CN101862454A - A kind of physically cross-linked hydrogel composition and its preparation method and application - Google Patents

Abstract

The invention belongs to the technical field of polymer materials and medicine, and relates to a physically cross-linked hydrogel composition and a preparation method and application thereof. The composition is a mixture of two or more polymers, and its water system has the property of temperature-sensitive reversible gelation. When the temperature is lower than the sol-gel transition temperature, the mixture can be dissolved in water. At the sol-gel transition temperature, the aqueous solution of the mixture forms a gel, and the process is reversible; the polymer includes a block copolymer composed of polyethylene glycol as a hydrophilic block and degradable polyester as a hydrophobic block things. The aqueous solution of the composition can be administered to warm-blooded animals via parenteral, eye, subcutaneous, intramuscular, vaginal, urethral, nasal cavity or lung, and forms a gel at a physiologically relevant temperature; it can also be administered in the form of a gel. The present invention adjusts the release rate by changing the mixing ratio, polymer composition, molecular weight and polydispersity.

Description

A kind of physically cross-linked hydrogel composition and its preparation method and application

technical field

The invention belongs to the technical field of polymer materials and medicine, and relates to a physically cross-linked hydrogel composition and a preparation method thereof, in particular to a physically cross-linked hydrogel with thermally reversible gel performance and a preparation method thereof, and the Applications of hydrogels in parenteral, eye, subcutaneous, intramuscular administration, etc.

Background technique

In recent years, with the development of biotechnology and genetic engineering, many peptide/protein drugs with pharmacological activity have been commercialized. However, peptide or protein drugs are easily degraded by digestive enzymes in the gastrointestinal tract, and their biological half-life is short, which makes their administration routes relatively limited. Generally, they can only be administered through intravenous, intramuscular, or subcutaneous injections. Studies have shown that in conventional solvents, peptide or protein drugs have limited solubility or stability, making them difficult to formulate and administer. In order to overcome the shortcomings of traditional drug dosage forms, a new Drug Delivery System (DDS) was developed to meet the needs of patients. Generally, the DDS system can continuously release drugs in the whole body or specific organs according to a predetermined direction within a fixed period of time, and control the blood drug concentration between the minimum effective concentration and the toxic concentration, increase the bioavailability of the drug, and reduce the toxic and side effects of the drug , to improve the compliance of patients with medication, among which, the degradable and high-performance drug carrier materials play a role in promoting and guaranteeing the slow/controlled release of drugs.

Currently, solid polymers represented by polylactic acid (PLA), polyglycolic acid (PGA), their copolymers (PLGA) and polycaprolactone (PCL) are the most widely studied implantable and degradable polymers. Drug sustained release carrier. Since these polymers are inherently hydrophobic, toxic organic solvents such as dichloromethane and chloroform are unavoidably used in the process of using these materials. However, the use of organic solvents makes it very difficult to completely remove them afterwards, and the remaining organic solvents will produce harmful side effects, such as carcinogenicity, neurotoxicity, and teratogenicity. Pharmacopoeias of various countries have clearly stipulated the maximum amount of organic solvents allowed in medicine. As stipulated by the United States Pharmacopoeia (USP): Residual dichloromethane<500ppm, trichloromethane<50ppm. At the same time, for these implanted polymer solid devices, the implantation process will inevitably bring trauma caused by the operation. Although injectable polyester microspheres (such as PLGA microspheres) do not require surgical implantation, the use of organic solvents cannot be avoided.

It has been reported in the literature that injectable and implantable drug delivery systems using low-toxic organic solvents, such as PLA, PLGA, PCL and other drugs, are dissolved in low-toxic organic solvents, such as methylpyrrolidone (NMP), dimethyl sulfoxide ( DMSO), ethyl acetate, etc., to obtain a polymer solution with a concentration of 30-70%; after subcutaneous injection into the body, due to the exchange of the solvent with the surrounding body fluid, the polymer wrapped in the drug precipitates to obtain an in situ transplantation device (Dunnet et al. al, US Patent No. 4938763). This system is more suitable for hydrophobic drugs, but it is still easy to inactivate protein drugs. The device obtained by the above system has random morphology and its solid rigidity easily leads to violent tissue reaction. At the same time, the difference in drug distribution during the precipitation process will lead to different release modes, and the untimely precipitation process will also lead to obvious burst release effects.

Semisolid oligoesters ( _Mw less than 5500) are another injectable carrier system (Loskos et al, Biomaterials, 1995, 16, 313-317). Mix the hydrophobic drug and oligoester evenly at high temperature, inject it into the body, and form a gel preparation as the temperature drops. This is actually a gel injection system. Manipulation of the system must be carefully controlled due to the high temperature in the drug encapsulation process that may lead to the failure of drug molecules.

Hydrogel is a polymer network that can swell in water without dissolving; it is filled with a large amount of aqueous solution, which is similar to the body tissue filled with a large amount of body fluid, so the hydrogel has good biocompatibility , has also become a unique drug sustained release carrier material. In recent years, injectable thermosensitive gelling hydrogel materials have attracted special attention, it has a sol-gel transition temperature (sol-gel transition temperature), when the transition temperature is appropriate, it can be used at room temperature or It exists in a solution state when it is lower than room temperature, and in this state it can embed biologically active substances such as drugs and cells; when it is injected into subcutaneous or muscle tissue, due to the increase in temperature, the solution embedded with drugs is rapidly transformed into a gelatinous solution. Gel: Driven by diffusion and/or gel self-degradation, the drug can be released from the inside of the gel smoothly, so as to achieve the purpose of sustained release. The sol-gel transformation process of this kind of material is a reversible process of physical change, does not involve organic solvents, and does not require chemical reactions, so it has low toxicity and less irritation. This type of polymer material is usually an amphiphilic block copolymer, which can self-assemble into micelles or nanoparticles in water, so it can effectively solubilize hydrophobic drug molecules and provide a solution for the administration of insoluble drugs. Polyethylene oxide (PEO)-polyoxypropylene (PPO)-polyoxyethylene (PEO) copolymer (also known as Poloxamer, Poloxamer) with suitable molecular weight and composition is a class of polymers with thermoreversible gel properties. material, but the material is not biodegradable, and can only exist in the body for a few days before being diluted and dissolved by body fluids, and the sustained release time of the drug that can be provided is limited.

Some studies have introduced degradable groups or components into temperature-sensitive polymer materials to obtain degradable and temperature-sensitive physical hydrogel materials, and to apply such materials in the fields of drug sustained release and tissue engineering. At present, research on degradable and temperature-sensitive polymers mainly includes triblock polyester-polyethylene glycol copolymers (R.C. Rath et al.: Chinese Patent No. ZL99812495.8) and the like. This type of polymer has a single composition and molecular weight distribution, and has thermally reversible gelation performance at a certain concentration.

But, the following problems still exist in this type of block copolymer of single component:

(1) Exceeding a certain composition and/or molecular weight, it can only be completely dissolved in water or partially or completely become precipitated, thereby losing the sol-gel transition and no longer having the relevant heat-sensitive gelling performance;

(2) In addition, even if some polymers can show heat-sensitive properties, their gelation temperature is not suitable for human application;

(3) The adjustment range and kinetic process of its degradation rate have certain limitations, which limits its medical use.

Contents of the invention

The purpose of the present invention is to overcome the defects of the prior art, to provide a physically cross-linked hydrogel composition and its preparation method, in particular to a degradable thermally reversible gelled hydrogel with wide adjustability The glue material and its preparation method, the material has good biocompatibility and can be widely used as an injectable slow-release carrier material.

A further object of the present invention is to provide a thermosensitive injectable sustained/controlled release drug delivery system for parenteral administration of hydrophilic and hydrophobic drugs, proteins and polypeptides, nucleic acids/genes, hormones and antineoplastic drugs medicine.

Specifically, the present invention provides a class of thermoreversible hydrogels composed of mixtures of polymers. The thermally reversible gelling hydrogel composition of the present invention is a mixture of two or more polymers, and its water system has the property of temperature-sensitive reversible gelling. When the temperature is lower than the sol-gel transition temperature When the polymer mixture is soluble in water, when the temperature is higher than the sol-gel transition temperature, the aqueous solution of the polymer mixture forms a gel, and this process is reversible; the polymer includes polyethylene glycol (PEG) is a block copolymer composed of a hydrophilic block and a degradable polyester is a hydrophobic block.

The water system with one or more block copolymers in the polymer mixture of the present invention alone does not have the property of thermally reversible gelation, and the one or more block copolymers themselves are in the range of 1-50°C All can only be dissolved in water, so thermally reversible gelation cannot occur alone; or, one or more block copolymers cannot dissolve in water or cannot be completely dissolved in water in the range of 1-50°C, so they can not be dissolved in water alone. Thermally reversible gelation cannot occur.

In the polymer mixture of the present invention, one or more than one block copolymers themselves can only be dissolved in water within the range of 1-50°C. Not soluble in water or not completely soluble in water.

The aqueous system of each block copolymer in the polymer mixture of the present invention may also not have the property of thermally reversible gelation.

The content of each block copolymer in the polymer mixture of the present invention is 5-95% by weight.

The block copolymer of the present invention comprises 10-90 wt% of a hydrophilic A polymer block containing polyethylene glycol having an average molecular weight of 400 to 8000 and 90-10 wt% of a hydrophobic B polymer block.

The hydrophobic B polymer block of the present invention is a polyester having an average molecular weight of 500-40,000.

The polyester of the present invention is selected from various polyDL-lactide, polyD-lactide, polyL-lactide, polyglycolide, polyorthoester, polyε-caprolactone, polyε- Any one of alkyl-substituted caprolactone, polyδ-valerolactone, polyesteramide, polycarbonate, polyacrylate, polyetherester, and any form of copolymer of the above-mentioned types of polyesters.

The block copolymer of the present invention is ABA, the triblock copolymer of BAB block configuration, the diblock copolymer of BA block configuration and A(BA) _n or B(AB) _n block configuration Multi-block copolymers, wherein n is an integer from 2 to 10.

The polymer mixture and solvent system of the present invention may include other types of polymer and/or non-polymer components in addition to the block copolymer and solvent.

The weight percentage content of the polymer mixture of the present invention in the aqueous solution is between 3-50%.

The solvent in the polymer mixture solution of the present invention can be pure water, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid or cell culture fluid, as well as other aqueous solutions and media not based on organic solvents.

The hydrogel composition of the present invention is prepared by the following method:

First mix two or more polymers, and then dissolve the polymer mixture in water at low temperature; or first dissolve two or more polymers separately at low temperature, and then mix their respective aqueous solutions; or first dissolve at low temperature with water solubility polymer, and then adding a polymer that does not have or does not have water solubility for solubilization to prepare a hydrogel composition. The low temperature mentioned above means below the sol-gel transition temperature of the composition. The prepared aqueous solution of the polymer mixture is capable of thermally reversible formation of a hydrogel at a temperature above the sol-gel transition temperature.

In the above method, low temperature refers to 0°C to room temperature.

In the above method, low temperature especially refers to the refrigerator storage temperature (4° C.).

In the above method, the polymer is a block copolymer composed of polyethylene glycol (PEG) as a hydrophilic block and degradable polyester as a hydrophobic block.

In the above method, the block copolymer is obtained by thermal condensation or ring-opening polymerization.

In the above method, the catalyst used in the ring-opening polymerization is stannous isooctanoate, calcium hydride or zinc powder.

In the above method, the water system with one or more block copolymers in the mixture does not have the property of thermally reversible gelation alone, and the one or more block copolymers themselves are homogeneous in the range of 1-50°C. It can only be dissolved in water, so thermally reversible gelation cannot occur alone; or, one or more block copolymers are insoluble in water or cannot be completely dissolved in water in the range of 1-50°C, so they cannot be dissolved alone Thermally reversible gelation occurs.

In the above method, one or more block copolymers in the mixture can only be dissolved in water in the range of 1-50°C, and at the same time, one or more block copolymers in the mixture can only be dissolved in water in the range of 1-50°C Insoluble in water or not completely soluble in water.

In the above method, the aqueous system of each block copolymer in the mixture does not have the property of thermally reversible gelation.

In the above method, the content of each block copolymer in the mixture is 5-95% by weight.

In the above method, the block copolymer comprises:

a) 10-90% by weight of a hydrophilic A polymer block containing polyethylene glycol having an average molecular weight of 400 to 8000;

b) 90-10 wt% of hydrophobic B polymer blocks.

In the above method, the hydrophobic B polymer block is a polyester having an average molecular weight of 500-40,000.

In the above method, the polyester is selected from various polyDL-lactide, polyD-lactide, polyL-lactide, polyglycolide, polyorthoester, polyε-caprolactone, polyε -Any one of alkyl-substituted caprolactone, polydelta-valerolactone, polyesteramide, polycarbonate, polyacrylate or polyetherester, and any form of copolymer of the above-mentioned types of polyesters.

In the above method, the block copolymer is a triblock copolymer of ABA, BAB block configuration, a diblock copolymer of BA block configuration or A(BA) _n or B(AB) _n block configuration A multi-block copolymer, wherein n is an integer from 2 to 10.

In the above method, the weight percentage of the polymer mixture in the aqueous solution is between 3-50%.

In the above method, the solvent in the polymer mixture solution can be pure water, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid or cell culture fluid, and other aqueous solutions and media that do not contain organic solvents as the main body.

In the above method, the ratio of the block copolymer can be adjusted to obtain the desired sol-gel transition temperature and degradation rate.

In the above method, other types of polymers and even non-polymer components can be further mixed in the mixture containing block copolymers to promote the appearance of physical gel or adjust the sol-gel transition temperature in solution, the material's Degradation rate and other parameters.

In the temperature-sensitive injectable sustained/controlled release drug delivery system composed of a polymer mixture solution and an effective amount of drugs uniformly contained therein, the polymer mixture is a mixture of two or more polymers It contains a block copolymer composed of polyethylene glycol (PEG) as a hydrophilic block and degradable polyester as a hydrophobic block. Its water system has the property of temperature-sensitive reversible gelation. When When the temperature is lower than the sol-gel transition temperature, the polymer mixture is soluble in water, and when the temperature is higher than the sol-gel transition temperature, the aqueous solution of the polymer mixture forms a gel.

In an injectable sustained/controlled release drug delivery system composed of a polymer mixture solution and a drug of the present invention, the drug is a hydrophilic drug or a hydrophobic drug, which can be a protein, a polypeptide, a nucleic acid, a gene, a hormone, and an antibacterial drug. One or more of the tumor drugs.

In the injectable sustained/controlled release drug delivery system composed of polymer mixture solution and drug of the present invention, the drug can be hydrophilic drug, hydrophobic drug or their mixture.

In the temperature-sensitive injectable sustained/controlled release drug delivery system of the present invention, the weight percentage content of the polymer mixture in the aqueous solution is between 3-50%.

The solvent in the polymer mixture solution in the temperature-sensitive injectable slow/controlled release drug delivery system of the present invention can be pure water, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid, cell culture fluid, As well as other aqueous solutions and media not based on organic solvents.

In the temperature-sensitive injectable sustained/controlled release drug delivery system of the present invention, the drug can be partially or completely dissolved in the polymer mixture solution. When the drug is partially dissolved or substantially insoluble, it may exist in the form of suspension or emulsion.

The temperature-sensitive injectable sustained/controlled release drug delivery system of the present invention can be administered through parenteral, eye, subcutaneous, intramuscular, vaginal, urethral, nasal or pulmonary injections to produce local or systemic therapeutic effects, wherein The drug loading of the system is not limited unless it affects the physical gelation behavior of the polymer mixture such that it cannot form a gel.

The present invention has the advantage that:

The hydrogel material proposed by the present invention has reversible thermosensitivity, and its polymer mixture can show water solubility at normal temperature or lower than normal temperature, and can be used under the physiological conditions of warm-blooded animals (that is, at a pH value of about 7 and at 37°C) ) can undergo reversible gelation, so that the preparation process of the drug delivery system is simple and the drug delivery is convenient.

The thermosensitive material based on the mixture proposed by the present invention obviously expands the use range of the corresponding block copolymer, so that many polymers that are completely dissolved in water without thermosensitive gelation and precipitate in water without thermosensitive gel The gelation phenomenon that did not exist in the mixed polymer appeared in the way of mixing, which is convenient for medical application.

Even for materials that can show heat-sensitive gelation in water, the mixing method proposed by the present invention also provides a convenient method for adjusting the gelation transition temperature; and as an injectable reversible heat-sensitive medical material, its sol - The gel transition temperature is expected to be between 0-37°C, which is of great significance in medical applications.

The hydrogel material proposed by the present invention has good biocompatibility, degradability and gel flexibility, and the material will be completely degraded into non-toxic α-alkyd and other corresponding monomers within a given time .

The hydrogel material proposed by the invention can increase the solubility of some insoluble drugs and improve the stability of the drugs.

The degradation rate of the material and the release rate of the drug in the temperature-sensitive injectable slow/controlled release drug delivery system proposed by the present invention can be changed by changing the mixing ratio of the polymer used for mixing, the composition of the polymer itself, and the concentration of the polymer. , molecular weight and polydispersity, adding other types of polymer or non-polymer components to adjust.

For ease of understanding, the present invention will be described in detail below through specific drawings and embodiments. It should be pointed out that the specific examples and accompanying drawings are only for illustration. Obviously, those skilled in the art can make various amendments and changes within the scope of the present invention according to the description herein. These amendments and Modifications are also included within the scope of the present invention.

Description of drawings

Fig. 1 illustrates the phase diagram of the aqueous solution of the block copolymer mixture mixed according to different weight ratios as the temperature changes, measured by the small tube inversion method.

Figure 2 illustrates the release curves of lysozyme from triblock copolymer mixture hydrogels obtained by mixing different weight ratios.

Detailed ways

Example 1

Add PEG (1500) in a 250ml three-necked flask, heat the oil bath to 150°C, and vacuum filter for three hours under stirring to remove the residual moisture in the PEG, then add DL-lactide and After glycolide was heated under vacuum to make it melt completely, 120 μl of stannous octoate was added, the temperature of the oil bath was raised to 160° C., and the reaction was continued for 24 hours under an argon atmosphere. After the reaction was completed, vacuum filtration was performed for two hours to remove unreacted monomers and low-boiling products. The initial product was dissolved in dichloromethane solution and precipitated with ether, the yield was about 80%. Measure the number average and weight average molecular weight ( _Mn , _Mw ) of the BAB block copolymer (PLGA-PEG-PLGA, Copolymer-1) by gel permeation chromatography (GPC) (using polystyrene as a standard sample) ) were 5510 and 6390, respectively, and the molecular weight distribution coefficient (M _w /M _n ) was 1.16. The copolymer itself does not have the property of thermally reversible gelation in water.

Example 2

Add single-ended methoxypolyethylene glycol MPEG (550) into a 250ml three-necked flask, heat the oil bath to 150°C, and vacuum filter for three hours under stirring to remove residual moisture in MPEG, and then add a molar ratio of 3 : 1 DL-lactide and glycolide, heated under vacuum to make it completely melted, then added 120 μl of stannous octoate, the oil bath was heated to 160° C., and the reaction was continued for 24 hours under an argon atmosphere. After the reaction was completed, vacuum filtration was performed for two hours to remove unreacted monomers and low-boiling products. The initial product was dissolved in dichloromethane solution and precipitated with ether, the yield was about 85%. Measure the number average and weight average molecular weight (M _n , M _w ) of the BA block copolymer (MPEG-PLGA, Copolymer-14) by gel permeation chromatography (GPC) (using polystyrene as a standard sample), respectively are 3550 and 4620, and the molecular weight distribution coefficient (M _w /M _n ) is 1.30. The copolymer itself does not have the property of thermally reversible gelation in water.

Example 3

Add the mixture of polyethylene glycol (1000) and PLGA ( _Mn 4750, _Mw 6020, LA/GA=1/1) in a 250ml three-necked flask, heat it under vacuum to make it melt completely, then heat up the oil bath to 160°C The condensation reaction was 18 hours. After the reaction is complete, the initial product is dissolved in dichloromethane solution and precipitated with a large amount of ether, and the yield is about 85%. The number average and weight average molecular weight (M _n , M _w ) of the BAB block copolymer measured by gel permeation chromatography (GPC) (using polystyrene as a standard sample) are 6520 and 8340 (PLGA-PEG- PLGA, Copolymer-15), the molecular weight distribution coefficient (M _w /M _n ) is 1.28. The copolymer itself does not have the property of thermally reversible gelation in water.

Example 4

Following the basic procedure given in Example 1, other block copolymers were synthesized using PEGs of different molecular weights and different monomers.

The block copolymers in Table 1 and Table 2 do not have the performance of thermally reversible gelation, wherein the block copolymers in Table 1 can only be dissolved in water, and the block copolymers in Table 2 cannot be dissolved in water or cannot It is completely soluble in water; and the block copolymers in Table 3 have thermally reversible gelation properties. One or more block copolymers can be selected from Table 3 and one or more block copolymers selected from Table 1 and/or Table 2 can be selected from Table 1 and/or Table 2. The mixture obtained by mixing in a certain proportion can be obtained at a temperature lower than the condensation temperature. Soluble in water at the gel transition temperature, when the temperature is higher than the gel transition temperature, the aqueous solution of the polymer mixture forms a gel, and this process is reversible; one or more blocks can also be selected from Table 1 The mixture obtained by mixing the copolymer with one or more block copolymers selected from Table 2 in a certain ratio also has the property of thermally reversible gelation.

Table 1

Table 2:

table 3:

Example 5

First mix the block copolymer Copolymer-1 in the table 1 and the block copolymer Copolymer-9 in the table 2 with the ratio of 1/1 to obtain the corresponding mixture, then add a certain amount of water, and it is formulated to have a concentration of 25% by weight % of the sample, and finally the polymer mixture was dissolved in water by magnetic stirring at refrigerator temperature (4° C.) to prepare the corresponding aqueous solution. The aqueous solution of the prepared polymer mixture can spontaneously form a gel at a temperature above the sol-gel transition temperature.

Example 6

First prepare an aqueous solution of block copolymer Copolymer-1 with a weight percentage concentration of 12.5% at room temperature, then add the same weight percentage of block copolymer Copolymer-9 to the above aqueous solution, and finally stir magnetically at room temperature to make the block The copolymer Copolymer-9 is solubilized into the solution, and the corresponding aqueous solution with a concentration of 25% by weight is prepared. The prepared aqueous solution of the polymer mixture can spontaneously form a gel when the temperature is higher than the sol-gel transition temperature; and the gel performance is the same as that of the sample prepared in Example 5.

Example 7

First prepare the aqueous solution of the block copolymer Copolymer-1 and the block copolymer Copolymer-16 of the same weight percent concentration at the refrigerated temperature (4 ℃) of the weight percent concentration of 25%, and then uniformly mix them in the ratio of 1/1 The above solutions were mixed to prepare aqueous solutions of the corresponding polymer mixtures. The prepared aqueous solution of the polymer mixture is capable of spontaneously forming a gel at a temperature above the sol-gel transition temperature.

Example 8

The gelation behavior of the triblock copolymer mixture obtained by mixing the block copolymers Copolymer-1 and Copolymer-9 according to different weight ratios in aqueous solution was studied and analyzed. Prepare aqueous solutions of the mixture with different weight percent concentrations from 5% to 25%, and measure the viscosity change between 0°C and 60°C. Gelation was defined by observing that no flow occurred within 20 seconds when the tube was inverted. Figure 1 shows the phase diagram of the sample obtained by mixing different weight ratios of Copolymer-1 and Copolymer-9 and its aqueous solutions with different concentrations as the temperature changes.

Example 9

When Copolymer-1 and Copolymer-9 were mixed in a 1/1 weight ratio to obtain a concentration of 25% aqueous solution, when 2% by weight PEG (2000) polymer was added, the sol-gel transition temperature decreased from 34°C to 32°C. ℃.

Example 10

In PBS with a pH of 7.4, the in vitro degradation of Copolymer-1 and Copolymer-9 mixed in a 1/1 or 1/2 weight ratio to obtain a 25% aqueous solution or gel (1 ml) at 37° C. was measured. It degrades through the hydrolysis of ester bonds, and its degradation period is more than 5 weeks, and the final products are lactic acid, glycolic acid, and polyethylene glycol.

Example 11

Research and observation Copolymer-1 and Copolymer-9 were mixed in a weight ratio of 1/1 or 1/2 to obtain a 25% aqueous solution, and 20 mg of lysozyme was dissolved in 1 ml of the above polymer aqueous solution. After gel formation at 37°C, 8 ml of PBS buffer solution with pH 7.4 was added. At intervals, remove 4ml of PBS buffer from the tube and add fresh 4ml of PBS buffer to keep the volume constant. Lysozyme can be continuously released for more than 50 days in vitro. Figure 2 shows the release profiles of lysozyme from triblock copolymer mixture hydrogels mixed in different weight ratios.

Example 12

Both hydroxycamptothecin and paclitaxel are hydrophobic drugs, which are almost insoluble in water. However, the present invention mixes Copolymer-1 and Copolymer-9 in a 1/2 weight ratio to obtain a concentration of 25% aqueous solution. The solubility of hydroxycamptothecin is as high as 5 mg/ ml, the solubility of paclitaxel is as high as 7mg/ml. And after storage for 90 days, more than 85% of the original drug is maintained, and the stability of the drug is significantly improved.

Example 13

The concentration of the block copolymer Copolymer-16 in Table 3 is that the 25% aqueous solution undergoes a sol-gel transition at 11° C. to form a hydrogel; the 25% aqueous solution of Copolymer-1 does not have the performance of thermosensitive gelation; The sol-gel transition temperature of the samples obtained by mixing the above two solutions in different weight ratios can be adjusted between 11°C and 37°C.

Claims (32)

1. A physically cross-linked hydrogel composition, characterized in that, it is mixed with two or more polymers to form a mixture, and its water system has the property of temperature-sensitive reversible gelation, when the temperature is lower than the sol- During the gel transition temperature, the mixture can be dissolved in water, and when the temperature is higher than the sol-gel transition temperature, the aqueous solution of the mixture forms a gel; wherein the polymer comprises polyethylene glycol as a hydrophilic block, Degradable polyester is a block copolymer composed of hydrophobic blocks. 2. The physically cross-linked hydrogel composition according to claim 1, wherein the aqueous system having one or more block copolymers in the mixture does not have the property of thermally reversible gelation alone . 3. The physically cross-linked hydrogel composition according to claim 2, characterized in that, in the mixture, one or more block copolymers themselves can only be dissolved in In water, thermally reversible gelation cannot occur alone, or cannot be dissolved in water or completely dissolved in water, and thermally reversible gelation cannot occur alone. 4. The physically cross-linked hydrogel composition according to claim 2, characterized in that, in the mixture, one or more block copolymers themselves can only be dissolved in In water, at the same time, one or more block copolymers cannot dissolve in water or completely dissolve in water within the range of 1-50°C. 5. The physically cross-linked hydrogel composition according to claim 1, wherein the aqueous system of each block copolymer in the mixture does not have the property of thermally reversible gelation alone. 6. The physically cross-linked hydrogel composition according to claim 1, wherein the content of each block copolymer in the mixture is 5-95% by weight. 7. The physically crosslinked hydrogel composition according to claim 1, wherein the block copolymer comprises: a) 10-90% by weight of a hydrophilic A polymer block containing polyethylene glycol having an average molecular weight of 400 to 8000; b) 90-10 wt% of hydrophobic B polymer blocks. 8. The physically cross-linked hydrogel composition according to claim 7, wherein the hydrophobic B polymer block is a polyester having an average molecular weight of 500-40,000. 9. The hydrogel composition of physical crosslinking according to claim 8, is characterized in that, described polyester is selected from various poly DL-lactide, poly D-lactide, poly L-lactide Lactide, polyglycolide, polyorthoester, polyε-caprolactone, polyε-alkyl substituted caprolactone, polyδ-valerolactone, polyesteramide, polycarbonate, polyacrylate or poly Any one of ether esters and any form of copolymer of the above-mentioned types of polyesters. 10. The hydrogel composition of physical crosslinking according to claim 1, is characterized in that, described block copolymer is the triblock copolymer of ABA, BAB block configuration, BA block configuration Diblock copolymers or multiblock copolymers of A(BA) _n or B(AB) _n block configuration, wherein n is an integer from 2 to 10. 11. The physically cross-linked hydrogel composition according to claim 1, wherein the weight percentage of the mixture in the aqueous solution is between 3-50%. 12. The physically cross-linked hydrogel composition according to claim 1, wherein the solvent in the mixture solution is selected from pure water, physiological saline, buffer solution, body fluids of animals, plants or human body, tissue culture Liquid or cell culture fluid, and other aqueous solutions and media not based on organic solvents. 13. A method for preparing a physically crosslinked hydrogel composition, characterized by comprising the steps of: First mix two or more polymers, and then dissolve the mixture in water at low temperature; or first dissolve two or more polymers at low temperature, and then mix their respective aqueous solutions; or first dissolve water-soluble polymers at low temperature substance, and then adding a polymer that does not have or does not have water solubility for solubilization to prepare a hydrogel composition; the low temperature is lower than the sol-gel transition temperature of the composition; the aqueous solution of the prepared mixture is in Thermally reversible formation of hydrogels is possible at temperatures above the sol-gel transition temperature. 14. The preparation method according to claim 13, characterized in that the low temperature is from 0°C to room temperature. 15. The preparation method according to claim 13, characterized in that, the low temperature is a refrigerator refrigeration temperature. 16. The preparation method according to claim 13, characterized in that, the polymer is a block copolymer composed of polyethylene glycol as a hydrophilic block and degradable polyester as a hydrophobic block. 17. The preparation method according to claim 13, characterized in that the polymer is prepared by thermal condensation or ring-opening polymerization. 18. The preparation method according to claim 13, characterized in that, the aqueous system containing one or more block copolymers in the mixture does not have the property of thermally reversible gelation alone. 19. The preparation method according to claim 13, characterized in that, in the mixture, one or more block copolymers themselves can only be dissolved in water within the range of 1-50°C, and cannot be thermally reversible alone. Gelation, or insoluble in water or incompletely soluble in water, thermally reversible gelation alone cannot occur. 20. The preparation method according to claim 13, characterized in that, in the mixture, one or more block copolymers themselves can only be dissolved in water within the range of 1-50°C, and at the same time, another Or more than one block copolymer is insoluble or insoluble in water within the range of 1-50°C. 21. The preparation method according to claim 13, characterized in that the aqueous system of each block copolymer in the mixture does not have the property of thermally reversible gelation alone. 22. The preparation method according to claim 13, characterized in that, the weight percent content of each block copolymer in the mixture is between 5-95%. 23. The preparation method according to claim 13, wherein the block copolymer comprises: a) 10-90% by weight of a hydrophilic A polymer block containing polyethylene glycol having an average molecular weight of 400 to 8000; b) 90-10 wt% of hydrophobic B polymer blocks. 24. The preparation method of the hydrogel composition according to claim 23, characterized in that, the hydrophobic B polymer block is a polyester with an average molecular weight of 500-40000. 25. The preparation method according to claim 24, wherein the polyester is selected from various polyDL-lactides, polyD-lactides, polyL-lactides, polyglycolides, Any of polyorthoester, polyε-caprolactone, polyε-alkyl substituted caprolactone, polyδ-valerolactone, polyesteramide, polycarbonate, polyacrylate or polyetherester and Copolymers of any of the above-mentioned types of polyesters. 26. The preparation method according to claim 13, characterized in that, the block copolymer is a triblock copolymer of ABA, BAB block configuration, a diblock copolymer of BA block configuration or A (BA) _n or B(AB) _n multi-block copolymers in block configuration, wherein n is an integer from 2 to 10. 27. The preparation method according to claim 13, characterized in that the weight percentage of the mixture in the aqueous solution is between 3-50%. 28. The preparation method according to claim 13, characterized in that, the solvent in the mixture solution can be pure water, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid or cell culture fluid, and Other aqueous solutions and media not based on organic solvents. 29. A temperature-sensitive injectable sustained/controlled release drug delivery system composed of a polymer mixture solution and a drug, characterized in that the mixture is the mixture of claim 1, and the drug is a protein, a polypeptide One or more of , nucleic acid, gene, hormone and antitumor drug. 30. The temperature-sensitive injectable sustained/controlled release drug delivery system according to claim 29, characterized in that the weight percentage of the mixture in the aqueous solution is between 3-50%. 31. The temperature-sensitive injectable sustained/controlled release drug delivery system according to claim 29, wherein the solvent in the mixture solution is pure water, physiological saline, buffer solution, animal, plant or human body fluid , tissue culture fluid or cell culture fluid, and other aqueous solutions and media not based on organic solvents. 32. The temperature-sensitive injectable slow/controlled release drug delivery system according to claim 29, characterized in that, the drug delivery system passes through the parenteral tract, eyes, subcutaneous, muscle, vagina, urethra, nasal cavity or Pulmonary injection, in which the drug loading of the drug delivery system is not limited, unless the physical gelation behavior of the mixture is affected so that it cannot form a gel.

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