Star-shaped glycolide-lactide copolymer as well as preparation method and application thereof

Abstract

The invention provides a star-shaped glycolide-lactide copolymer as well as a preparation method and application thereof. The star-shaped glycolide-lactide copolymer comprises a core and a plurality of layers of shells, the core is formed by removing hydrogen atoms on hydroxyl of polyhydric alcohol or polyhydric phenol; the multi-layer shell is composed of multiple layers of glycolide and / or lactide polymer blocks, and the number of layers of the multi-layer shell is larger than or equal to 2; the number of layers refers to a polymer block of glycolide and / or lactide obtained through one-time polymerization reaction. According to the star-shaped glycolide-lactide copolymer, the degradation rate of the star-shaped glycolide-lactide copolymer can be controlled by controlling the monomer proportion of glycolide and lactide and the number of layers of the blocks, accurate control over the drug release amount is achieved, star-shaped glycolide-lactide copolymers of different structures can be prepared according to specific clinical needs, and therefore accurate control over the drug release amount is achieved.

Description

Technical Field

[0001] The present invention relates to the field of biodegradable polymers. Further, it relates to a star-shaped glycolide-lactide copolymer, a preparation method thereof, and an application thereof. Background Art

[0002] Poly(glycolide-lactide) (PGLA) is a kind of aliphatic polyester. Generally, high-molecular-weight PGLA is prepared from glycolide and lactide, and the molecular weight is adjusted to meet different application requirements. Due to the excellent biodegradability, biocompatibility, and processability of PGLA, it is widely used in medical materials such as surgical sutures and drug sustained-release capsules.

[0003] In the field of drug-loaded microspheres, there are often high requirements for the degradation rate of the drug-loaded carrier to control the precise release of the drug. It is necessary to regulate the release rate of the drug according to different medical needs. For example, a lower drug concentration is required in the early stage of medication, while a larger dosage is needed in the later stage of treatment. Ordinary-structured PGLA materials cannot meet the complex drug release requirements. The star-shaped glycolide-lactide block copolymer described in this patent has multi-layer shells with different monomer ratios and different degradation rates. After the degradation of the previous layer of shell is completed, the degradation of the subsequent layer of shell will start, thereby achieving the effect of controlling the drug concentration in multiple stages. At the same time, by adjusting the monomer ratio of each layer of shell, the drug sustained-release rate can be precisely regulated to meet the requirements of various dosages.

[0004] However, the existing poly(glycolide-lactide) (PGLA) cannot precisely control the drug sustained-release rate in stages, and it is necessary to study a glycolide-lactide copolymer that can precisely control the drug sustained-release rate. Summary of the Invention

[0005] In order to solve the technical problems existing in the prior art, the present invention provides a star-shaped glycolide-lactide copolymer, a preparation method thereof, and an application thereof.

[0006] The star-shaped glycolide-lactide copolymer of the present invention has a core of a group that removes the hydrogen atom on the hydroxyl group of a polyol or polyphenol, and a multi-block copolymer composed of glycolide and / or lactide forms a multi-layered shell. The number of layers of the shell is preferably 2 to 5 layers. Since the polyglycolide block has a slow degradation rate, the poly(lactide) has a fast degradation rate, and the degradation rate of the poly(glycolide-lactide) copolymer changes with the monomer ratio, the present invention can control the degradation rate of the star-shaped glycolide-lactide copolymer by controlling the monomer ratio of glycolide and lactide and the number of layers of the block, so as to precisely control the drug release amount. Different structures of star-shaped glycolide-lactide copolymers can be prepared according to the specific clinical needs, thereby achieving precise control of the drug release amount.

[0007] One of the objectives of the present invention is to provide a star-shaped glycolide-lactide copolymer, which includes a core and multiple layers of outer shells; the core is formed by removing the hydrogen atoms on the hydroxyl groups of polyols or polyphenols; the multiple layers of outer shells are composed of multiple polymer blocks of glycolide and / or lactide, and the number of layers of the multiple layers of outer shells ≥ 2 layers; the number of layers refers to the polymer blocks of glycolide and / or lactide obtained from a single polymerization reaction.

[0008] The number of layers does not refer to the number of blocks. In the presence of a catalyst and an initiator, glycolide and / or lactide are polymerized in a protective gas atmosphere to obtain one layer at a time. One layer can be a block of glycolide, a block of lactide, or a copolymer block of glycolide and lactide. When a mixture of glycolide and lactide is added in a single reaction, in the layer obtained, glycolide and lactide may be randomly copolymerized and regarded as one layer as a whole. The ratios of glycolide and lactide in each layer are different, so the degradation rate of each layer is variable and can change with the monomer ratio, thereby achieving precise control of the degradation rate to achieve the purpose of precisely controlling the drug release amount.

[0009] Since the obtained star-shaped glycolide-lactide copolymer is multi-layered and the specific structural formula is relatively complex, the structural schematic diagrams of the star-shaped glycolide-lactide copolymer with triols and tetrols as the core are given below to help understand the multi-layer structure of the star-shaped glycolide-lactide copolymer:

[0010]

[0011] In a preferred embodiment of the present invention,

[0012] the number of hydroxyl groups of the polyol or polyphenol is 3 - 6, preferably at least one of glycerol, pentaerythritol, trimethylolpropane, glycerol pentaerythritol, hexahydroxybenzene;

[0013] the number of layers of the multi-layer outer shell composed of polymer blocks of glycolide and / or lactide is 2 - 5 layers;

[0014] in the multi-layer outer shell, the molar ratio of the total amount of glycolide to the total amount of lactide is (5 - 95):(5 - 95), preferably (50 - 95):(5 - 50), and more preferably (70 - 90):(10 - 30).

[0015] Another objective of the present invention is to provide a preparation method of a star-shaped glycolide-lactide copolymer, which includes the following steps:

[0016] (1) Polymerize monomer A in the presence of a catalyst and an initiator in a protective gas atmosphere to obtain a polymer with one layer of outer shell;

[0017] (2) Add monomer B to the polymer obtained in step (1), and carry out a polymerization reaction under a protective gas atmosphere to obtain a block copolymer with a two-layer shell;

[0018] (3) Optionally, add monomer C to the polymer obtained in step (2), and carry out a polymerization reaction under a protective gas atmosphere to obtain a polymer with a three-layer shell; and so on. Add monomer M to the polymer with an (n - 1)-layer shell, and carry out a polymerization reaction under a protective gas atmosphere to obtain a polymer with an n-layer shell; preferably, n is 3, 4 or 5;

[0019] (4) Remove the residual monomers to obtain the star-shaped glycolide-lactide block copolymer;

[0020] The monomer A, monomer B, and monomer M are each independently selected from at least one of glycolide and lactide, and at least one of monomer A and monomer B includes both glycolide and lactide.

[0021] Monomer M refers to the monomer added after the block copolymer with a two-layer shell, including monomer C, monomer D, monomer E, etc.; for example, adding monomer C to react to obtain a block copolymer with a three-layer shell, adding monomer D to the block copolymer with a three-layer shell to react to obtain a block copolymer with a four-layer shell, adding monomer E to the block copolymer with a four-layer shell to react to obtain a block copolymer with a five-layer shell, and so on, until a block copolymer with an n-layer shell is obtained, where monomer C, monomer D, and monomer E are each independently selected from at least one of glycolide and lactide.

[0022] In a preferred embodiment of the present invention,

[0023] Step (1),

[0024] The reaction temperature is 130 - 220 °C, preferably 180 - 200 °C;

[0025] The protective gas is at least one of nitrogen and inert gas; the reactor is purged with the protective gas before the reaction;

[0026] The polymerization reaction time is 5 min to 10 h, preferably 30 min to 2 h;

[0027] The catalyst is at least one of metal catalysts and non-metal catalysts, preferably at least one of stannous octanoate, stannous chloride, and organic guanidine reagents;

[0028] The mass of the catalyst is 5 - 2000 ppm of the total mass of the monomers, preferably 40 - 500 ppm, and more preferably 50 - 200 ppm;

[0029] The initiator is at least one of polyol or polyphenol initiators. The number of hydroxyl groups of the polyol or polyphenol initiator is preferably 3 to 6, and the initiator is more preferably at least one of glycerol, pentaerythritol, trimethylolpropane, glycerol pentaerythritol, and hexahydroxybenzene;

[0030] The molar ratio of the initiator to the total amount of monomers is 1:(50 - 5000), preferably 1:(500 - 3000), and more preferably 1:(500 - 1000).

[0031] In a preferred embodiment of the present invention,

[0032] In step (2),

[0033] The molar ratio of monomer A to monomer B is (5 - 95):(5 - 95), preferably (10 - 90):(10 - 90);

[0034] The protective gas is at least one of nitrogen and inert gas;

[0035] The polymerization reaction temperature is 130 - 220 °C, preferably 180 - 200 °C;

[0036] The polymerization reaction time is 5 min - 10 h, preferably 30 min - 4 h, and more preferably 1 - 3 h.

[0037] In a preferred embodiment of the present invention,

[0038] In step (3),

[0039] The molar ratio of monomer A to monomer B is (5 - 95):(5 - 95), preferably (10 - 90):(10 - 90);

[0040] The protective gas is at least one of nitrogen and inert gas;

[0041] The polymerization reaction temperature is 130 - 220 °C, preferably 180 - 200 °C;

[0042] The polymerization reaction time is 5 min - 10 h, preferably 30 min - 4 h, and more preferably 1 - 3 h.

[0043] In a preferred embodiment of the present invention,

[0044] In step (4),

[0045] The method for removing residual monomers is screw devolatilization, and after devolatilization, it is directly extruded and pelletized.

[0046] Screw devolatilization can adopt the common processes in the prior art. Preferably, the devolatilization temperature is 200 - 250 °C, the devolatilization time is 5 - 20 min, and the devolatilization vacuum degree is 100 - 300 Pa.

[0047] In a preferred embodiment of the present invention,

[0048] In the multi-layer shell, the molar ratio of the total amount of glycolide to the total amount of lactide is (5 - 95):(5 - 95), preferably (50 - 95):(5 - 50), and more preferably (70 - 90):(10 - 30);

[0049] The water content of the glycolide is 50 - 1000 ppm, preferably 50 - 200 ppm, and the acid value is 2 - 100 mol / t, preferably 2 - 5 mol / t;

[0050] The water content of the lactide is 50 - 1000 ppm, preferably 50 - 200 ppm, and the acid value is 2 - 100 mol / t, preferably 1 - 5 mol / t;

[0051] The polymerization reaction is carried out in a reactor, and the reactor is at least one of a kettle reactor, a static reactor, and a screw extruder.

[0052] The third object of the present invention is to provide a star-shaped glycolide-lactide copolymer obtained by the above preparation method.

[0053] The fourth object of the present invention is to provide an application of the star-shaped glycolide-lactide copolymer in biodegradable materials, preferably in medical degradable materials.

[0054] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0055] The star-shaped glycolide-lactide copolymer of the present invention has a core of a group that removes the hydrogen atom on the hydroxyl group by a polyol or a polyphenol, and a multi-block copolymer composed of glycolide and lactide forms a multi-layer structure shell. The number of layers of the shell is preferably 2 - 5 layers. Since the degradation rate of the polyglycolide block is slow and the degradation rate of the polylactide block is fast, and the degradation rate of the polyglycolide-lactide copolymer changes with the monomer ratio, the present invention can control the degradation rate of the star-shaped glycolide-lactide copolymer by controlling the monomer ratio of glycolide and lactide and the number of layers of the block, so as to accurately control the drug release amount. Different structures of star-shaped glycolide-lactide copolymers can be prepared according to the specific clinical needs, thereby realizing accurate control of the drug release amount. Specific embodiments

[0056] The present invention will be specifically described below in conjunction with specific embodiments. It is necessary to point out here that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art to the present invention based on the content of the present invention still fall within the protection scope of the present invention.

[0057] The raw materials used in the embodiments are all conventional commercially available raw materials;

[0058] Among them,

[0059] Glycolide: The water content is 200 ppm and the acid value is 2 mol / t;

[0060] L-Lactide: The water content is 200 ppm and the acid value is 1 mol / t.

[0061] Test method:

[0062] Determination of intrinsic viscosity ([η]):

[0063] Using hexafluoroisopropanol as the solvent, in a constant temperature water bath at 25 °C with an Ubbelohde viscometer, by measuring the efflux times t o and t of the pure solvent and the sample solution, it is obtained by the "one-point method" formula.

[0064]

[0065] In vitro degradation test: Conducted according to the national standard YY / T 1806.1-2021.

[0066] Example 1

[0067] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm of the total monomer mass), and 23.5 g (0.1727 mol) of pentaerythritol (molar ratio to the total monomer amount is 1:1000) were added to a nitrogen-purged autoclave reactor for reaction. The reaction temperature was 200 °C and the time was 1 h. After the reaction, a polymer with 1 layer of shell was obtained.

[0068] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide (with a water content of 200 ppm and an acid value of 1 mol / t) were added to the obtained polymer with 1 layer of shell for reaction. The reaction temperature was 200 °C and the time was 2 h, obtaining a block copolymer with 2 layers of shell.

[0069] The obtained block copolymer with a two-layer shell was subjected to screw devolatilization at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized to obtain a star-shaped glycolide-lactide block copolymer (PGLA resin) with an intrinsic viscosity of 1.50 dL / g.

[0070] The in vitro degradation weight loss rate was tested to be 48% after 30 days and 63% after 60 days.

[0071] Example 2

[0072] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 2.12 g of stannous octoate (100 ppm of the total monomer mass), and 15.9 g of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a nitrogen-purged autoclave reactor for reaction at a reaction temperature of 200 °C for 40 min. After the reaction, a polymer with a one-layer shell was obtained.

[0073] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide were added to the obtained polymer with a one-layer shell for reaction at a reaction temperature of 200 °C for 1 h 20 min to obtain a block copolymer with a two-layer shell.

[0074] The obtained block copolymer with a two-layer shell was subjected to screw devolatilization at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized to obtain a star-shaped glycolide-lactide block copolymer (PGLA resin) with an intrinsic viscosity of 1.54 dL / g.

[0075] The in vitro degradation weight loss rate was tested to be 49% after 7 days and 61% after 14 days.

[0076] Example 3

[0077] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm of the total monomer mass), and 31.8 g (0.3453 mol) of glycerol (molar ratio to the total monomer amount of 1:500) were added to a nitrogen-purged autoclave reactor for reaction at a reaction temperature of 200 °C for 1 h. After the reaction, a polymer with a one-layer shell was obtained.

[0078] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide were added to the obtained polymer with a one-layer shell for reaction at a reaction temperature of 200 °C for 2 h to obtain a block copolymer with a two-layer shell.

[0079] The obtained block copolymer with a two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) obtained was 1.33 dL / g.

[0080] The in vitro degradation weight loss rate was tested to be 53% after 30 days and 67% after 60 days.

[0081] Example 4

[0082] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm of the total monomer mass), and 15.9 g (0.1726 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor that had been purged with nitrogen and reacted at a temperature of 200 °C for 1 h. After the reaction, a polymer with a one-layer shell was obtained.

[0083] 6 kg (51.7 mol) of glycolide and 4.96 kg (34.4 mol) of lactide were added to the obtained polymer with a one-layer shell and reacted at a temperature of 200 °C for 2 h to obtain a polymer with a two-layer shell.

[0084] The obtained polymer with a two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) obtained was 1.50 dL / g.

[0085] The in vitro degradation weight loss rate was tested to be 40% after 30 days and 60% after 60 days.

[0086] Example 5

[0087] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm), and 15.9 g (0.1726 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor that had been purged with nitrogen and reacted at a temperature of 200 °C for 1 h. After the reaction, a polymer with a one-layer shell was obtained.

[0088] 7 kg (60.3 mol) of glycolide and 3.72 kg (25.8 mol) of lactide were added to the obtained polymer with a one-layer shell and reacted at a temperature of 200 °C for 2 h to obtain a polymer with a two-layer shell.

[0089] The obtained polymer with two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) thus prepared was 1.55 dL / g.

[0090] The weight loss rate of in vitro degradation was tested to be 37% after 30 days and 58% after 60 days.

[0091] Example 6

[0092] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm of the total monomer mass), and 15.9 g (0.1726 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor that had been purged with nitrogen and reacted at a temperature of 190 °C for 1.5 h. After the reaction, a polymer with a one-layer shell was obtained.

[0093] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide were added to the obtained polymer with a one-layer shell and reacted at a temperature of 190 °C for 2.5 h to obtain a polymer with a two-layer shell.

[0094] The obtained polymer with two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) thus prepared was 1.58 dL / g.

[0095] The weight loss rate of in vitro degradation was tested to be 46% after 30 days and 60% after 60 days.

[0096] Example 7

[0097] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 4.24 g of stannous octoate (200 ppm of the total monomer mass), and 15.9 g (0.1726 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor that had been purged with nitrogen and reacted at a temperature of 200 °C for 30 min. After the reaction, a polymer with a one-layer shell was obtained.

[0098] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide were added to the obtained polymer with a one-layer shell and reacted at a temperature of 200 °C for 1 h to obtain a polymer with a two-layer shell.

[0099] The obtained polymer with two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) obtained was 1.55 dL / g.

[0100] The in vitro degradation weight loss rate was tested to be 42% after 30 days and 59% after 60 days.

[0101] Example 8

[0102] 10 kg (86.2 mol) of glycolide with an acid value of 2 mol / t and a water content of 100 ppm, 1.06 g of stannous octoate (50 ppm of the total monomer mass), and 15.9 g (0.1726 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor purged with nitrogen for reaction. The reaction temperature was 180 °C and the time was 2 h. After the reaction, a polymer with one-layer shell was obtained.

[0103] 5 kg (43.1 mol) of glycolide and 6.2 kg (43.1 mol) of lactide were added to the obtained polymer with one-layer shell for reaction. The reaction temperature was 180 °C and the time was 3 h, obtaining a polymer with two-layer shell.

[0104] The obtained polymer with two-layer shell was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The intrinsic viscosity of the star-shaped glycolide-lactide block copolymer (PGLA resin) obtained was 1.5 dL / g.

[0105] The in vitro degradation weight loss rate was tested to be 49% after 30 days and 64% after 60 days.

[0106] Comparative Example 1

[0107] 5 kg (43.1 mol) of glycolide, 6.2 kg (43.1 mol) of lactide, 0.56 g of stannous octoate (50 ppm of the total monomer mass), and 7.9 g (0.0862 mol) of glycerol (molar ratio to the total monomer amount of 1:1000) were added to a kettle reactor purged with nitrogen for reaction. The reaction temperature was 180 °C and the time was 2 h. After the reaction, a random copolymer was obtained.

[0108] The obtained random copolymer was subjected to devolatilization treatment by a screw extruder at a temperature of 220 °C for 10 min under a vacuum of 200 Pa, and then extruded and pelletized. The obtained glycolide-lactide copolymer (PGLA resin) had an intrinsic viscosity of 1.57 dL / g.

[0109] The in vitro degradation weight loss rate was 46% after 30 days of testing and 93% after 60 days of testing.

[0110] Table 1 In vitro degradation weight loss rates of Examples 1-8 and Comparative Example 1 after 30 days and 60 days

[0111]

[0112] As can be seen from Table 1, compared with Examples 1-3 and 6-8, Comparative Example 1 only prepared a poly (glycolide-co-lactide) random copolymer with a single-layer shell structure, and the dosage ratios of the raw material components were the same as those of the second layer shell of Examples 1-3 and 6-8. However, Examples 1-3 and 6-8 have a two-layer shell. The 30-day degradation weight loss rate of Examples 1-8 corresponds to the degradation weight loss rate of the outer layer (the second layer) shell. The difference between the 60-day and 30-day degradation weight loss rates can be estimated as the 30-day degradation weight loss rate of the first layer shell. Thus, the differences between the 60-day and 30-day degradation weight loss rates of Examples 1-3 and 6-8 were 15%, 12%, 19%, 19%, 17%, and 15% respectively, which proved that the degradation rate of the first layer shell with only the glycolide block was slower; while the 30-day degradation weight loss rate of Comparative Example 1 was 46%, and the difference between the 60-day and 30-day degradation weight loss rates was 47%. Since it only had one layer, the degradation rate remained consistent throughout and was comparable to the degradation rate of the second layer of Examples 1-3 and 6-8.

[0113] Examples 1-3 and 6-8 have a two-layer shell, and the degradation rates in the first 30 days and the next 30 days are variable. This is because the degradation rate of lactide is much higher than that of glycolide. The higher the lactide content in each layer, the relatively faster the degradation rate of the polymer in this layer. By this method, the more layers the shell is set, through the difference in the thickness of each layer and the different ratios of glycolide and lactide in the polymer segments of each layer, the variation of the polymer degradation rate can be made diverse, thus achieving the effect of precisely controlling the degradation time.

[0114] The molar ratios of glycolide and lactide in the second layer shell of Examples 4-6 were 60:40, 70:30, and 50:50 respectively, and their 30-day in vitro degradation weight loss rates were 40%, 37%, and 46% respectively, which also proved that different ratios of glycolide and lactide in the polymer segments of each layer resulted in different degradation rates.

[0115] The star-shaped glycolide-lactide block copolymers prepared in Examples 1 to 8 have a core formed by the hydrogen atom-removing group of a polyol or polyphenol, and a multi-block copolymer composed of glycolide and lactide forms a shell with a 2-5 layer structure. Since the degradation rate of the polyglycolide block is slow and the degradation rate of the polylactide is fast, and the degradation rate of the polyglycolide-lactide copolymer varies with the monomer ratio, by controlling the monomer ratio of glycolide and lactide and the number of layers of the blocks, the degradation rate of the star-shaped glycolide-lactide copolymer can be controlled to precisely control the drug release amount. Different structures of star-shaped glycolide-lactide copolymers can be prepared according to the specific clinical needs, thereby achieving precise control of the drug release amount.

Claims

1. A star-shaped glycolide-lactide copolymer, comprising a core and multiple layers of shells; the core is formed by removing the hydrogen atoms on the hydroxyl groups of polyols or polyphenols; the multiple layers of shells are composed of polymer blocks of multiple layers of glycolide and / or lactide, and the number of layers of the multiple layers of shells ≥ 2 layers; the number of layers refers to the polymer blocks of glycolide and / or lactide obtained from a single polymerization reaction.

2. The star-shaped glycolide-lactide copolymer according to claim 1, wherein: the number of hydroxyl groups of the polyol or polyphenol is 3 to 6, preferably at least one of glycerol, pentaerythritol, trimethylolpropane, glycerol pentitol, hexahydroxybenzene; and / or, the number of layers of the multiple layers of shells composed of the polymer blocks of glycolide and / or lactide is 2 to 5 layers; and / or, in the multiple layers of shells, the molar ratio of the total amount of glycolide to the total amount of lactide is (5 - 95):(5 - 95), preferably (50 - 95):(5 - 50), more preferably (70 - 90):(10 - 30).

3. A method for preparing the star-shaped glycolide-lactide copolymer according to claim 1 or 2, comprising the following steps: (1) Polymerizing monomer A in the presence of a catalyst and an initiator under a protective gas atmosphere to obtain a polymer with 1 layer of shell; (2) Adding monomer B to the polymer obtained in step (1) and polymerizing under a protective gas atmosphere to obtain a block copolymer with 2 layers of shells; (3) Optionally, adding monomer C to the polymer obtained in step (2) and polymerizing under a protective gas atmosphere to obtain a polymer with 3 layers of shells; and so on, adding monomer M to the polymer with n - 1 layers of shells and polymerizing under a protective gas atmosphere to obtain a polymer with n layers of shells; preferably n is 3, 4 or 5; (4) Removing the residual monomers to obtain the star-shaped glycolide-lactide block copolymer; the monomer A, monomer B, and monomer M are each independently selected from at least one of glycolide and lactide, and at least one of monomer A and monomer B contains both glycolide and lactide.

4. The method for preparing the star-shaped glycolide-lactide copolymer according to claim 3, wherein: In step (1), the reaction temperature is 130 - 220°C, preferably 180 - 200°C; and / or, the protective gas is at least one of nitrogen and inert gas; and / or, the polymerization reaction time is 5 min to 10 h, preferably 30 min to 2 h; and / or, the catalyst is at least one of metal catalysts and non-metal catalysts, preferably at least one of stannous octanoate, stannous chloride, and organic guanidine reagents; and / or, the mass of the catalyst is 5 - 2000 ppm of the total mass of the monomers, preferably 40 - 500 ppm, more preferably 50 - 200 ppm; and / or, the initiator is at least one of polyol or polyphenol initiators, the number of hydroxyl groups of the polyol or polyphenol initiator is preferably 3 to 6, and the initiator is more preferably at least one of glycerol, pentaerythritol, trimethylolpropane, glycerol pentitol, and hexahydroxybenzene; and / or, The molar ratio of the initiator to the total amount of monomers is 1:(50 - 5000), preferably 1:(300 - 3000), and more preferably 1:(500 - 1000).

5. The method for preparing the star-shaped glycolide-lactide copolymer according to claim 3, characterized in that: in step (2), the molar ratio of monomer A to monomer B is (5 - 95):(5 - 95), preferably (10 - 90):(10 - 90); and / or, the protective gas is at least one of nitrogen and inert gas; and / or, the polymerization reaction temperature is 130 - 220 °C, preferably 180 - 200 °C; and / or, the polymerization reaction time is 5 min - 10 h, preferably 30 min - 4 h, and more preferably 1 - 3 h.

6. The method for preparing the star-shaped glycolide-lactide copolymer according to claim 3, characterized in that: in step (3), the molar ratio of monomer M to monomer A is (5 - 95):(5 - 95), preferably (10 - 90):(10 - 90); and / or, the protective gas is at least one of nitrogen and inert gas; and / or, the polymerization reaction temperature is 130 - 220 °C, preferably 180 - 200 °C; and / or, the polymerization reaction time is 5 min - 10 h, preferably 30 min - 4 h, and more preferably 1 - 3 h.

7. The method for preparing the star-shaped glycolide-lactide copolymer according to claim 3, characterized in that: step (4), the method for removing the residual monomers is screw devolatilization, and direct extrusion and pelletizing are carried out after devolatilization.

8. The method for preparing the star-shaped glycolide-lactide copolymer according to claim 3, characterized in that: in the multi-layer shell, the molar ratio of the total amount of glycolide to the total amount of lactide is (5 - 95):(5 - 95), preferably (50 - 95):(5 - 50), and more preferably (70 - 90):(10 - 30); and / or, the water content of the glycolide is 50 - 1000 ppm, preferably 50 - 200 ppm, and the acid value is 2 - 100 mol / t, preferably 2 - 5 mol / t; and / or, the water content of the lactide is 50 - 1000 ppm, preferably 50 - 200 ppm, and the acid value is 1 - 100 mol / t, preferably 1 - 5 mol / t; and / or, the polymerization reaction is carried out in a reactor, and the reactor is at least one of a kettle reactor, a static reactor, and a screw extruder.

9. A star-shaped glycolide-lactide copolymer obtained by the preparation method according to any one of claims 3 - 8.

10. An application of the star-shaped glycolide-lactide copolymer according to any one of claims 1 - 2, 9 in biodegradable materials, preferably in medical degradable materials.

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