1 and Table 1 that the drug release rate of polyurethane-guar gum microspheres is more stable and has wider application value .

Table 1: The drug release index data of the microspheres of Examples 1-4 and Comparative Examples

time Embodiment one Embodiment two Embodiment Three Embodiment four comparative example 0 0.4 0.5 0.48 0.529 0.3 2.5 0.8 0.83 0.824 0.812 0.5 5 0.77 0.84 0.826 0.782 0.8 7.5 0.79 0.81 0.806 0.79 0.9 10 0.78 0.79 0.788 0.798 1.1 12.5 0.81 0.84 0.834 0.813 1.3 15 0.84 0.82 0.824 0.828 0.9 17.5 0.79 0.8 0.798 0.787 0.8 20 0.8 0.78 0.784 0.812 0.7 22.5 0.82 0.84 0.836 0.814 0.72 25 0.79 0.8 0.798 0.803 0.68

The specific embodiments of the present invention have been described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, equivalent changes and modifications made without departing from the spirit and scope of the present invention shall fall within the scope of the present invention.

Claims (8)

1. a kind of preparation method of polyurethane/guar gum complex microsphere, which is characterized in that including：

Step 1：The acetone of Aethoxy Sklerol and its 1-5 times of quality is added in a reservoir, heating stirring simultaneously steams moisture；

Step 2：The isocyanates of metering is added dropwise, ensures that NCO/OH values are (1~6)：1, pre-polymerization is carried out at 75~95 DEG C, is obtained The acetone soln of polyurethane prepolymer；

Step 3：System temperature is then down to 45~65 DEG C, 1%~8% chain extender that isocyanate is added is expanded Chain reaction, then system temperature is reduced to and is accelerated mixing speed, triethylamine is added dropwise into reaction system and carries out neutralization reaction, obtains The acetone soln of polyurethane；

Step 4：Heating steams acetone extra in reaction system, and the water of content of monomer is added, is vigorously stirred, obtains certain density Aqueous polyurethane；

Step 5：Prepare mass percent be 5-20% aqueous guar glue solution, by polyurethane, guar gum aqueous solution according to matter Amount is than (0.1~1):3 progress are compound, and to get composite solution, composite solution is then added dropwise to mass percent is standing and defoaming The CaCl of 5-10%₂In aqueous solution, polyurethane/guar gum complex microsphere is finally obtained；

The Aethoxy Sklerol is any one in polytetrahydrofuran diol (PTMG) and polyethylene glycol (PEG)；

The isocyanates is that toluene di-isocyanate(TDI) (TDI), methyl diphenylene diisocyanate (MDI), isophorone two are different Any one in cyanate (IPDI) and isopropyl isocyanate (HDI).

2. preparation method according to claim 1, which is characterized in that the guar gum is guar gum original powder, esterification modification melon Any one in your glue or etherification modified guar gum.

3. preparation method according to claim 1, which is characterized in that the chain extender is 2,2- dihydromethyl propionic acids (DMPA) With any one in 2,2- dimethylolpropionic acids (DMBA).

4. preparation method according to claim 1, which is characterized in that in the step 1, the additive amount of acetone is Aethoxy Sklerol 1-2 times；The container is the three-necked flask equipped with blender and reflux condensing tube.

5. preparation method according to claim 1, which is characterized in that in the step 2, NCO/OH values are (2~4)：1；Institute It states in step 3, the additive amount of the chain extender is the 1%~2% of isocyanate.

6. preparation method according to claim 1, which is characterized in that in the step 5, the polyurethane, guar gum water The mass ratio of solution is (0.5~1):1；The CaCl₂The mass percent of aqueous solution is 8%；The aqueous guar glue solution Mass percent is 10-15%.

7. polyurethane/guar gum complex microsphere that a kind of preparation method as described in claim 1-6 any one obtains.

8. a kind of polyurethane as described in claim 7/application of the guar gum complex microsphere in pharmaceutical carrier field.