A lactic acid-glycolic acid copolymer with controllable end group carbon chain length, and a preparation method and application thereof

Abstract

The application discloses a lactic acid-glycolic acid copolymer with adjustable end carbon chain length and a preparation method and application thereof. 20 The lactic acid-glycolic acid copolymer with adjustable end carbon chain length is alcohol-terminated lactic acid-glycolic acid copolymer, and a structural formula is as shown in the following formula: wherein R is selected from C1-C The alcohol-terminated lactic acid-glycolic acid copolymer provided by the application can change the degradation speed of the polymer by controlling the carbon chain length of the end group, can be used as a carrier of a sustained-release drug delivery system of various drugs, can meet the requirement of different sustained-release time, and has a wide application range.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of high polymer materials and pharmaceutical excipients, and particularly relates to a lactic acid-glycolic acid copolymer with controllable end group carbon chain length, a preparation method and application thereof. BACKGROUND

[0002] Lactic acid-glycolic acid copolymer (PLGA) has attracted extensive interest and research in the biomedical field due to its excellent biocompatibility and biodegradable properties. In particular, in the field of drug delivery, lactic acid-glycolic acid copolymer 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 action time of drugs, improve the bioavailability of drugs, and reduce the toxic and side effects of drugs. As a polymer approved by FDA and EMA, lactic acid-glycolic acid copolymer has great potential in research and future clinical applications. As of 2023, the US Food and Drug Administration (FDA) has approved 12 PLGA-based microsphere drug products, and in addition, a large number of researches are focused on the development of long-acting microspheres, including new and old active ingredients and products for new indications. Therefore, lactic acid-glycolic acid copolymer-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, there are still challenges in translating research findings into actual clinical applications. Studies have shown that changes in the structure of lactic acid-glycolic acid copolymer can cause changes in the properties and performance of lactic acid-glycolic acid copolymer formulations, especially its degradation performance. Currently, the common method for regulating the structure and degradation performance of lactic acid-glycolic acid copolymer is to change its molecular weight or the ratio of lactic acid and glycolic acid, but both methods have the disadvantages of complicated operation and low repeatability. Studies have shown that end groups may also have some influence on the performance and degradation of lactic acid-glycolic acid copolymer, but there is currently little research on regulating polymer structure and degradation performance by changing end groups. The existing synthesis reports change the end groups by first synthesizing lactic acid-glycolic acid copolymer and then attaching the desired end groups through chemical reactions. This method has low reaction efficiency, is difficult to purify, and the effect on degradation performance is not clear.

[0004] How to simply and efficiently regulate the properties and degradation performance of lactic acid-glycolic acid copolymer, and how to achieve reproducible preparation, are still important limiting factors that restrict the development of lactic acid-glycolic acid copolymer microsphere drug products. Therefore, there is still a need to develop a simple and efficient method for regulating the structure and degradation performance of lactic acid-glycolic acid copolymer and for reproducible production. SUMMARY

[0005] The present application aims to provide a lactate-glycolate copolymer with controllable end group carbon chain length, a preparation method thereof and applications thereof.

[0006] To achieve the aforementioned application purposes, the present application adopts the technical solutions comprising:

[0007] One aspect of the present application provides a lactate-glycolate copolymer with controllable end group carbon chain length, which is an alcohol-terminated lactate-glycolate copolymer, and its structural formula is shown as formula (I):

[0008]

[0009] wherein R is selected from C1-C 20 alkyl; m is 20-600, and n is 20-400.

[0010] Another aspect of the present application provides a preparation method of the lactate-glycolate copolymer with controllable end group carbon chain length, which comprises: initiating ring-opening polymerization reaction of lactide and glycolide with alcohol as an initiator to prepare the lactate-glycolate copolymer with controllable end group carbon chain length.

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

[0012] R-OH

[0013] Formula (II)

[0014] wherein R is selected from C1-C 20 alkyl.

[0015] Another aspect of the present application also provides the lactate-glycolate copolymer with controllable end group carbon chain length prepared by the aforementioned preparation method.

[0016] Another aspect of the present application also provides applications of the aforementioned lactate-glycolate copolymer with controllable end group carbon chain length in preparing biodegradable materials.

[0017] Another aspect of the present application also provides applications of the aforementioned lactate-glycolate copolymer with controllable end group carbon chain length in carriers of drug sustained and controlled release drug delivery systems.

[0018] Compared with the prior art, the technical solutions of the present application have at least the following advantages:

[0019] The application realizes simple controllable end groups of lactic acid-glycolic acid copolymer by simply adjusting the carbon chain length of alcohol as an initiator, so as to change the degradation speed of the polymer, and the longer the carbon chain length of the end group is, the longer the degradation time is; the prepared lactic acid-glycolic acid copolymer can be used as a carrier of various drug sustained-release drug delivery systems, meets the needs of different sustained-release time, and has a wide application range; and the synthesis reaction in the application is 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 DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments described in the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0021] Figure 1 The reaction flow chart of the preparation method of the lactic acid-glycolic acid copolymer with adjustable carbon chain length of end group in a typical embodiment of the present application is shown in the figure.

[0022] Figure 2 The molecular weight test result graph of the PLGA prepared in Example 1 of the present application is shown in the figure.

[0023] Figure 3 The molecular weight test result graph of the PLGA prepared in Example 2 of the present application is shown in the figure.

[0024] Figure 4 The molecular weight test result graph of the PLGA prepared in Example 3 of the present application is shown in the figure.

[0025] Figure 5 The molecular weight test result graph of the PLGA prepared in Example 4 of the present application is shown in the figure.

[0026] Figure 6 The molecular weight test result graph of the PLGA prepared in Example 5 of the present application is shown in the figure.

[0027] Figure 7 The molecular weight test result graph of the PLGA prepared in Example 6 of the present application is shown in the figure.

[0028] Figure 8 The molecular weight test result graph of the PLGA prepared in Example 7 of the present application is shown in the figure.

[0029] Figure 9 The molecular weight test result graph of the PLGA prepared in Comparative Example 1 of the present application is shown in the figure.

[0030] Figure 10Determination of the ratio of lactic acid and glycolic acid of the PLGA prepared for Example 1 of the present application by nuclear magnetic hydrogen spectrum;

[0031] Figure 11 Determination of the ratio of lactic acid and glycolic acid of the PLGA prepared for Example 2 of the present application by nuclear magnetic hydrogen spectrum;

[0032] Figure 12 Determination of the ratio of lactic acid and glycolic acid of the PLGA prepared for Example 3 of the present application by nuclear magnetic hydrogen spectrum;

[0033] Figure 13 Determination of the ratio of lactic acid and glycolic acid of the PLGA prepared for Example 4 of the present application by nuclear magnetic hydrogen spectrum;

[0034] Figure 14 Determination of the ratio of lactic acid and glycolic acid of the PLGA prepared for Comparative Example 1 of the present application by nuclear magnetic hydrogen spectrum;

[0035] Figure 15 Nuclear magnetic resonance carbon spectrum of the PLGA prepared for Example 1 of the present application;

[0036] Figure 16 Nuclear magnetic resonance carbon spectrum of the PLGA prepared for Comparative Example 1 of the present application;

[0037] Figure 17 Comparison chart of the change of degradation quality of the tablets after tableting of the PLGA prepared for Examples 1-3 and Comparative Example 1 of the present application;

[0038] Figure 18 Comparison chart of the change of degradation pH of the tablets after tableting of the PLGA prepared for Examples 1-3 and Comparative Example 1 of the present application. DETAILED DESCRIPTION

[0039] The present application will be more fully understood by reading the following detailed description together with the accompanying drawings. It is noted that, as the application herein disclosed can be implemented in various forms, the specific embodiments thereof described below are not intended to be limiting, and it is only representative as a representative basis for teaching one of ordinary skill in the art to employ the present application in virtually any appropriate detailed embodiment. It is also noted that, for the sake of brevity, the

[0040] As one aspect of the technical solution of the present application, it relates to an end group carbon chain length controllable lactic acid-glycolic acid copolymer, which is an alcohol-terminated lactic acid-glycolic acid copolymer, and its structural formula is shown as formula (I):

[0041]

[0042] wherein R is selected from C1-C 20hydrocarbyl; m is 20-600, and n is 20-400.

[0043] In some embodiments, the lactate-glycolate copolymer with tunable end group carbon chain length has a weight average molecular weight of 5000-100000.

[0044] In some preferred embodiments, the lactate-glycolate copolymer with tunable end group carbon chain length has a weight average molecular weight of 7000-50000.

[0045] As another aspect of the technical solution of the present application, it relates to a preparation method of a lactate-glycolate copolymer with tunable end group carbon chain length, which comprises: initiating ring-opening polymerization of lactide and glycolide with an alcohol as an initiator to prepare the lactate-glycolate copolymer with tunable end group 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 hydrocarbyl.

[0050] The principle of the synthetic reaction of the present application is shown as follows:

[0051]

[0052] The alcohol with the structure of formula (II) is used as a reaction initiator, and an initiator with a suitable carbon chain length can be selected according to requirements to obtain a polylactic acid-glycolic acid copolymer terminated by an alcohol with a corresponding carbon chain length, and the degradation performance of the polylactic acid-glycolic acid copolymer is adjusted by adjusting the carbon chain length of the end group.

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

[0054]

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

[0056] In some embodiments, the preparation method comprises: mixing the alcohol, lactide, glycolide and a catalyst, and performing ring-opening polymerization in a protective atmosphere to prepare the lactate-glycolate copolymer with tunable end group carbon chain length.

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

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

[0059] In some preferred embodiments, the protective atmosphere includes 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 for 4-12 hours.

[0061] In some preferred embodiments, the molar ratio of lactide to glycolide is 50-85:15-50. By adjusting the amount of lactide and glycolide fed in a certain proportion, lactic acid-glycolic acid copolymers with different ratios of lactide and glycolide can be obtained.

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

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

[0064] In some implementation schemes, see Figure 1 The reaction flow diagram shown illustrates the preparation method, which includes: adding an initiator and a catalyst to a reaction system of lactide and glycolide, carrying out a ring-opening polymerization reaction under 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 it to obtain the lactic acid-glycolic acid copolymer with adjustable end-group carbon chain length. Both good and poor solvents are used to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst.

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

[0066] In some preferred embodiments, the undesirable 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 end-group carbon chain length prepared by the aforementioned preparation method.

[0068] As another aspect of the technical solution of the present invention, it also relates to the application of the aforementioned lactic acid-glycolic acid copolymer with adjustable end-group carbon chain length in the preparation of biodegradable materials.

[0069] As another aspect of the technical solution of the present invention, it also relates to the application of the aforementioned lactic acid-glycolic acid copolymer with adjustable end-group carbon chain length in the carrier of the drug sustained-release drug delivery system.

[0070] In summary, the prior art generally controls the degradation time of lactic acid-glycolic acid copolymer by molecular weight and L / G component, the present application uses a new mechanism and method to control the degradation time, specifically, the present application realizes simple controllable end group of lactic acid-glycolic acid copolymer by simply adjusting the alcohol carbon chain length as an initiator, so as to change the degradation rate of the polymer, the reaction is a one-step reaction, the preparation process is simple, the energy consumption is low, the preparation can be repeated, the obtained product can be used as a carrier of various drug controlled release drug delivery systems, it is a new design of polymer idea, which has very important significance and broad development prospect.

[0071] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The reagents and raw materials used in the following examples are commercially available, and the test methods not specified in the following examples are generally carried out according to conventional conditions or according to the 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 the lactide can be DL-lactide; in addition, the flasks referred to in the following examples are all dried; the reaction pressure in the examples is atmospheric pressure.

[0072] Example 1

[0073] Put 79g of lactide, 21g of glycolide, n-hexanol (1.0wt% of the total mass of lactide and glycolide) and stannous octoate (0.1wt% of the total mass of lactide and glycolide) into a flask, fill the flask with nitrogen, react at 140℃ for 4 hours, dissolve the crude product in dichloromethane, precipitate into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst, obtain lactic acid-glycolic acid copolymer n-hexanol end-capped, the weight average molecular weight is 14262, the yield is 92%.

[0074] Example 2

[0075] Put 79g of lactide, 21g of glycolide, dodecanol (1.9wt% of the total mass of lactide and glycolide) and stannous octoate (0.1wt% of the total mass of lactide and glycolide) into a flask, fill the flask with nitrogen, react at 140℃ for 4 hours, dissolve the crude product in dichloromethane, precipitate into methanol to remove oligomers, unreacted monomers (lactide and glycolide) and residual catalyst, obtain lactic acid-glycolic acid copolymer dodecanol end-capped, the weight average molecular weight is 14562, the yield is 89%.

[0076] Example 3

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

[0078] Example 4

[0079] A flask was charged with 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), and the flask was filled with nitrogen. The reaction was carried out at 140°C for 4 hours, and the crude product was dissolved in dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst, thereby obtaining lactic acid-glycolic acid copolymer dodecanol-terminated with a weight average molecular weight of 14805 and a yield of 89%.

[0080] Example 5

[0081] A flask was charged with 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), and the flask was filled with nitrogen. The reaction was carried out at 140°C for 12 hours, and the crude product was dissolved in dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst, thereby obtaining lactic acid-glycolic acid copolymer dodecanol-terminated with a weight average molecular weight of 48221 and a yield of 89%.

[0082] Example 6

[0083] A flask was charged with 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), and the flask was filled with nitrogen. The reaction was carried out at 150°C for 6 hours, and the crude product was dissolved in dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst, thereby obtaining lactic acid-glycolic acid copolymer eicosanol-terminated with a weight average molecular weight of 53364 and a yield of 80%.

[0084] Example 7

[0085] Into a flask, 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, the flask was filled with nitrogen, and the reaction was carried out at 160°C for 8 hours. The crude product was dissolved in dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst, thereby obtaining 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] Into a flask, 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, the flask was filled with nitrogen, and the reaction was carried out at 140°C for 4 hours. The crude product was dissolved in dichloromethane and precipitated into methanol to remove oligomers, unreacted monomers (lactide and glycolide), and residual catalyst, thereby obtaining a lactic acid-glycolic acid copolymer capped with carboxyl groups, with a weight average molecular weight of 14045 and a yield of 90%.

[0088] The lactic acid-glycolic acid copolymers prepared in Examples 1-7 and Comparative Example 1 were subjected to structural characterization and performance testing:

[0089] Intrinsic viscosity test: Intrinsic viscosity can be used as a measure of molecular weight, and the intrinsic viscosity of the reaction polymer. 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 solution was measured using an Ubbelohde viscometer to obtain the results.

[0090] The viscosity of Example 1 was 0.19 dL / g, the viscosity of Example 2 was 0.19 dL / g, the viscosity of Example 3 was 0.18 dL / g, and the viscosity of Comparative Example 1 was 0.20 dL / g. From this test, it can be seen that changing the type of initiator has little effect on the intrinsic viscosity of the product, and the intrinsic viscosity can be excluded from interfering with the degradation test.

[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 using a needle filter 0.22 μm filter, and measured using a Waters HPLC pump and a Waters HPLC automatic sampler in combination with a series of ACQUITY APC XT chromatographic columns. The sample was monitored using a refractive index detector. The calibration curve was constructed using software and polystyrene standard polymers. The mobile phase was tetrahydrofuran, flowing at a rate of 0.5 mL / min, the run time was 20 minutes, and the injection volume was 20 ul. The relative molecular weight of the lactic acid-glycolic acid copolymer was detected to determine its structural characteristics.

[0092] The molecular weight test results of Examples 1-7 and Comparative Example 1 are in turn 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 in turn 14262, 14562, 14990, 14805, 48221, 53364, 6387, 14045. From the molecular weight, it can be found that only changing the length of the carbon chain of the initiator can keep the molecular weight at a level, excluding the influence of molecular weight on degradation, and at the same time, the molar ratio of the initiator can be simply changed to regulate the molecular weight.

[0093] NMR hydrogen spectrum test: The lactic acid-glycolic acid copolymer prepared in Examples 1-4 and Comparative Example 1 was dissolved in deuterated chloroform to 10 mg / mL, and then transferred into an NMR tube. The spectrum of each sample was collected by NMR hydrogen spectrum spectrometry, 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 5.2 ppm and 4.8 ppm. Different ratios can significantly affect the performance of polylactic acid-glycolic acid copolymer.

[0094] The NMR hydrogen spectra of Examples 1-4 and Comparative Example 1 are in turn Figures 10 to 14 The molar ratio of lactic acid and glycolic acid in the products of Examples 1-3 and Comparative Example 1 is 73 / 27, and the molar ratio of lactic acid and glycolic acid in the product of Example 4 is 48 / 52. From the results obtained by integrating the NMR hydrogen spectrum, it is found that keeping the ratio of lactide and glycolide unchanged, changing the length of the alcohol carbon chain of the initiator does not affect the ratio of lactic acid and glycolic acid in the final product. At the same time, due to the faster ring-opening polymerization rate of glycolide than lactide, the proportion of glycolic acid in the product is larger, and because 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 the hydrophilic performance, thereby affecting the degradation.

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

[0097] V 样 : the volume of the sample consumed titration solution (mL)

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

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

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

[0101] W 样 : Weight of sample

[0102] The calculation results are 1.12 for Example 1, 1.05 for Example 2, 0.98 for Example 3, and 10.52 for Comparative Example 1. It can be found from the acid value results that only changing the length of the carbon chain of the initiator does not affect the acid value, and the acid value can be maintained at a level. At the same time, when the initiator carbon chain contains a carboxyl group, the acid value will increase sharply, changing the hydrophilicity of the product and thus affecting its degradation performance.

[0103] NMR Carbon Spectrum Test: The lactic acid-glycolic acid copolymer prepared from Example 1 and Comparative Example 1 was dissolved in a diluent to 15 mg / mL, and then the obtained polymer solution was transferred to an NMR tube. The end group of the lactic acid-glycolic acid copolymer was confirmed by NMR carbon spectrum, and 12000 scans were performed. The end group was confirmed by whether there was a specific peak at 14 ppm in the NMR spectrum. Different end groups will directly affect the degradation performance of the lactic acid-glycolic acid copolymer.

[0104] The NMR carbon spectra of Example 1 and Comparative Example 1 are Figure 15 and Figure 16 respectively. It can be found from the NMR carbon spectrum that the end group is successfully connected.

[0105] Degradation Test: The lactic acid-glycolic acid copolymer prepared from Examples 1-3 and Comparative Example 1 was weighed at 150 mg, respectively, and a tablet with a diameter of 14 mm and a thickness of 0.90 mm was prepared by a tablet press under a pressure of 30 Mpa. The tablet was placed in 15 mL of phosphate buffer with pH = 7.4. And in a shaking bed at 37℃ with a speed of 100 rpm. At predetermined time intervals, the tablet was taken out, washed with pure water three times, vacuum dried for 72 hours, weighed, and the pH of the degradation solution was measured.

[0106] The mass change comparison chart of Examples 1-3 and Comparative Example 1 is shown in Figure 17 , and the pH change comparison chart is shown in Figure 18The mass change can be seen, with the increase of the end group carbon chain, the mass change is smaller, because the lactic acid-glycolic acid copolymer degradation can produce soluble material to cause the mass loss, so the faster mass change indicates the faster degradation, and the pH change of the degradation solution, all show that the end group can affect the degradation. Figure 17 It can be seen that the longer the carbon chain length of the end group, the longer the degradation time, and the mass loss of the lactic acid-glycolic acid copolymer with different end groups is between 60 days and 120 days (from the degradation graph of 40 days, the linear degradation can be fitted, and the mass loss half-time can be calculated from the fitted function).

[0107] From the above test, it can be seen that by changing only the alcohol with different carbon chain lengths, lactic acid-glycolic acid copolymers with only different end groups can be obtained, and other factors affecting performance and degradation include intrinsic viscosity, molecular weight, lactic acid and glycolic acid ratio, and acid value results are similar, and these factors can be kept from affecting degradation, and only the end group is changed under the same conditions to judge the effect of the end group on degradation. According to the degradation experiment results, with the increase of the length of the end group carbon chain, the degradation time of the lactic acid-glycolic acid copolymer also increases, so the performance of the lactic acid-glycolic acid copolymer can be simply and conveniently controlled by regulating the end group.

[0108] In addition, the inventors of the present case also refer to the aforementioned examples, and other raw materials, process operations, and process conditions described in the specification are tested, and all ideal results are obtained.

[0109] The above-described embodiments only express several embodiments of the present application, which are described in detail and in detail, but should not be understood as limiting the scope of the patent. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the scope of protection of the present application should be subject to the appended claims.

Claims

1. A method for controlling the properties of a lactic-glycolic acid copolymer by regulating the length of the terminal carbon chain, characterized in that, The application relates to a method for preparing a lactic acid-glycolic acid copolymer with controllable carbon chain length of end groups. The method comprises the following steps: mixing alcohol, lactide and glycolide with a catalyst, and initiating ring-opening polymerization of the lactide and the glycolide in a protective atmosphere with the alcohol as an initiator to prepare the lactic acid-glycolic acid copolymer with controllable carbon chain length of end groups. By changing only the alcohol with different carbon chain lengths, the lactic acid-glycolic acid copolymers with different end groups are obtained. The longer the carbon chain length of the end groups of the lactic acid-glycolic acid copolymer is, the longer the degradation time of the lactic acid-glycolic acid copolymer is. The alcohol comprises n-hexanol, dodecanol, cetyl alcohol or eicosanol. The catalyst is selected from any one or a combination of stannous octoate and stannous chloride. The ring-opening polymerization reaction is carried out at a temperature of 120-180 DEG C for 4-12 h. The molar ratio of the lactide to the glycolide is 50-85:15-50. The alcohol is added in an amount of 0.1-6.0 wt% of the total mass of the lactide and the glycolide.

2. The method for controlling the properties of poly(lactic-co-glycolic acid) by regulating the length of terminal carbon chain according to claim 1, characterized in that, The catalyst is added in an amount of 0.05-0.2 wt% of the total mass of the lactide and the glycolide.

3. The method for controlling the properties of poly(lactic-co-glycolic acid) by regulating the length of terminal carbon chain according to claim 1, characterized in that, The lactide comprises any one or a combination of DL-lactide and L-lactide.

4. The method for controlling the properties of poly(lactic-co-glycolic acid) by regulating the length of terminal carbon chain according to claim 1, characterized in that, The protective atmosphere comprises a nitrogen atmosphere or an argon atmosphere. ; wherein R is selected from C6, C 12 , C16or C 20 alkyl groups; m is 20-600 and n is 20-400.

5. The method for controlling the properties of poly(lactic-co-glycolic acid) by regulating the length of terminal carbon chain according to claim 1, characterized in that, The lactic acid-glycolic acid copolymer has a structural formula as shown in formula (II).

6. The method for controlling the properties of poly(lactic-co-glycolic acid) by regulating the length of terminal carbon chain according to claim 1, wherein, The weight average molecular weight of the lactic acid-glycolic acid copolymer is 5000-100000. The weight average molecular weight of the lactic acid-glycolic acid copolymer is 7000-50000.

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