Lactic acid-glycolic acid copolymer with adjustable and controllable end group carbon chain length as well as preparation method and application of lactic acid-glycolic acid copolymer

Abstract

The invention discloses a lactic acid-glycolic acid copolymer with adjustable end group carbon chain length and a preparation method and application thereof. The lactic acid-glycolic acid copolymer with the adjustable end group carbon chain length is an alcohol-terminated lactic acid-glycolic acid copolymer, and the structural formula of the lactic acid-glycolic acid copolymer is as follows: # imgabs0 #, wherein R is selected from C1-C20 alkyl; m is 20 to 600, and n is 20 to 400. According to the alcohol-terminated lactic acid-glycolic acid copolymer, the degradation speed of the polymer is changed by controlling the length of a carbon chain of a terminal group, and the alcohol-terminated lactic acid-glycolic acid copolymer can be used as a carrier of a sustained and controlled release drug delivery system of various drugs, meets the requirements of different sustained release time and is wide in application range.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer materials and pharmaceutical excipients, and particularly relates to a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, and a preparation method and application thereof. Background Art

[0002] Poly(lactic acid-glycolic acid) (PLGA) has aroused extensive interest and research in the biomedical field due to its excellent biocompatibility and biodegradable properties. Especially in the field of drug delivery, poly(lactic acid-glycolic acid) is widely used to prepare microspheres, nanoparticles, micelles and other carriers to achieve controlled release and targeted delivery of drugs. This technology can prolong the duration of drug action, improve the bioavailability of drugs, and reduce the toxic side effects of drugs. As a polymer approved for use by the FDA and EMA, poly(lactic acid-glycolic acid) has great potential in research and future clinical applications. As of 2023, the U.S. Food and Drug Administration (FDA) has approved 12 PLGA-based microsphere drug products. In addition, there is still a lot of research focusing on the development of extended-release microspheres, including new and old active ingredients and products for new indications. Therefore, poly(lactic acid-glycolic acid)-based carriers are considered to be reliable sustained-release drug delivery systems.

[0003] However, although significant progress has been made in the preparation of lactic acid-glycolic acid copolymer drug carriers, it is still challenging to convert research results into actual clinical applications. Studies have shown that changes in the structure of lactic acid-glycolic acid copolymers may cause changes in the properties and performance of lactic acid-glycolic acid copolymer preparations, especially their degradation properties. At present, the common regulation of the structure and degradation properties of lactic acid-glycolic acid copolymers is mainly achieved by changing their molecular weight or changing the ratio of lactic acid and glycolic acid. However, both of the above methods have the disadvantages of cumbersome operation and low repeatability. Studies have shown that the end group may also have a certain effect on the performance and degradation of lactic acid-glycolic acid copolymers, but there are currently few studies on the regulation of polymer structure and degradation properties by end groups. The way to change the end group in existing synthetic reports is to first synthesize lactic acid-glycolic acid copolymers and then connect the required end groups through chemical reactions. This method has low reaction efficiency, difficult purification, and the effect on degradation properties is still unclear.

[0004] How to simply and efficiently achieve the properties and degradation performance of lactic acid-glycolic acid copolymers can be regulated, and how to achieve reproducible preparation, these issues are still important limiting factors restricting the development of lactic acid-glycolic acid copolymer microsphere pharmaceutical products. Therefore, there is still a need to develop a preparation method that can simply and efficiently regulate the structure and degradation performance of lactic acid-glycolic acid copolymers and can be produced reproducibly. Summary of the invention

[0005] The main purpose of the present invention is to provide a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length and a preparation method and application thereof, so as to overcome the deficiencies in the prior art.

[0006] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0007] One aspect of the present invention provides a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, wherein the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is an alcohol-terminated lactic acid-glycolic acid copolymer, and its structural formula is shown in formula (I):

[0008]

[0009] Wherein, R is selected from C1-C 20 m is 20-600, n is 20-400.

[0010] Another aspect of the present invention provides a method for preparing a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, comprising: using alcohol as an initiator to initiate a ring-opening polymerization reaction of lactide and glycolide to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length;

[0011] The alcohol has a structure shown in formula (II):

[0012] R-OH

[0013] Formula (II)

[0014] Wherein, R is selected from C1-C 20 of hydrocarbon groups.

[0015] Another aspect of the present invention also provides a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, which is prepared by the above-mentioned preparation method.

[0016] Another aspect of the present invention also provides the use of the aforementioned lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length in the preparation of biodegradable materials.

[0017] Another aspect of the present invention also provides the use of the aforementioned lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length in a carrier of a drug sustained-release drug delivery system.

[0018] Compared with the prior art, the technical solution of the present invention has at least the following advantages:

[0019] The invention realizes simple and controllable terminal groups of the lactic acid-glycolic acid copolymer by simply adjusting the carbon chain length of the alcohol as an initiator, thereby changing the degradation speed of the polymer. The longer the carbon chain length of the terminal group is, the longer the degradation time is. The prepared lactic acid-glycolic acid copolymer can be used as a carrier of a sustained-release drug delivery system of various drugs, meets the requirements of different sustained-release times, and has a wide range of applications. In addition, the synthesis reaction in the invention is a one-step reaction, the preparation process is simple, the energy consumption is low, the preparation can be repeated, and it is conducive to large-scale batch production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 The reaction flow chart of a method for preparing a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length in a typical embodiment of the present invention;

[0022] Figure 2 This is a graph showing the molecular weight test results of PLGA prepared in Example 1 of the present invention;

[0023] Figure 3 This is a graph showing the molecular weight test results of PLGA prepared in Example 2 of the present invention;

[0024] Figure 4 This is a graph showing the molecular weight test results of PLGA prepared in Example 3 of the present invention;

[0025] Figure 5 This is a graph showing the molecular weight test results of PLGA prepared in Example 4 of the present invention;

[0026] Figure 6 This is a graph showing the molecular weight test results of PLGA prepared in Example 5 of the present invention;

[0027] Figure 7 This is a graph showing the molecular weight test results of PLGA prepared in Example 6 of the present invention;

[0028] Figure 8 This is a graph showing the molecular weight test results of PLGA prepared in Example 7 of the present invention;

[0029] Fig. 9 This is a graph showing the molecular weight test results of PLGA prepared in Comparative Example 1 of the present invention;

[0030] Fig.10The ratio of lactic acid and glycolic acid was determined for the PLGA prepared in Example 1 of the present invention;

[0031] Fig.11 The ratio of lactic acid and glycolic acid was determined for the PLGA prepared in Example 2 of the present invention by H NMR spectrum;

[0032] Fig.12 The ratio of lactic acid and glycolic acid was determined for the PLGA prepared in Example 3 of the present invention;

[0033] Fig.13 The ratio of lactic acid and glycolic acid was determined for the PLGA prepared in Example 4 of the present invention by H NMR spectrum;

[0034] Fig.14 The ratio of lactic acid and glycolic acid is determined by H NMR spectrum of PLGA prepared in Comparative Example 1 of the present invention;

[0035] Fig.15 This is the carbon NMR spectrum of PLGA prepared in Example 1 of the present invention;

[0036] Fig.16 This is the carbon nuclear magnetic resonance spectrum of PLGA prepared in Comparative Example 1 of the present invention;

[0037] Fig.17 A comparison chart of degradation quality changes of PLGA tablets prepared in Examples 1-3 of the present invention and Comparative Example 1 after tableting;

[0038] Fig.18 This is a comparison chart of the degradation pH changes of the PLGA tablets prepared in Examples 1-3 of the present invention and Comparative Example 1 after tableting. DETAILED DESCRIPTION

[0039] The present invention will be more fully understood by reading the following specific embodiments. However, it should be understood that the specific embodiments disclosed below are only exemplary of the present invention, and the present invention can be embodied in various forms. Therefore, the specific functional details disclosed herein should not be interpreted as limiting, but only as the basis for the claims and as a representative basis for teaching those skilled in the art to adopt the present invention in different ways in any appropriate detailed embodiment.

[0040] As one aspect of the technical solution of the present invention, it relates to a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, wherein the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is an alcohol-terminated lactic acid-glycolic acid copolymer, and its structural formula is shown in formula (I):

[0041]

[0042] Wherein, R is selected from C1-C 20m is 20-600, n is 20-400.

[0043] In some embodiments, the weight average molecular weight of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is 5,000-100,000.

[0044] In some preferred embodiments, the weight average molecular weight of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is 7,000-50,000.

[0045] As another aspect of the technical solution of the present invention, a method for preparing a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length comprises: using alcohol as an initiator to initiate a ring-opening polymerization reaction of lactide and glycolide to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length;

[0046] The alcohol has a structure shown in formula (II):

[0047] R-OH

[0048] Formula (II)

[0049] Wherein, R is selected from C1-C 20 of hydrocarbon groups.

[0050] The synthesis reaction principle of the present invention is as follows:

[0051]

[0052] An alcohol having the structural formula (II) is optionally used as a reaction initiator. An initiator with a suitable carbon chain length can be selected according to demand to obtain an alcohol-terminated polylactic acid-glycolic acid copolymer with a corresponding carbon chain length. The degradation performance of the polylactic acid-glycolic acid copolymer can be regulated by adjusting the terminal carbon chain length.

[0053] The reaction of synthesizing PLGA using an initiator with a diol structure in the prior art is as follows:

[0054]

[0055] The PLGA synthesized by the initiator with diol structure is a hydroxyl-terminated structure.

[0056] In some embodiments, the preparation method comprises: mixing the alcohol, lactide, glycolide and a catalyst, and performing a ring-opening polymerization reaction in a protective atmosphere to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length.

[0057] In some preferred embodiments, the lactide includes but is not limited to any one of DL-lactide and L-lactide or a combination of both.

[0058] In some preferred embodiments, the catalyst includes but is not limited to stannous octoate, stannous chloride and other organic acid stannous.

[0059] In some preferred embodiments, the protective atmosphere comprises a nitrogen atmosphere or an argon atmosphere.

[0060] In some preferred embodiments, the ring-opening polymerization reaction is carried out at a temperature of 120-160° C. and for a time of 4-12 hours.

[0061] In some preferred embodiments, the molar ratio of lactide to glycolide is 50-85:15-50. The feeding amounts of lactide and glycolide are adjusted in a certain ratio to obtain lactic acid-glycolic acid copolymers with different ratios of lactide to glycolide.

[0062] In some preferred embodiments, the alcohol is added in an amount of 0.1-6.0 wt % based on the total mass of lactide and glycolide.

[0063] In some preferred embodiments, the catalyst is added in an amount of 0.05-0.2 wt % based on the total mass of lactide and glycolide.

[0064] In some embodiments, see Figure 1 The reaction flow chart shown in the figure, the preparation method comprises: adding an initiator and a catalyst to the reaction system of lactide and glycolide, performing a ring-opening polymerization reaction in a protective atmosphere to obtain a crude product, dissolving the crude product in a good solvent, adding a poor solvent to obtain a precipitate, and drying to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length. The good solvent and the poor solvent are used to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalysts.

[0065] In some preferred embodiments, the good solvent includes but is not limited to dichloromethane.

[0066] In some preferred embodiments, the poor solvent includes but is not limited to methanol.

[0067] As another aspect of the technical solution of the present invention, it also relates to a lactic acid-hydroxyacetic acid copolymer with adjustable terminal carbon chain length prepared by the aforementioned preparation method.

[0068] As another aspect of the technical solution of the present invention, it also involves the use of the aforementioned lactic acid-hydroxyacetic acid copolymer with adjustable terminal carbon chain length in the preparation of biodegradable materials.

[0069] As another aspect of the technical solution of the present invention, it also involves the use of the aforementioned lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length in a carrier of a drug sustained-release drug delivery system.

[0070] In summary, the prior art usually controls the degradation time of the lactic acid-glycolic acid copolymer by molecular weight and L / G components. The present invention uses a new mechanism and method to control the degradation time. Specifically, the present invention achieves simple and controllable end groups of the lactic acid-glycolic acid copolymer by simply adjusting the length of the alcohol carbon chain as an initiator, thereby changing the degradation rate of the polymer. The reaction is a one-step reaction, and the preparation process is simple, the energy consumption is low, and the preparation can be repeated. The obtained product can be used as a carrier for a sustained-release drug delivery system of various drugs. It is a new idea for designing polymers and has very important significance and broad development prospects.

[0071] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. The reagents and raw materials used in the following examples are all commercially available, and the test methods without specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers. For example, the monomer raw materials, initiators and catalysts used in the following examples can be directly obtained from the market, and DL-lactide can be used as lactide; in addition, the flasks referred to in the following examples are all dried; the reaction pressure in each example is atmospheric pressure.

[0072] Example 1

[0073] 79 g of lactide, 21 g of glycolide, n-hexanol (1.0 wt% of the total mass of lactide and glycolide) and stannous octoate (0.1 wt% of the total mass of lactide and glycolide) were put into a flask, filled with nitrogen, and reacted at 140° C. for 4 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with n-hexanol, with a weight average molecular weight of 14262 and a yield of 92%.

[0074] Example 2

[0075] 79 g of lactide, 21 g of glycolide, dodecanol (1.9 wt% of the total mass of lactide and glycolide) and stannous octoate (0.1 wt% of the total mass of lactide and glycolide) were put into a flask, filled with nitrogen, and reacted at 140° C. for 4 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with dodecanol, with a weight average molecular weight of 14562 and a yield of 89%.

[0076] Example 3

[0077] 79g of lactide, 21g of glycolide, hexadecanol (2.4wt% of the total mass of lactide and glycolide) and stannous octoate (0.1wt% of the total mass of lactide and glycolide) were put into a flask, filled with nitrogen, and reacted at 140°C for 8 hours. The crude product was dissolved with chloroform and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain polylactic acid-glycolic acid copolymer capped with hexadecanol, with a weight average molecular weight of 14990 and a yield of 87%.

[0078] Example 4

[0079] 55.4 g of lactide, 44.6 g of glycolide, dodecanol (1.9 wt% of the total mass of lactide and glycolide) and stannous octoate (0.1 wt% of the total mass of lactide and glycolide) were put into a flask, filled with nitrogen, and reacted at 140° C. for 4 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with dodecanol, with a weight average molecular weight of 14805 and a yield of 89%.

[0080] Example 5

[0081] 79 g of lactide, 21 g of glycolide, dodecanol (0.5 wt % of the total mass of lactide and glycolide) and stannous octoate (0.1 wt % of the total mass of lactide and glycolide) were placed in a flask, filled with nitrogen, and reacted at 140° C. for 12 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with dodecanol, with a weight average molecular weight of 48221 and a yield of 89%.

[0082] Example 6

[0083] 79 g of lactide, 21 g of glycolide, eicosanol (0.1 wt% of the total mass of lactide and glycolide) and stannous chloride (0.2 wt% of the total mass of lactide and glycolide) were placed in a flask, filled with nitrogen, and reacted at 150° C. for 6 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with eicosanol, with a weight average molecular weight of 53364 and a yield of 80%.

[0084] Example 7

[0085] 79 g of lactide, 21 g of glycolide, eicosanol (6.0 wt% of the total mass of lactide and glycolide) and stannous octoate (0.05 wt% of the total mass of lactide and glycolide) were placed in a flask, filled with nitrogen, and reacted at 160° C. for 8 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a lactic acid-glycolic acid copolymer capped with eicosanol, with a weight average molecular weight of 6387 and a yield of 75%.

[0086] Comparative Example 1

[0087] 79 g of lactide, 21 g of glycolide, glycolic acid (1.1 wt% of the total mass of lactide and glycolide) and stannous octoate (0.1 wt% of the total mass of lactide and glycolide) were placed in a flask, filled with nitrogen, and reacted at 140° C. for 4 hours. The crude product was dissolved with dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst to obtain a carboxyl-terminated lactic acid-glycolic acid copolymer with a weight average molecular weight of 14045 and a yield of 90%.

[0088] The structure characterization and performance test of the lactic acid-glycolic acid copolymers prepared in Examples 1-7 and Comparative Example 1 were performed:

[0089] Intrinsic viscosity test: Intrinsic viscosity can be used as a measure of molecular weight and the properties of reactive polymers. The lactic acid-glycolic acid copolymers prepared in Examples 1-3 and Comparative Example 1 were dissolved in chloroform to 5 g / L, and the solutions were measured using an Ubbelohde viscometer to obtain the results.

[0090] The viscosity of Example 1 is 0.19 dL / g, the viscosity of Example 2 is 0.19 dL / g, the viscosity of Example 3 is 0.18 dL / g, and the viscosity of Comparative Example 1 is 0.20 dL / g. From this test, it can be seen that simply changing the type of initiator has little effect on the intrinsic viscosity of the product, and the interference of the intrinsic viscosity in the degradation test can be eliminated.

[0091] Molecular weight test: The lactic acid-glycolic acid copolymers prepared in Examples 1-7 and Comparative Example 1 were dissolved in tetrahydrofuran to 2 mg / mL, then filtered with a 0.22 μm syringe filter, and measured using a Waters HPLC pump and a Waters HPLC autosampler in conjunction with a series of ACQUITY APC XT columns. The samples were monitored using a refractive index detector. The calibration curve was obtained using The software was constructed with polystyrene standard polymers. The mobile phase was tetrahydrofuran, flowing at a rate of 0.5 mL / min, the running time was 20 minutes, and the injection volume was 20 ul. The relative molecular weight of lactic acid-glycolic acid copolymer was detected to determine its structural characteristics.

[0092] The molecular weight test results obtained in Examples 1-7 and Comparative Example 1 are: Figures 2 to 9 As can be seen from the figure, the weight average molecular weights of Examples 1-7 and Comparative Example 1 are 14262, 14562, 14990, 14805, 48221, 53364, 6387, and 14045, respectively. From the molecular weight, it can be found that only changing the length of the initiator carbon chain can keep the molecular weight at a certain level, eliminating the effect of the molecular weight on degradation. At the same time, the molecular weight can also be simply adjusted by changing the molar ratio of the initiator.

[0093] Proton NMR spectrum test: The lactic acid-glycolic acid copolymer prepared by Example 1-4 and Comparative Example 1 was dissolved to 10 mg / mL with deuterated chloroform, and then moved into an NMR tube. The spectrum of each sample was collected by proton NMR spectrum spectroscopy, with 16 scans, 0.5 second relaxation delay and 45 degree pulse angle. The ratio of lactic acid and glycolic acid was determined by comparing the proton intensity at chemical shift 5.2ppm and 4.8ppm. Different ratios can significantly affect the performance of polylactic acid-glycolic acid copolymer.

[0094] The nuclear magnetic resonance proton spectra obtained in Examples 1-4 and Comparative Example 1 are respectively Figures 10 to 14 The molar ratio of lactic acid to glycolic acid in the products of Examples 1-3 and Comparative Example 1 is 73 / 27, and the molar ratio of lactic acid to glycolic acid in the product of Example 4 is 48 / 52. The results obtained from the nuclear magnetic hydrogen spectrum integration show that keeping the ratio of lactide to glycolide unchanged and changing the length of the initiator alcohol carbon chain will not affect the ratio of lactic acid to glycolic acid in the final product. At the same time, since the ring-opening polymerization rate of glycolide is faster than that of lactide, the proportion of glycolic acid in the product is relatively large. At the same time, since the degradation performance of glycolic acid is stronger than that of lactic acid, the higher the proportion of lactic acid in the product, the slower the degradation rate.

[0095] Acid-base titration test: The lactic acid-glycolic acid copolymer prepared in Examples 1-3 and Comparative Example 1 was dissolved in a diluent to 0.1 g / mL, and the diluent composition was chloroform: dioxane: methanol = 730:135:135. The solution was titrated with 0.1 mol / L tetrabutylammonium hydroxide solution, and a blank (diluent) titration was performed. The acid value of the polylactic acid-glycolic acid copolymer was calculated according to the formula. Different acid values ​​will affect its hydrophilicity, thereby affecting its degradation.

[0096] Acid value = (V 样 -V 空 )×C 滴 ×M 分子量 ÷W 样

[0097] V 样 : Volume of titrant consumed by sample (mL)

[0098] V 空 :Volume of blank consumed titrant (mL)

[0099] C 滴 : Concentration of titration solution (0.1mol / L)

[0100] M 分子量 : Molecular weight of potassium hydroxide (g / mol), 56.11

[0101] W 样 : Sample weight

[0102] The calculated results are 1.12 for Example 1, 1.05 for Example 2, 0.98 for Example 3, and 10.52 for Comparative Example 1. From the acid value results, it can be found that only changing the length of the initiator carbon chain will not affect the acid value, and the acid value can be kept at a certain level. At the same time, when the initiator carbon chain contains a carboxyl group, the acid value will surge, changing the hydrophilicity of the product, thereby affecting its degradation performance.

[0103] Carbon-NMR spectrum test: the lactic acid-glycolic acid copolymer prepared by Example 1 and Comparative Example 1 is dissolved to 15 mg / mL with a diluent, and then the resulting polymer solution is pipetted into an NMR tube. The end groups of the lactic acid-glycolic acid copolymer are confirmed by carbon-NMR spectrum, and 12,000 scans are performed. The end groups are confirmed by whether there is a specific peak at 14 ppm in the nuclear magnetic spectrum. The difference in the end groups directly affects the degradation performance of the lactic acid-glycolic acid copolymer.

[0104] The carbon nuclear magnetic resonance spectra obtained in Example 1 and Comparative Example 1 are respectively Fig.15 and Fig.16 From the carbon NMR spectrum, it can be found that the end group was successfully connected.

[0105] Degradation test: Weigh 150 mg of the lactic acid-glycolic acid copolymers prepared in Examples 1-3 and Comparative Example 1, respectively, and press them with a tablet press at a pressure of 30 MPa to obtain tablets with a diameter of 14 mm and a thickness of 0.90 mm. Place the tablets in 15 mL of phosphate buffer with a pH of 7.4. Shake them horizontally at a speed of 100 rpm in a shaking table at 37°C. Take out the tablets at a predetermined time interval, wash them three times with pure water, vacuum dry them for 72 hours, weigh them, and measure the pH of the degradation solution at the same time.

[0106] The comparison of the quality changes of Examples 1-3 and Comparative Example 1 is shown in the figure Fig.17 As shown in the figure, the pH change comparison is as follows Fig.18As shown in the figure, the mass change shows that as the carbon chain of the terminal group increases, the mass change becomes smaller. Since the degradation of lactic acid-glycolic acid copolymer may produce soluble substances, which leads to a decrease in mass, the faster the mass change, the faster the degradation. At the same time, the pH change of the degradation solution also shows that the terminal group will affect the degradation. Fig.17 It can be seen that the longer the carbon chain length of the end group, the longer the degradation time. The time for the mass loss of the lactic acid-glycolic acid copolymer with different end groups is between 60 and 120 days (the 40-day degradation graph can be fitted as linear degradation, and the time for the mass loss to be half is inferred from the fitting function).

[0107] From the above tests, it can be seen that by only changing the alcohols with different carbon chain lengths, lactic acid-glycolic acid copolymers with different end groups can be obtained. Other main factors affecting performance and degradation, including intrinsic viscosity, molecular weight, ratio of lactic acid to glycolic acid, and acid value, are similar. These factors can be kept from affecting degradation, and only the end groups are changed under the same conditions to determine the effect of the end groups on degradation. According to the degradation experiment results, as the length of the end group carbon chain increases, the degradation time of the lactic acid-glycolic acid copolymer also increases. Therefore, the performance of the lactic acid-glycolic acid copolymer can be simply and conveniently controlled by regulating the end groups.

[0108] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0109] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, characterized in that: The lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is an alcohol-terminated lactic acid-glycolic acid copolymer, and its structural formula is shown in formula (I): Wherein, R is selected from C1-C 20 m is 20-600, n is 20-400.

2. The lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length according to claim 1, characterized in that: The weight average molecular weight of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is 5000-100000.

3. The lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length according to claim 2, characterized in that: The weight average molecular weight of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length is 7000-50000.

4. A method for preparing a lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, characterized in that: include: Using alcohol as an initiator to initiate a ring-opening polymerization reaction of lactide and glycolide to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length; The alcohol has a structure shown in formula (II): R-OH Formula (II) Wherein, R is selected from C1-C 20 of hydrocarbon groups.

5. The preparation method according to claim 4, characterized in that: include: The alcohol, lactide, glycolide and a catalyst are mixed and subjected to a ring-opening polymerization reaction in a protective atmosphere to obtain the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length.

6. The preparation method according to claim 5, characterized in that: The lactide includes any one of DL-lactide and L-lactide or a combination of both; And / or, the catalyst comprises any one of stannous octoate and stannous chloride or a combination of both; And / or, the protective atmosphere comprises a nitrogen atmosphere or an argon atmosphere; And / or, the ring-opening polymerization reaction is carried out at a temperature of 120-180° C. and for a time of 4-12 hours.

7. The preparation method according to claim 5, characterized in that: The molar ratio of lactide to glycolide is 50-85:15-50; and / or, the amount of the alcohol added is 0.1-6.0wt% of the total mass of lactide and glycolide; And / or, the amount of the catalyst added is 0.05-0.2 wt % of the total mass of lactide and glycolide.

8. A lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length, prepared by the preparation method according to any one of claims 4 to 7.

9. Use of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length according to any one of claims 1 to 3 and 8 in the preparation of biodegradable materials.

10. Use of the lactic acid-glycolic acid copolymer with adjustable terminal carbon chain length according to any one of claims 1 to 3 and 8 in a carrier of a drug sustained-release and controlled-release drug delivery system.

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