Temperature-sensitive hydrogel and its preparation method and application

Abstract

The present application relates to a kind of temperature-sensitive hydrogel and its preparation method and application, the temperature-sensitive hydrogel includes polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglyceride and water;Wherein, the melting point of the triglyceride is less than or equal to 37 ℃, the number average molecular weight of polycaprolactone segment of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 500Da~4000Da.The temperature-sensitive hydrogel of the present application can form dense, firm and high energy storage modulus gel quickly in room temperature environment.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, and in particular to a thermosensitive hydrogel, its preparation method, and its application. Background Technology

[0002] Thermosensitive hydrogels, due to their ability to achieve autonomous solution-gel phase transitions in response to temperature changes, have shown great application potential in biomedical fields such as controlled drug release, three-dimensional cell culture, and tissue regeneration and repair. Among them, amphiphilic block copolymers composed of polyethylene glycol (PEG) and polycaprolactone (PCL), such as polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) block copolymers, have attracted much attention due to their good biocompatibility, biodegradability, and unique thermosensitive gel behavior.

[0003] Studies have shown that the gelation mechanism of aqueous solutions of polycaprolactone-polyethylene glycol-polycaprolactone block copolymers is generally as follows: with increasing temperature, the hydrophobic polycaprolactone segments dehydrate, inducing aggregation and stacking between micelles, thereby forming a three-dimensional network structure. However, existing thermosensitive hydrogel systems formed by polycaprolactone-polyethylene glycol-polycaprolactone block copolymers still face some challenges in practical applications. First, their gelation process often depends on increasing temperature, limiting their applicability in heat-sensitive applications, such as when blended with heat-labile drugs or cells. Second, the gelation time of polycaprolactone-polyethylene glycol-polycaprolactone block copolymers is relatively long, and their mechanical strength often fails to meet the requirements of specific tissue engineering scaffolds. Summary of the Invention

[0004] Therefore, it is necessary to provide a thermosensitive hydrogel, its preparation method and application, which can rapidly form a dense, strong gel with high energy storage modulus at room temperature.

[0005] A temperature-sensitive hydrogel, the temperature-sensitive hydrogel comprising polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglycerides and water;

[0006] The triglyceride has a melting point of less than or equal to 37°C, and the polycaprolactone segments have a number-average molecular weight of 500 Da to 4000 Da.

[0007] In one embodiment, the fatty acid in the triglyceride is a straight-chain saturated fatty acid.

[0008] In one embodiment, the fatty acid in the triglyceride is selected from at least one of fatty acids having C6 to C10 carbon atoms;

[0009] And / or, the melting point of the triglyceride is -25°C to 37°C.

[0010] In one embodiment, the triglyceride is selected from at least one of trihexanoic acid glyceride, tricaprylic acid glyceride, or tridecanoic acid glyceride.

[0011] In one embodiment, the number-average molecular weight ratio of polyethylene glycol segments to polycaprolactone segments in the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 0.5 to 1.5.

[0012] In one embodiment, the number average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 2000 Da to 10000 Da.

[0013] And / or, the number average molecular weight of the polyethylene glycol segments is 1000 Da to 2000 Da.

[0014] In one embodiment, the mass ratio of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer to water is 0.1:1 to 0.3:1;

[0015] And / or, the mass ratio of the triglyceride to the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 0.005:1 to 0.15:1.

[0016] A method for preparing a thermosensitive hydrogel as described above, the method comprising: mixing polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglyceride and water at 4°C to 25°C, and then allowing it to stand at 20°C to 25°C to form a thermosensitive hydrogel.

[0017] A medical implant made of the thermosensitive hydrogel described above.

[0018] In one embodiment, the medical implant is a thermosensitive drug preparation, which includes a thermosensitive hydrogel and a thermosensitive drug encapsulated in the thermosensitive hydrogel.

[0019] In the thermosensitive hydrogel of the present invention, the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer can form micelles with polycaprolactone segments as the hydrophobic core. At the same time, by controlling the melting point range of triglycerides and the number-average molecular weight of polycaprolactone segments, good water solubility compatibility between triglycerides and polycaprolactone-polyethylene glycol-polycaprolactone block copolymer can be ensured, so that the completely hydrophobic triglycerides can effectively penetrate and solubilize the hydrophobic core, increasing its volume. This allows the system to rapidly form a dense, strong gel with high storage modulus at room temperature. Detailed Implementation

[0020] To facilitate understanding of the present invention, it will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to make the disclosure of the present invention more thorough and complete.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments or examples only and is not intended to limit the invention. The optional scope of the term "and / or" as used herein includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all related listed items.

[0022] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe features or characteristics, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0023] This invention provides a thermosensitive hydrogel, which comprises polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglycerides, and water;

[0024] The triglyceride has a melting point of less than or equal to 37°C, and the polycaprolactone segments have a number-average molecular weight of 500 Da to 4000 Da.

[0025] In this invention, the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer can form micelles with polycaprolactone segments as the hydrophobic core. Simultaneously, by controlling the melting point range of triglycerides and the number-average molecular weight of the polycaprolactone segments, good water solubility and compatibility between the triglycerides and the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer can be ensured. This allows the completely hydrophobic triglycerides to effectively penetrate and solubilize the hydrophobic core, increasing its volume and thus enhancing the hydrophobic interaction between micelles. Under the synergistic hydrophobic effect of triglycerides and polycaprolactone segments, the system can drive micelle aggregation at room temperature, forming a physical cross-linked network, thereby rapidly forming a dense, robust gel with a high storage modulus at room temperature. Specifically, at 20℃~25℃, the required gelation time is 2min~12min, and the storage modulus of the gelled thermosensitive hydrogel is 480Pa~2000Pa.

[0026] Optionally, the fatty acids in the triglycerides can be saturated fatty acids or unsaturated fatty acids, or straight-chain fatty acids or branched fatty acids. Preferably, the fatty acids in the triglycerides are saturated straight-chain fatty acids. Saturated straight-chain fatty acids can form tighter intermolecular interactions with polycaprolactone segments, thereby better exerting the hydrophobic synergistic effect.

[0027] In order to enable the triglyceride and polycaprolactone segments to exert a hydrophobic synergistic effect while effectively suppressing phase separation caused by excessively long fatty acid chains, preferably, the fatty acid in the triglyceride is selected from at least one of fatty acids with C2 to C10 carbon atoms, for example, the triglyceride is selected from at least one of glyceryl tartrate, glyceryl trihexanoate, glyceryl tricaprylate or glyceryl tricaprate.

[0028] To further improve the compatibility of triglycerides with polycaprolactone-polyethylene glycol-polycaprolactone block copolymers, so as to facilitate the formation of thermosensitive hydrogels that can gel at room temperature, the melting point of the triglycerides is -25°C to 37°C. For example, the triglycerides are selected from at least one of trihexanoic acid glyceride, tricaprylic acid glyceride, or tridecanoic acid glyceride. Further, the melting point of the triglycerides is preferably 8°C to 31°C, for example, the melting point is any one of 8°C, 10°C, 15°C, 20°C, 25°C, or 31°C, or any range between two of them.

[0029] To improve the water solubility of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, the number-average molecular weight ratio of polyethylene glycol segments to polycaprolactone segments in the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is preferably 0.5 to 1.5, and can be any value among 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 or any range between the two.

[0030] Optionally, the number-average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is preferably between 2000 Da and 10000 Da, and can be selected from any value or a range between 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, or 10000 Da; the number-average molecular weight of the polycaprolactone segments can be selected from any value or a range between 500 Da, 1000 Da, 1500 Da, 2000 Da, 2500 Da, 3000 Da, 3500 Da, or 4000 Da. The number-average molecular weight of the polyethylene glycol segments is preferably 1000 Da to 2000 Da, and can be any value or a range between 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, or 2000 Da. By controlling the number-average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer and its various segments within this range, the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer has better water solubility and is more conducive to the rapid gelation of the thermosensitive hydrogel at room temperature.

[0031] Optionally, the number-average molecular weights of the two polycaprolactone segments in the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer can be the same or different. For example, when the number-average molecular weight of the polyethylene glycol segment is 1500 Da, the number-average molecular weights of the two polycaprolactone segments are both 1500 Da, or the number-average molecular weights of the two polycaprolactone segments are 1500 Da and 1000 Da, respectively. Alternatively, when the number-average molecular weight of the polyethylene glycol segment is 2000 Da, the number-average molecular weights of the two polycaprolactone segments are both 4000 Da, or the number-average molecular weights of the two polycaprolactone segments are 3500 Da and 4000 Da, respectively. Preferably, this invention uses a polycaprolactone-polyethylene glycol-polycaprolactone block copolymer with the same number-average molecular weight of the polycaprolactone segments.

[0032] Optionally, the mass ratio of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer to water is preferably 0.1:1 to 0.3:1, and can be any ratio selected from 0.1:1, 0.15:1, 0.2:1, 0.25:1 or 0.3:1; the mass ratio of the triglyceride to the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is preferably 0.005:1 to 0.15:1, and can be any ratio selected from 0.005:1, 0.01:1, 0.05:1, 0.08:1, 0.10:1, 0.13:1 or 0.15:1. Within this range, the thermosensitive hydrogel in a room temperature environment can achieve faster gelation and obtain higher mechanical strength.

[0033] This invention also provides a method for preparing the thermosensitive hydrogel as described above. The method includes mixing polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglycerides, and water at 4°C to 25°C, and then allowing the mixture to stand at 20°C to 25°C to form a thermosensitive hydrogel. The thermosensitive hydrogel preparation method of this invention is simple, uses mild conditions, requires no organic solvents, and can form a gel at room temperature.

[0034] Optionally, the mixing temperature of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglyceride and water can be any value of 4°C, 5°C, 10°C, 15°C, 20°C or 25°C or any range between two; the standing temperature can be any value of 20°C, 21°C, 22°C, 23°C, 24°C or 25°C or any range between two.

[0035] Optionally, the preparation method of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is as follows: under the protection of an inert gas, stannous octoate is used as a catalyst, and polyethylene glycol initiates the ring-opening polymerization reaction of ε-caprolactone (ε-CL) to obtain polycaprolactone-polyethylene glycol-polycaprolactone block copolymer.

[0036] The present invention also provides a medical implant made using the aforementioned thermosensitive hydrogel.

[0037] Optionally, the medical implant is a thermosensitive drug preparation, which includes a thermosensitive hydrogel and a thermosensitive drug coated by the thermosensitive hydrogel.

[0038] The technical solution of the present invention will be further described below through specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without specified manufacturers are all commercially available conventional products.

[0039] Example 1

[0040] 15 g of dehydrated polyethylene glycol (Aladdin, purity >98%) with a number average molecular weight of 1500 Da was added to a Schlenk flask, along with 30 g of ε-caprolactone and 0.015 g of stannous octoate catalyst. The gas in the Schlenk flask was purged with nitrogen, and the reaction was stirred in an oil bath at 150 °C for 6 h. After the reaction was complete, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise again to precipitate the product. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight to obtain a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer with a number average molecular weight of 4500 Da, wherein the number average molecular weight of each polyethylene glycol and polycaprolactone segment was 1500 Da.

[0041] Weigh 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above and place it in a 20mL vial. Then add 0.075g of tricaprylic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 8℃) and gently shake to mix. Then, at 25℃, slowly add 8.5g of deionized water and magnetically stir for about 2 minutes until the mixture is homogeneous. Stop stirring and keep it at 25℃ for about 5 minutes. After that, the system loses its fluidity, resulting in a uniform, non-flowing milky white thermosensitive hydrogel.

[0042] Example 2

[0043] The difference between Example 2 and Example 1 is only that: 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial, and then 0.15g of tridecanoic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 31℃) was added, and the mixture was gently shaken to mix. Then, at 25℃, 8.5g of deionized water was slowly added, and the mixture was magnetically stirred for about 2 minutes until it was uniform. The stirring was stopped and the mixture was kept at 25℃ for about 3 minutes until it lost its fluidity, resulting in a uniform, non-flowing milky white thermosensitive hydrogel.

[0044] Example 3

[0045] The difference between Example 3 and Example 1 is only that: 15g of dehydrated polyethylene glycol (brand: Aladdin, purity >98%) with a number average molecular weight of 1000 Da, 30g of ε-caprolactone, and 0.015g of stannous octoate catalyst were added to a Schlenk flask. The gas in the Schlenk flask was replaced with nitrogen, and the reaction was stirred in an oil bath at 150°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise to precipitate it. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight, yielding a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer with a number average molecular weight of 3000 Da, wherein the number average molecular weight of the polyethylene glycol segment was 1000 Da and the number average molecular weight of the polycaprolactone segment was 1000 Da.

[0046] A uniform, non-flowing, milky-white thermosensitive hydrogel was prepared using the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer obtained above.

[0047] Example 4

[0048] The difference between Example 4 and Example 1 is only that: 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial, and then 0.15g of tricaprylic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 8℃) was added, and the mixture was gently shaken to mix. Then, at 25℃, 8.5g of deionized water was slowly added, and the mixture was magnetically stirred for about 2 minutes until it was uniform. The stirring was stopped and the mixture was kept at 25℃ for about 4 minutes until it lost its fluidity, resulting in a uniform, non-flowing milky white thermosensitive hydrogel.

[0049] Example 5

[0050] The difference between Example 5 and Example 1 is only that: 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial, and then 0.225g of tricaprylic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 8℃) was added, and the mixture was gently shaken to mix. Then, at 25℃, 8.5g of deionized water was slowly added, and the mixture was magnetically stirred for about 2 minutes until it was uniform. The stirring was stopped and the mixture was kept at 25℃ for about 12 minutes until it lost its fluidity, resulting in a uniform, non-flowing milky white thermosensitive hydrogel.

[0051] Example 6

[0052] 20 g of dehydrated polyethylene glycol (Aladdin, purity >98%) with a number average molecular weight of 2000 Da was added to a Schlenk flask, along with 30 g of ε-caprolactone and 0.015 g of stannous octoate catalyst. The gas in the Schlenk flask was purged with nitrogen, and the reaction was stirred in an oil bath at 150 °C for 6 h. After the reaction was complete, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise again to precipitate the product. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight to obtain a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer with a number average molecular weight of 5000 Da, wherein the number average molecular weight of the polyethylene glycol segments was 2000 Da and the number average molecular weight of the polycaprolactone segments was 1500 Da.

[0053] Weigh 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above and place it in a 20mL vial. Then add 0.15g of tricaprylic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 8℃) and gently shake to mix. Then, at 25℃, slowly add 8.5g of deionized water and magnetically stir for about 2 minutes until the mixture is homogeneous. Stop stirring and keep it at 25℃ for about 2 minutes. After that, the system loses its fluidity, resulting in a uniform, non-flowing milky white thermosensitive hydrogel.

[0054] Example 7

[0055] 15 g of dehydrated polyethylene glycol (Aladdin, purity >98%) with a number average molecular weight of 2000 Da was added to a Schlenk flask, along with 50 g of ε-caprolactone and 0.015 g of stannous octoate catalyst. The gas in the Schlenk flask was purged with nitrogen, and the reaction was stirred in an oil bath at 150 °C for 6 h. After the reaction was complete, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise again to precipitate the product. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight to obtain a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer with a number average molecular weight of 7000 Da, wherein the number average molecular weight of the polyethylene glycol segments was 2000 Da and the number average molecular weight of the polycaprolactone segments was 2500 Da.

[0056] Weigh 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above and place it in a 20mL vial. Then add 0.225g of glyceryl tartrate (brand: Sigma-Aldrich, purity >98%, melting point: -75℃) and gently shake to mix. Then, at 25℃, slowly add 8.5g of deionized water and magnetically stir for about 2 minutes until the mixture is homogeneous. Stop stirring and let stand at 25℃ for about 22 minutes to obtain a milky white weak gel.

[0057] Example 8

[0058] The difference between Example 8 and Example 1 is only that: 10g of dehydrated polyethylene glycol (brand: Aladdin, purity >98%) with a number average molecular weight of 1000 Da was added to a Schlenk flask, along with 45g of ε-caprolactone and 0.015g of stannous octoate catalyst. The gas in the Schlenk flask was replaced with nitrogen, and the reaction was stirred in an oil bath at 150°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was then collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise to precipitate it. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight to obtain a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer. The number average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer was 5500 Da, wherein the number average molecular weight of the polyethylene glycol segment was 1000 Da and the number average molecular weight of the polycaprolactone segment was 2250 Da.

[0059] The polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above suffers from a severe imbalance in molecular affinity and hydrophobicity, making it difficult to demonstrate the hydrophobic synergistic effect; only a milky white weak gel is obtained.

[0060] Example 9

[0061] The difference between Example 9 and Example 1 is only that: 15g of dehydrated polyethylene glycol (brand: Aladdin, purity >98%) with a number average molecular weight of 1500 Da, 10g of ε-caprolactone, and 0.015g of stannous octoate catalyst were added to a Schlenk flask. The gas in the Schlenk flask was replaced with nitrogen, and the reaction was stirred in an oil bath at 150°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise to precipitate it. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight to obtain a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer. The number average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer was 2500 Da, wherein the number average molecular weight of the polyethylene glycol segment was 1500 Da and the number average molecular weight of the polycaprolactone segment was 500 Da.

[0062] A uniform, non-flowing, milky-white thermosensitive hydrogel was prepared using the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer obtained above.

[0063] Comparative Example 1

[0064] The only difference between Comparative Example 1 and Example 1 is that: at 25°C, 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial. 8.5g of deionized water was slowly added and the mixture was magnetically stirred for 60min. The system was a low-viscosity, fluid solution. The temperature was raised to 37°C and allowed to stand for 38min to form a gel.

[0065] Comparative Example 2

[0066] The only difference between Comparative Example 2 and Example 1 is that: 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial, and then 0.075g of glyceryl tristearate (melting point: 72℃) was added. The mixture was heated to 80℃ and gently shaken to mix the two. Then, at 25℃, 8.5g of deionized water was slowly added, and the mixture was magnetically stirred for about 2 minutes until it was uniformly mixed. Stirring was stopped and the mixture was allowed to stand at 25℃. Obvious insoluble particles appeared in the system, and no uniform gel was formed.

[0067] Comparative Example 3

[0068] The only difference between Comparative Example 3 and Example 1 is that 15g of dehydrated polyethylene glycol (brand name: Aladdin, purity >98%) with a number average molecular weight of 1500 Da, 100g of ε-caprolactone, and 0.015g of stannous octoate catalyst were added to a Schlenk flask. The gas in the Schlenk flask was replaced with nitrogen, and the reaction was stirred in an oil bath at 150°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and excess diethyl ether was slowly added dropwise to precipitate the product. The crude product was collected by filtration. The crude product was dissolved in dichloromethane, and diethyl ether was slowly added dropwise to precipitate it. This process was repeated three times. The resulting product was dried under vacuum at room temperature to constant weight, yielding a white powder of polycaprolactone-polyethylene glycol-polycaprolactone block copolymer. The number average molecular weight of this polycaprolactone-polyethylene glycol-polycaprolactone block copolymer was 11,500 Da, wherein the number average molecular weight of the polyethylene glycol segment was 1,500 Da, and the number average molecular weight of the polycaprolactone segment was 5,000 Da.

[0069] Weigh 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above and place it in a 20mL vial. Then add 0.075g of tricaprylic acid glyceride (brand: Sigma-Aldrich, purity >98%, melting point: 8℃) and gently shake to mix. Next, slowly add 8.5g of deionized water at 25℃ and magnetically stir for about 2 minutes until homogeneous. Stop stirring and let stand at 25℃. The polycaprolactone-polyethylene glycol-polycaprolactone block copolymer precipitates out, and no gel is obtained.

[0070] Comparative Example 4

[0071] The only difference between Comparative Example 4 and Example 1 is that: 1.5g of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer prepared above was weighed and placed in a 20mL vial, then 0.075g of glyceryl caprylate was added, and the mixture was gently shaken to mix. Then, at 25°C, 8.5g of deionized water was slowly added, and the mixture was magnetically stirred for about 2 minutes until homogeneous. The stirring was stopped, and the mixture was allowed to stand at 25°C for 60 minutes, remaining a flowing liquid. The temperature was then raised to 37°C, and after standing for 30 minutes, a weak gel was formed.

[0072] The gelation time at 25℃ or 37℃ was tested using the inverted test tube method. The test method was as follows: following the experimental schemes of Examples 1 to 9, Comparative Examples 1 and 4, polycaprolactone-polyethylene glycol-polycaprolactone block copolymer and triglyceride were weighed and mixed. Then, 8.5g of deionized water was slowly added at 25℃, and the mixture was magnetically stirred for about 2 minutes until it was uniformly mixed to obtain a mixed liquid that did not form a hydrogel. The mixed liquid was quickly transferred to a constant temperature water bath at 25℃ or 37℃. The sample was taken out and inverted every 30 seconds. The gelation time was recorded as long as the sample no longer flowed. The results are shown in Table 1.

[0073] The thermosensitive hydrogels prepared in Examples 1 to 9, Comparative Examples 1 and 4 were subjected to rheological tests at 25°C or 37°C. The test method was as follows: a Haake rheometer was used with a parallel plate rotor (diameter 25 mm) and a gap of 0.5 mm. Frequency scanning (1 Hz) was performed at 25°C or 37°C, and the storage modulus (G') was recorded. The results are shown in Table 1.

[0074] Table 1

[0075]

[0076] As can be seen from Examples 1-9, the introduction of triglycerides with a melting point below 37°C can yield thermosensitive hydrogels that gel rapidly at room temperature and have high mechanical strength (storage modulus). When the melting point of triglycerides is in the range of -25°C to 37°C, it is beneficial to shorten the gelation time at room temperature and improve the mechanical strength of the thermosensitive hydrogel. Specifically, the gelation time is 2 min to 12 min, and the storage modulus of the thermosensitive hydrogel is 480 Pa to 2000 Pa. As can be seen from Comparative Example 2, when the fatty acid chain of triglycerides is too long and the melting point is too high, the compatibility with the system is poor, resulting in phase separation and failure to form a uniform gel.

[0077] As can be seen from Examples 1, 8 and 9, controlling the number-average molecular weight ratio of polyethylene glycol segments to polycaprolactone segments within the range of 0.5 to 1.5 is more conducive to obtaining thermosensitive hydrogels that gel rapidly at room temperature and have high mechanical strength.

[0078] As can be seen from Example 1 and Comparative Example 3, the length of the polycaprolactone segment in the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, i.e. the length of the hydrophobic segment, needs to be appropriate. If the polycaprolactone segment is too long, the water solubility of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is poor, and it cannot form a gel under room temperature conditions.

[0079] As can be seen from Comparative Example 1 and Comparative Example 4, monoglycerides cannot promote the gelation of polycaprolactone-polyethylene glycol-polycaprolactone block copolymers at room temperature. This is because monoglycerides contain free hydroxyl groups, which are mainly located at the interface of the micelles of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer. They cannot effectively solubilize the hydrophobic core of the polycaprolactone segments. Therefore, monoglycerides cannot produce a "hydrophobic synergy" effect with the polycaprolactone segments to accelerate gelation.

[0080] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0081] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A temperature-sensitive hydrogel, characterized in that, The thermosensitive hydrogel comprises polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglycerides, and water; Wherein, the melting point of the triglyceride is less than or equal to 37°C, and the number average molecular weight of the polycaprolactone segments in the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 500 Da to 4000 Da.

2. The thermosensitive hydrogel according to claim 1, characterized in that, The fatty acids in the triglycerides are straight-chain saturated fatty acids.

3. The thermosensitive hydrogel according to claim 1 or claim 2, characterized in that, The fatty acid in the triglyceride is selected from at least one of fatty acids having C6 to C10 carbon atoms; And / or, the melting point of the triglyceride is -25°C to 37°C.

4. The thermosensitive hydrogel according to claim 3, characterized in that, The triglyceride is selected from at least one of trihexanoic acid glyceride, tricaprylic acid glyceride, or tridecanoic acid glyceride.

5. The thermosensitive hydrogel according to claim 1, characterized in that, In the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, the number-average molecular weight ratio of polyethylene glycol segments to polycaprolactone segments is 0.5 to 1.

5.

6. The thermosensitive hydrogel according to claim 5, characterized in that, The number average molecular weight of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 2000 Da to 10000 Da. And / or, the number average molecular weight of the polyethylene glycol segments is 1000 Da to 2000 Da.

7. The thermosensitive hydrogel according to claim 1, characterized in that, The mass ratio of the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer to water is 0.1:1 to 0.3:1; And / or, the mass ratio of the triglyceride to the polycaprolactone-polyethylene glycol-polycaprolactone block copolymer is 0.005:1 to 0.15:

1.

8. A method for preparing a thermosensitive hydrogel as described in any one of claims 1 to 7, characterized in that, The preparation method includes: mixing polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, triglycerides and water at 4℃~25℃, and then allowing it to stand at 20℃~25℃ to form a thermosensitive hydrogel.

9. A medical implant made of a thermosensitive hydrogel as described in any one of claims 1 to 7.

10. The medical implant made of the thermosensitive hydrogel according to claim 9, characterized in that, The medical implant is a thermosensitive drug preparation, which includes a thermosensitive hydrogel and a thermosensitive drug coated by the thermosensitive hydrogel.

Images