CN113461973B - Injectable medical hydrogel - Google Patents

Injectable medical hydrogel Download PDF

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CN113461973B
CN113461973B CN202110827431.5A CN202110827431A CN113461973B CN 113461973 B CN113461973 B CN 113461973B CN 202110827431 A CN202110827431 A CN 202110827431A CN 113461973 B CN113461973 B CN 113461973B
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polyethylene glycol
arm
aldehyde
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CN113461973A (en
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潘震
闫振坤
陈亮
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Shanghai Ruining Biotechnology Co ltd
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Abstract

The invention discloses a medical hydrogel, which is formed by cross-linking aldehyde-terminated star-shaped multi-arm polyethylene glycol, polyethyleneimine and hydrazide-terminated multi-arm polyethylene glycol, wherein the number of arms of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 2-8, and the molecular weight of a single arm is 1000-5000Da. The invention obtains the injectable hydrogel with rapid gelling and long-term stability by selecting the molar ratio of aldehyde-terminated multi-arm polyethylene glycol, polyethyleneimine and hydrazide-terminated polyethylene glycol.

Description

Injectable medical hydrogel
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a medical hydrogel which can be used as a radiation protection material for fields of radiotherapy gaskets, vascular embolization, postoperative tissue sealing and leakage prevention, tissue adhesion prevention, tissue fillers, tissue repair, skin dressing, drug release and the like.
Background
The hydrogel is a soft material containing a large amount of moisture, which is obtained by crosslinking a hydrophilic polymer. The hydrogel has excellent physical and chemical properties and biological characteristics, such as high water content, high elasticity, softness, biocompatibility and the like, and has important application value in the biomedical research fields of drug delivery, tissue engineering and the like. Injectable hydrogels are hydrogels having a certain fluidity, which can be applied by an injection method, exhibit phase transition between sol and gel for external stimuli (changes in temperature, temperature/pH, etc.), are in a liquid state or a semi-solid state having shear thinning properties before being injected into a human body, and can form gel in situ after being injected into the human body, thereby eliminating the need for invasive surgery, effectively avoiding the risk of infection, and reducing the pain of patients. Various injectable PEG hydrogels that have been developed so far include amphiphilic polyester/polypeptide hydrogels with PEG as the hydrophilic segment, PEG hydrogels prepared by supramolecular interactions, and PEG hydrogels prepared by mild chemical reactions.
Polyethylene glycol (PEG) is a class of nonionic polymers, and is a class of synthetic polymers approved by the U.S. Food and Drug Administration (FDA) for clinical applications in humans due to its good biocompatibility and safety. PEG can be used as a pharmaceutic adjuvant, and can also be used for modifying (pegylating) a medicament by using PEG containing a terminal active functional group. The pegylation technology has more advantages, and particularly has the characteristics of prolonging the in vivo circulation time, enhancing the biological activity, avoiding proteolysis and reducing the immune response in the aspect of modifying protein and polypeptide medicaments. Polyethylene glycol conjugates can be prepared by attaching reactive terminal functional groups such as amino, thiol, azide, alkynyl, and aldehyde groups to improve the performance of polyethylene glycol.
The PEG hydrogel is one of ideal materials for tumor radiotherapy gaskets and postoperative tissue sealing, leakage prevention and the like. These application scenarios generally require hydrogels to have a relatively fast gel formation speed and to maintain stability in vivo for a period of time.
CN105963792A discloses a medical hydrogel composition, comprising a first component and a second component, wherein the first component comprises polylysine and polyethyleneimine; the second component comprises one or more of four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate and four-arm-polyethylene glycol-succinimide carbonate. When the gel is used, the nucleophilic reagent (polylysine and polyethyleneimine) of the first component and the electrophilic reagent (one or more of four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate and four-arm-polyethylene glycol-succinimide carbonate) of the second component are subjected to Michael addition reaction, so that the gel can be rapidly formed and has the excellent property of low swelling. However, the succinimide organic acid ester-terminated polyethylene glycol material has a short half-life in water, is very easily hydrolyzed, requires a special technique to be stored in a powder form at room temperature for a long period of time, and is used within a short time (generally 1 hour) after dissolution, and is low in convenience.
Chinese patent document CN109646723A discloses a medical hydrogel which is formed by adopting aldehyde-terminated multi-arm polyethylene glycol and a mixture of polyethyleneimine and polylysine. The polylysine serving as a special polyamino compound can form hydrogel with high stability with aldehyde-group-terminated polyethylene glycol, but Schiff base structures formed by amino groups and benzaldehyde groups of most polyamino compounds are easy to hydrolyze, so that the gel stability is poor.
Apostolides et al (Macromolecules 2017,50,5, 2155-2164) disclose the use of hydrazide-terminated polyethylene glycols to react with benzaldehyde-terminated polyethylene glycols to produce highly stable hydrogels, greatly expanding the variety of polymers that can be used to produce highly stable hydrogels. However, the reaction speed of the benzaldehyde and hydrazide-terminated polyethylene glycol is slow under neutral pH, so that the gel forming speed is slow, and the method is not suitable for many application scenes needing rapid gelation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an injectable medical hydrogel, and the hydrogel has higher gelling speed and gel stability through specific system regulation.
The specific technical scheme of the invention is as follows:
a medical hydrogel is prepared by in-situ crosslinking of aldehyde-terminated star-shaped multi-arm polyethylene glycol, hydrazide-terminated star-shaped multi-arm polyethylene glycol and polyamino compounds.
Preferably, the molar ratio of aldehyde group, hydrazide group and amino group in polyethyleneimine is 1:0.2 to 5:0.2 to 5. More preferably 1. More preferably 1:1:1.
the aldehyde group and the star-shaped multi-arm polyethylene glycol are connected by ester bonds, ether bonds, amido bonds, urethane bonds, imine bonds or urea bonds.
Preferably, the aldehyde group is connected with the star-shaped multi-arm polyethylene glycol through an amido bond or an ester bond, and the hydrazide group is connected with the star-shaped multi-arm polyethylene glycol, the aldehyde-terminated star-shaped multi-arm polyethylene glycol and the hydrazide-terminated star-shaped multi-arm polyethylene glycol can be the same or different, and are preferably the same. The star-shaped multi-arm polyethylene glycol has an arm number of 2-8, more preferably 4-8, and a single-arm molecular weight of 1000-5000Da.
The aldehyde group of the medical hydrogel is selected from one or more of aromatic aldehyde group and alkyl aldehyde group, and is preferably benzaldehyde group.
The invention also aims to provide application of the medical hydrogel in the fields of radiotherapy gaskets, vascular embolization, postoperative tissue sealing and leakage prevention, tissue adhesion prevention, tissue fillers, tissue repair, skin dressing, drug release and the like.
The invention also provides a preparation method of the medical hydrogel, which comprises the steps of dissolving the aldehyde-terminated star-shaped multi-arm polyethylene glycol in a buffer solution with the pH value of 4-10 to prepare an aldehyde-terminated star-shaped multi-arm polyethylene glycol solution; dissolving a polyamino compound and multi-arm star-shaped polyethylene glycol terminated by hydrazide groups in a buffer solution with the pH value of 4-10 to prepare a solution; mixing the two to obtain the medical hydrogel.
The above pH4-10 buffer is preferably a phosphate or borate buffer having a pH of 4-10.
Preferably, the final concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol solution is 2-30% (w/v), preferably 5-20% (w/v); the concentration of the polyamino compound solution is 0.5-20%, preferably 0.5-5% (w/v).
The two-component hydrogel is prepared from a first component containing nucleophilic functional groups and a second component containing electrophilic functional groups, wherein the first component is an aldehyde-terminated hydrophilic compound, the number of arms is not less than two, the hydrophilic compound is aldehyde-terminated star-shaped multi-arm polyethylene glycol, preferably 8-arm, 6-arm and 4-arm polyethylene glycol (the single-arm molecular weight is 1000-5000 Da), and the aldehyde group is one or more of aromatic aldehyde and alkyl aldehyde, preferably benzaldehyde. The aldehyde groups can be linked to the polymer with stable or hydrolysable chemical bonds.
The second component is a mixed component of hydrazide-terminated multi-arm polyethylene glycol and polyethyleneimine.
Figure BDA0003174248690000031
Ester bond connection benzaldehyde end-capped 8-arm polyethylene glycol
Figure BDA0003174248690000032
Ester bond connection benzaldehyde end-capped 6-arm polyethylene glycol
Figure BDA0003174248690000041
Ester bond connection benzaldehyde end-capped 4-arm polyethylene glycol
Figure BDA0003174248690000042
Hydrazide-terminated 8-arm polyethylene glycol
Figure BDA0003174248690000051
Hydrazide-terminated 6-arm polyethylene glycol
Figure BDA0003174248690000052
Hydrazide-terminated 4-arm polyethylene glycol
Figure BDA0003174248690000053
Polyethylene imine
Both of the above components may be provided in the form of an aqueous solution or powder due to the stability of the aldehyde group and the amino group in the aqueous solution. When in use, the two components are respectively dissolved in the buffer solution, and then the components are mixed to obtain the hydrogel. The two components of the hydrogel can be stored in a double-syringe respectively, and the two components are sprayed out through a mixing head or injected to a designated position to form the gel when in use.
The invention utilizes the aldehyde group at the end of the multi-arm polyethylene glycol, the hydrazide group at the end of the multi-arm polyethylene glycol and the amino group of the polyamino compound to react to generate schiff base so as to generate crosslinking and form the medical injectable gel.
The invention has the advantages that:
in view of the fact that hydrogel formed between aldehyde-terminated polyethylene glycol and hydrazide-terminated polyethylene glycol in the prior art cannot meet the requirement of gel forming speed easily, and aldehyde-terminated polyethylene glycol and amino-terminated polyethylene glycol cannot meet the requirement of high stability easily. Compared with the prior art, the medical hydrogel provided by the invention has the advantages of high gelling speed and higher stability.
According to the invention, the molar ratio between the aldehyde group of the aldehyde-group-terminated star-shaped multi-arm polyethylene glycol and the hydrazide group of the hydrazide-group-terminated star-shaped multi-arm polyethylene glycol and the molar ratio between the aldehyde group and the amino group in polyethyleneimine are selected, so that the hydrogel with high gelling speed and high stability is obtained, and the gelling speed and stability can be further adjusted through the molecular weight and the arm number of the polyethylene glycol.
Detailed Description
The following examples illustrate specific steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The invention is described in further detail below with reference to specific examples and data, it being understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1 examination of the Effect of polyethyleneimine and hydrazide-terminated polyethylene glycols on gel formation Rate and gel stability
200mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 10kDa, one-arm molecular weight 1250 Da) was dissolved in 2mL of a phosphate buffer solution (pH 5.6) as a solution A; preparing borax buffer solution (pH9.2) containing 8-arm polyethylene glycol (molecular weight 10kDa, single-arm molecular weight 1250 Da) and/or polyethyleneimine (M.W.1.8K) blocked by hydrazide as solution B; and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Molar ratio of polyethyleneimine amino, hydrazide group to benzaldehyde group Gel forming time Gel stability
1 0:1:1 45min More than 6 weeks
2 1:0:1 4s Less than 24 hours
3 1:1:1 7s For more than 4 weeks
Experimental results show that the gelling speed of the benzaldehyde-terminated polyethylene glycol and the hydrazide-terminated polyethylene glycol is low (45 min) but the stability of the formed gel is high, and the gelling speed of the benzaldehyde-terminated polyethylene glycol and polyethyleneimine is high but the stability of the formed gel is poor. The gel forming speed of the benzaldehyde-terminated polyethylene glycol and the mixed solution is high, and the gel stability is high.
Example 2 the effect of amino terminated multi-arm star polyethylene glycol and hydrazide terminated star polyethylene glycol on gel formation time and stability was examined.
200mg of benzaldehyde-terminated star-shaped multi-arm polyethylene glycol connected by an ester bond is dissolved in 2mL of phosphate buffer (pH 5.6) to be used as A solution; preparing a borax buffer solution (pH 9.2) containing hydrazide-terminated or amino-terminated multi-arm polyethylene glycol (the molar ratio of hydrazide groups or amino groups to benzaldehyde groups is 1) and polyethyleneimine (M.W.1.8K, the molar ratio of benzaldehyde to amino groups is 1) as a solution B; and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Multi-arm polyethylene glycol Terminal group Gel forming time(s) Time of degradation
1 8 arm, 10kDa Hydrazide group 7 For more than 4 weeks
2 8 arm, 20kDa Hydrazide group 25 More than 3 weeks
3 8 arm, 10kDa Amino group 8 Less than 24h
4 8 arm, 20kDa Amino group 28 Less than 24h
The experimental result shows that compared with the polyethylene glycol blocked by the hydrazide group, the gel formed by the polyethylene glycol blocked by the amino group has poor stability, and the chemical bond formed by the benzaldehyde and the hydrazide group is more stable than the chemical bond formed by the benzaldehyde and the amino group.
Example 3 examination of the Effect of other polyamino Compounds on gel time relative to polyethyleneimine
200mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 10kDa, one-arm molecular weight 1250 Da) was dissolved in 2mL of a phosphate buffer (pH 5.6) to prepare a solution A; preparing borax buffer solution (pH 9.2) solution containing 8-arm polyethylene glycol (with the molecular weight of 10kDa and the single-arm molecular weight of 1250 Da) with an acyl hydrazine end capping (the molar ratio of hydrazide to benzaldehyde group is 1); and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Class of polyamino compounds Molar ratio of amino group to benzaldehyde group Gel forming time
1 Polyethylene imine 1:1 7s
2 Polylysine 1:1 50s
The experimental results show that the gel forming speed of the hydrogel based on polyethyleneimine is obviously higher than that of polylysine.
Example 4 examination of gel formation speed and gel stability of gels formed by different concentrations of polyethyleneimine
200mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 10kDa, one-arm molecular weight 1250 Da) was dissolved in 2mL of a phosphate buffer solution (pH 5.6) as a solution A; preparing a borax buffer solution (pH 9.2) containing 8-arm polyethylene glycol (with the molecular weight of 10kDa and the single-arm molecular weight of 1250Da and the molar ratio of hydrazide groups to benzaldehyde groups of 1) and polyethyleneimine (M.W.1.8K) of an acyl-hydrazide end-capped terminal as a B solution; and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Molar ratio of polyethyleneimine amino groups to benzaldehyde groups Gel forming time Gel stability
1 0:1 45min More than 6 weeks
2 0.25:1 109s For more than 4 weeks
3 0.5:1 10s For more than 4 weeks
4 1:1 7s For more than 4 weeks
The results show that the use amount of the polyethyleneimine remarkably influences the gelling speed of the hydrogel, when the polyethyleneimine is not added, the gelling time is slow, and when the molar ratio of the amino group to the benzaldehyde group of the polyethyleneimine is more than 0.25, the gelling time is remarkably shortened. The amount of polyethyleneimine also affects the stability of the hydrogel, with gel stability being highest when no polyethyleneimine is added, and over 6 weeks, the addition of polyethyleneimine can affect gel stability, although the gel can still remain stable for 4 weeks.
Example 5 examination of the Effect of the molar ratio of hydrazide to benzaldehyde group in hydrazide-terminated Star-shaped Multi-armed polyethylene glycol on gel formation speed and gel stability
200mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 10kDa, one-arm molecular weight 1250 Da) was dissolved in 2mL of a phosphate buffer solution (pH 5.6) as a solution A; preparing borax buffer solution (pH9.2) containing 8-arm polyethylene glycol (with a molecular weight of 10kDa and a single-arm molecular weight of 1250 Da) and polyethyleneimine (M.W.1.8K, and the molar ratio of the polyethyleneimine to a benzaldehyde amino group is 1) of an acyl hydrazine end capping as a B solution; and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Figure BDA0003174248690000081
The result shows that the molar ratio of the hydrazide to the aldehyde group in the hydrazide-terminated star-shaped multi-arm polyethylene glycol has little influence on the gelling time under the same polyethyleneimine concentration; the mole ratio of the hydrazide group to the aldehyde group obviously influences the gel stability, the gel stability is poor when no hydrazide-terminated polyethylene glycol is added, and the gel stability is obviously improved when the mole ratio of the hydrazide group to the aldehyde group is more than 0.2.
Example 6 examination of the Effect of polyethylene glycols of different molecular weights and arm counts on gel formation Rate and gel stability
200mg of benzaldehyde-terminated star-shaped multi-arm polyethylene glycol connected by an ester bond is dissolved in 2mL of phosphate buffer (pH 5.6) to be used as A solution; preparing a borax buffer solution (pH 9.2) containing hydrazide-terminated multi-arm polyethylene glycol (the molar ratio of hydrazide to benzaldehyde is 1); and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Number of arms of multi-arm polyethylene glycol Multi-arm polyethylene glycol single arm molecular weight Gel forming time(s) Time of degradation
1 8 1250 7 For more than 4 weeks
2 8 2500 25 More than 3 weeks
3 6 1250 9 More than 3 weeks
4 6 2500 28 For more than 2 weeks
5 4 1250 12 More than 3 weeks
6 4 2500 40 For more than 2 weeks
The results show that the number of arms and the single-arm molecular weight of the star-shaped multi-arm polyethylene glycol influence the gelling time and the gelling stability of the gel. The number of the arms has certain influence on the gel stability in the gel forming time, and the higher the number of the arms is, the shorter the gel forming time is, and the higher the gel stability is; the single-arm molecular weight has obvious influence on the gelling time and the gel stability, and the higher the single-arm molecular weight is, the longer the gelling time is, and the lower the gel stability is.
Example 7 examination of the influence of the kind of bond between aldehyde group and polyethylene glycol in aldehyde-terminated polyethylene glycol on gel Properties
200mg of benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight: 10 kDa) linked by an ester bond or an amide bond was dissolved in 2mL of a phosphate buffer solution (pH 5.6) to prepare a solution A; preparing a borax buffer solution (pH 9.2) containing 8-arm polyethylene glycol (10 kDa, single-arm molecular weight 1250 Da) with a hydrazide end capping (the molar ratio of hydrazide to benzaldehyde group is 1) and polyethyleneimine (M.W.1.8K) as a B solution; and mixing the solution A and the solution B in equal volume to obtain the viscous hydrogel.
Formulation of Connection key type Gel forming time Gel stability
1 Ester bond 7s For more than 4 weeks
2 Amide bond 6s For more than 4 weeks
The result shows that the connection bond between the aldehyde group and the polyethylene glycol has little influence on the performance of the gel, and the prepared hydrogel has the characteristics of high gelling speed and high gel stability.

Claims (7)

1. The medical hydrogel is characterized by being formed by in-situ crosslinking of aldehyde-terminated star-shaped multi-arm polyethylene glycol, hydrazide-terminated star-shaped multi-arm polyethylene glycol and polyethyleneimine, wherein the molar ratio of aldehyde to amino in the polyethyleneimine is 1:0.2 to 5, wherein the molar ratio of the aldehyde group to the hydrazide group is 1:0.2 to 5, the number of arms of the star-shaped multi-arm polyethylene glycol is 2 to 8, the molecular weight of a single arm is 1000 to 5000Da, and the hydrogel is prepared by the following method:
dissolving the aldehyde-terminated star-shaped multi-arm polyethylene glycol in a phosphate buffer solution with the pH value of 5.6 to prepare an aldehyde-terminated star-shaped multi-arm polyethylene glycol solution; dissolving a polyamino compound and multi-arm star-shaped polyethylene glycol capped by hydrazide groups in a borax buffer solution with the pH value of 9.2 to prepare a solution; mixing the two to obtain the medical hydrogel, wherein the final concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol solution is 2-30% and w/v, the final concentration of the hydrazide-terminated star-shaped multi-arm polyethylene glycol solution is 2-30% and w/v, and the concentration of the polyamino compound solution is 0.5-20% and w/v.
2. The medical hydrogel according to claim 1, wherein the molar ratio of aldehyde groups, hydrazide groups to amino groups in polyethyleneimine is 1:1:1.
3. the medical hydrogel of claim 1, wherein the aldehyde group is chemically linked to the star-shaped multi-armed polyethylene glycol via an ester, ether, amide, urethane, imine or urea linkage.
4. The medical hydrogel according to claim 3, wherein said aldehyde group is linked to said star-shaped multi-arm polyethylene glycol via an amide bond or an ester bond.
5. The medical hydrogel of claim 4, wherein the number of arms of said star-shaped multi-arm polyethylene glycol is from 4 to 8.
6. The medical hydrogel according to claim 1, wherein the aldehyde group is selected from one or more of aromatic aldehyde group and alkyl aldehyde group.
7. Use of the medical hydrogel according to any one of claims 1 to 6 for the preparation of a gasket for radiotherapy, vascular embolization, post-operative tissue sealing and leakage prevention, prevention of tissue adhesion, tissue bulking agent, tissue repair, skin dressing and drug release material.
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