Amphiphilic block copolymer, stereocomplex, and preparation method therefor and use thereof

Abstract

The present disclosure belongs to the technical field of block copolymers, and specifically relates to an amphiphilic block copolymer, a stereocomplex, and a preparation method therefor and the use thereof. The amphiphilic block copolymer contains a polyester block and a water-soluble polymer block. By forming a monomer of the polyester block and introducing a second monomer having stereoregularity on the premise that raw materials, such as D- and L-lactide, are used as a first monomer, the stability of the amphiphilic block copolymer can be improved; in addition, the water solubility or self-dispersibility thereof are still maintained, micelles or nanoparticles are formed, and high drug loading capacity is maintained.

Description

Amphiphilic block copolymers, stereocomplexes, and methods of making and using the same TECHNICAL FIELD

[0001] The present disclosure is in the field of block copolymers, and in particular, to amphiphilic block copolymers, stereocomplexes, and methods of making and using the same. BACKGROUND

[0002] Many new molecular drugs developed in recent years are non-water soluble, which leads to low bioavailability, and difficulty in developing prescriptions and producing drug products. In order to improve water solubility and bioavailability, various technologies have been tried, including reducing drug particle size (e.g., microcrystals or nanocrystals), solid dispersions, emulsions, liposomes, lipid particles, polymeric micelles, nanoparticles, surfactants, solvents, etc. However, there are limited suitable solubilizing excipients available, and there are still great challenges in developing non-water soluble drug prescriptions and finished drug products.

[0003] Amphiphilic block copolymers can form polymeric micelles or nanoparticles, and are effective carriers for hydrophobic drugs. Block copolymers of biodegradable polyesters and polyethylene glycol (including its monomethyl ether) have good biocompatibility, and thus are widely studied as drug delivery carriers. Under proper hydrophobic / hydrophilic balance, block copolymers form micelles or nanoparticles in aqueous solution, and can be effective carriers for hydrophobic drugs. For example, diblock poly-lactide-co-racemic-glycolide monomethyl ether polyethylene glycol (PDLLA-MePEG) is used to solubilize paclitaxel and docetaxel, and has been successfully commercialized as polymeric micelle formulations, which significantly reduce the side effects of traditional surfactant formulations.

[0004] A large number of studies have shown that polymeric micelles are more effective in solubilizing hydrophobic drugs and have higher drug loading capacity than low molecular weight surfactants such as polysorbate. However, the commercial application of polyester-monomethyl ether polyethylene glycol as a drug carrier is still limited to paclitaxel and docetaxel, and both are injectable. The limited application is largely due to the fact that the polyester block is too sensitive to water and is prone to hydrolytic degradation, which leads to instability, especially during long-term storage at room temperature.

[0005] Crystalline poly(L-lactide) (PLLA) or poly(D-lactide) (PDLA) is more stable than amorphous poly(D,L-lactide) (PDLLA). However, due to its crystalline nature, PLLA-MePEG and PDLA-MePEG have lower drug loading capacity compared to their amorphous counterpart PDLLA-MePEG. In addition, PLLA-MePEG and PDLA-MePEG are not self-soluble in water and alcohol, so micelles or nanoparticles must be formed by dissolving the polymer in other organic solvents, mixing into the aqueous phase, and removing the solvent, which is a complex manufacturing process. In order to increase the storage stability, micelles / nanoparticles are usually further processed by freeze-drying or spray-drying, which can cause aggregation during the drying process.

[0006] In summary, the existing block copolymers based on biodegradable polyesters cannot simultaneously have the following properties: (1) good stability (such as 25℃ storage conditions); (2) self-soluble or self-dispersible in water to form micelles or nanoparticles; (3) higher drug loading capacity. This greatly limits the application of block copolymers in drug solubilization.

[0007] In view of this, the present disclosure is proposed.

[0008] SUMMARY

[0009] The purpose of the present disclosure includes providing an amphiphilic block copolymer, a stereocomplex and a preparation method and application thereof, aiming to provide an amphiphilic block copolymer that has the following advantages: good stability; self-soluble or self-dispersible in water to form micelles or nanoparticles; and higher drug loading capacity.

[0010] In order to achieve the above-mentioned purpose of the present disclosure, the following technical solutions can be used:

[0011] In a first aspect, the present disclosure provides a scheme including an amphiphilic block copolymer, comprising: a block copolymer formed by a polyester and a water-soluble polymer;

[0012] The monomer used to form the polyester includes a first monomer and a second monomer.

[0013] The first monomer is at least one of D, L-lactide and meso-lactide, and the second monomer is at least one selected from L-lactide and D-lactide.

[0014] And / or, the first monomer is at least one of D, L-lactide, meso-lactide, L-lactide, and D-lactide, and the second monomer is ε-caprolactone.

[0015] In some embodiments of the present disclosure, in the process of preparing the amphiphilic block copolymer, the mass fraction of the water-soluble polymer is X, the mass fraction of the first monomer is Y, and the mass fraction of the second monomer is Z, X, Y, and Z satisfy:

[0016] X = 40% - 90%;

[0017] Y = a x (100% - X), a is 10% - 90%;

[0018] Z = 100% - X - Y.

[0019] In some embodiments of the present disclosure, the water-soluble polymer is selected from at least one of polyethylene glycol, methoxypolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide, polyamino acid, and polyacrylate; preferably, the water-soluble polymer is methoxypolyethylene glycol or polyethylene glycol.

[0020] And / or, the number average molecular weight of the water-soluble polymer is 350 - 1,000,000, preferably 750 - 20,000, and more preferably 1,300 - 8,000.

[0021] In the second aspect, the present disclosure provides a preparation method of the amphiphilic block copolymer, comprising: polymerizing the water-soluble polymer with the first monomer and the second monomer.

[0022] In some embodiments of the present disclosure, the preparation method comprises: after heating the water-soluble polymer PEG or MePEG, mixing it with one monomer for forming polyester, and performing a first polymerization reaction in the presence of a catalyst, and then adding another monomer for forming polyester to perform a second polymerization reaction, to obtain a MePEG-containing triblock copolymer or a PEG-containing pentablock copolymer.

[0023] In some embodiments of the present disclosure, in the preparation of the triblock or pentablock copolymer, the mass ratio of the water-soluble polymer, the first monomer, and the second monomer is (40 - 90) : (5 - 45) : (5 - 45).

[0024] And / or, the reaction temperature of the first polymerization reaction is 120°C - 150°C, and the polymerization time is 2h - 72h;

[0025] And / or, the reaction temperature of the second polymerization reaction is 120°C - 150°C, and the polymerization time is 2h - 72h.

[0026] In some embodiments of the present disclosure, the preparation method comprises: after heating the water-soluble polymer, mixing it with the first monomer and the second monomer, and performing polymerization in the presence of a catalyst to obtain a MePEG-containing diblock copolymer or a PEG-containing triblock copolymer.

[0027] In some embodiments of the present disclosure, when preparing the diblock or triblock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer is controlled to be (40-90):(5-45):(5-45);

[0028] And / or, when preparing the diblock or triblock copolymer, the polymerization temperature is controlled to be 120-150℃, and the polymerization time is controlled to be 5-72h.

[0029] In some embodiments of the present disclosure, the catalyst is selected from at least one of stannous octoate, zinc lactate, alkoxides of stannous, alkoxides of aluminum and alkoxides of zinc;

[0030] And / or, the mass ratio of the total mass of the water-soluble polymer, the first monomer and the second monomer to the mass of the catalyst is 100:(0.02-0.5).

[0031] In some embodiments of the present disclosure, after the water-soluble polymer is heated to the polymerization temperature, the raw materials are melted and then subjected to vacuum treatment to remove residual moisture, and then the first monomer and / or the second monomer is added for polymerization.

[0032] In a third aspect, the present disclosure provides a stereocomplex, comprising at least two amphiphilic block copolymers, wherein the amphiphilic block copolymers are the amphiphilic block copolymers in any of the above embodiments or prepared by the preparation method in any of the above embodiments.

[0033] In some embodiments of the present disclosure, the stereocomplex comprises a first amphiphilic block copolymer and a second amphiphilic block copolymer,

[0034] The water-soluble polymer used for preparing the first amphiphilic block copolymer and the second amphiphilic block copolymer is selected from at least one of polyethylene glycol, methoxypolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide, polyamino acid and polyacrylate, and the first monomer used is at least one of D, L-lactide and meso-lactide.

[0035] In some embodiments of the present disclosure, the second monomer used for preparing the first amphiphilic block copolymer is L-lactide, and the second monomer used for preparing the second amphiphilic block copolymer is D-lactide.

[0036] And / or, the water-soluble polymer is selected from at least one of polyethylene glycol and methoxypolyethylene glycol;

[0037] And / or, the mass ratio of the first amphiphilic block copolymer to the second amphiphilic block copolymer is 1:(0.8-1.2).

[0038] In a fourth aspect, the present disclosure provides a preparation method of the stereocomplex, comprising: mixing two amphiphilic block copolymers in a molten or solution state.

[0039] In some embodiments of the present disclosure, the melting and mixing temperature is controlled to be 40-60°C, and the mixing time is 15-120 min.

[0040] In a fifth aspect, the present disclosure provides an application of the amphiphilic block copolymer provided by any of the above embodiments or the amphiphilic block copolymer prepared by the preparation method provided by any of the above embodiments or the stereocomplex provided by any of the above embodiments or the stereocomplex prepared by the preparation method provided by any of the above embodiments as a carrier in drug delivery.

[0041] In some embodiments of the present disclosure, the loaded drug is selected from at least one of cinacalcet hydrochloride, cinacalcet, nimodipine, amiodarone, posaconazole, docetaxel, paclitaxel, clarithromycin, and indomethacin.

[0042] In some embodiments of the present disclosure, the method for loading the drug is selected from at least one of preparing a freeze-dried preparation, preparing a drug-polymer matrix by solvent evaporation, preparing a drug-polymer matrix by melting and mixing, and an ethanol solution preparation;

[0043] In some embodiments of the present disclosure, the process of preparing a freeze-dried preparation comprises: dissolving the drug and the carrier, removing the solvent, and then dissolving again to form a drug-loaded micelle, followed by liquid separation, freeze-drying;

[0044] The process of preparing a drug-polymer matrix by solvent evaporation comprises: dissolving the drug, the carrier, and the solvent, heating to remove the solvent to obtain a drug-polymer matrix, and dissolving again to form a micelle solution;

[0045] The process of preparing a drug-polymer matrix by melting and mixing comprises: mixing and heating the drug and the carrier to obtain a molten material, cooling the molten material to obtain a drug-polymer solid matrix, and re-dissolving the drug-polymer solid matrix to obtain a micelle solution;

[0046] The process of preparing an ethanol solution preparation comprises: dissolving the drug and the carrier in ethanol, and diluting with an aqueous diluent to form a drug-loaded micelle.

[0047] The amphiphilic block copolymer provided by the present disclosure contains a polyester block and a water-soluble polymer block. By introducing a second monomer with stereoregularity based on the first monomer of D, L-lactide and the like, the stability of the amphiphilic block copolymer can be improved, while still maintaining its water solubility or self-dispersibility, forming micelles or nanoparticles, and maintaining high drug loading capacity. Attached Figure Description

[0048] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this disclosure and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0049] Figure 1 shows the polymer synthesized in Example 6. 1 H-NMR spectrum;

[0050] Figure 2 shows an example of GPC chromatograms of the synthesized block copolymers; in the figure, (a) represents PDLLA-MePEG 2000-50 / 50 (lot NB009-029); (b) represents PDLLA-PLLA-MePEG 2000-35 / 15 / 50 (lot NB009-050); and (c) represents 50% PDLLA-PDLA-MePEG 2000-35 / 15 / 50 + 50% PDLLA-PLLA-MePEG 2000-35 / 15 / 50 (lots 50% NB009-048 + 50% NB009-050).

[0051] Figures 3-5 are examples of differential scanning calorimetry (DSC) spectra of the synthesized block copolymers, showing that their polyester blocks are amorphous; in the figures, Figure 3 represents PDLLA-MePEG 2000-50 / 50, lot NB009-029; Figure 4 represents PDLLA / DLA-MePEG 2000-25 / 25 / 50, lot NB009-177-4; Figure 5 represents 50% PDLLA / LLA-MePEG 2000-25 / 25 / 50 (lot NB009-177-3) + 50% PDLLA / DLA-MePEG 2000-25 / 25 / 50 (lot NB009-177-4);

[0052] Figure 6 shows the change in oligomer content of the synthesized block copolymer when stored at 40°C, demonstrating that the stereoregular polymer has good stability.

[0053] Figures 7-10 are particle size distribution of polymeric micelle formulations measured by DLS; Figure 7 represents 10% cinacalcet loaded PDLLA-MePEG 2000-50 / 50 polymeric micelle formulation (Lot NB009-030); Figure 8 represents 10% cinacalcet loaded PDLLA-PLLA-MePEG 2000-35 / 15 / 50 polymeric micelle formulation (Lot NB009-066); Figure 9 represents 10% cinacalcet loaded 50% PDLLA-PLLA-MePEG 2000-35 / 15 / 50 + 50% PDLA-PDLA MePEG 2000-35 / 15 / 50 polymeric micelle formulation (Lot NB009-067); Figure 10 represents 10% cinacalcet loaded 50% PLLA-PDLLA-MePEG 2000-15 / 35 / 50 + 50% PLLA-PDLLA MePEG 2000-15 / 35 / 50 polymeric micelle formulation (Lot NB013-011). DETAILED DESCRIPTION

[0054] The embodiments of the present disclosure will be described in detail with reference to the following examples, but the skilled person will understand that the following examples are for illustration only and should not be construed as limiting the scope of the present disclosure. In the examples, where specific conditions are not specified, they are carried out under conventional conditions or under conditions recommended by the manufacturer. Where the manufacturer of the reagent or instrument used is not specified, it is a conventional product that can be obtained commercially.

[0055] The endpoints of the ranges and any values disclosed in the present disclosure are not limited to the precise values stated. The endpoints of the ranges and any values are provided as approximate values, and the ranges and values should be understood to encompass values approximately the same as the stated values. For numeric values, the endpoints of each range, the endpoints of each range and individual point values, and individual point values can be combined with each other to form one or more new numeric ranges, which should be considered as specifically disclosed herein.

[0056] PDLLA-MePEG and other block copolymers can self-dissolve or self-disperse in water, with high drug loading capacity, but are not stable under long-term storage conditions at room temperature. PLLA-MePEG and PDLA-MePEG block copolymers are more stable in room temperature storage, but do not self-dissolve or self-disperse in water, and have lower drug loading capacity. Therefore, the existing polymers are limited in successful commercial applications in drug solubilization, for example: the drug solubilization based on biodegradable polyester and polyethylene glycol block copolymers has not yet been applied in oral solid dosage forms.

[0057] In view of this, the present disclosure improves the composition of the polyester block, introduces stereoregularity into the amorphous poly-L-lactide (e.g. PDLLA) block, which can improve the stability of the amphiphilic block copolymer while still maintaining its water solubility or self-dispersibility and high drug loading capacity.

[0058] The present disclosure provides an amphiphilic block copolymer, comprising: a block copolymer formed by a polyester and a water-soluble polymer, that is, the amphiphilic block copolymer contains a polyester block and a water-soluble polymer block, which can be synthesized by ring-opening polymerization.

[0059] The monomers used to form the polyester include a first monomer and a second monomer.

[0060] In some embodiments, the first monomer is at least one of D, L-lactide and meso-lactide, and the second monomer is selected from at least one of L-lactide and D-lactide.

[0061] In some embodiments, the first monomer is at least one of D, L-lactide, meso-lactide, L-lactide, and D-lactide, and the second monomer is ε-caprolactone.

[0062] By introducing the second monomer, stereoregularity can be introduced into the polyester block, which can improve the stability while maintaining self-dispersibility and high drug loading capacity. Specifically, D, L-lactide refers to a mixture of L-lactide and D-lactide in a ratio of 1:1. The polyester copolymer can be a random copolymer (e.g. poly(DLLA-co-LLA) or a block copolymer (e.g. poly(LLA-b-DLLA)). The amphiphilic block copolymer can be a multi-block, such as a diblock, a triblock, a branched chain, a star, etc.

[0063] It should be noted that by changing the composition of the polyester, the chain length (or molecular weight) of the block copolymer (such as PEG and PLA), the material properties can be adjusted, including amphiphilicity, stereoregularity, solid state properties (e.g. amorphous and semi-crystalline, glass transition temperature), etc., thereby enhancing the stability, water solubility or self-dispersibility, and drug loading capacity of the polymer.

[0064] In preferred embodiments, the first monomer is D, L-lactide; the second monomer is selected from at least one of L-lactide and D-lactide, and the second monomer can be any one or several of the above. By optimizing the types of the first monomer and the second monomer, the stability and drug loading capacity of the product can be further improved.

[0065] In some embodiments of the present disclosure, the water-soluble polymer is selected from at least one of polyethylene glycol, methoxypolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide, polyamino acid and polyacrylate, and the water-soluble polymer can be any one or several of the above. Preferably, the water-soluble polymer is methoxypolyethylene glycol or polyethylene glycol, which can further improve the stability of the block copolymer.

[0066] Further, the number average molecular weight of the water-soluble polymer is 350-1000000 (such as 350, 500, 1000, 1500, 2000, 3000, 5000, 10000, 50000, 100000, 500000, 1000000, etc.), and the water-soluble polymer can have a wide range of molecular weights, which can all increase the stability of the product. The number average molecular weight of the water-soluble polymer is 750-20000, preferably 1300-8000, which can further improve the stability of the product without affecting the dispersion performance and high drug loading capacity. The polymer component and molecular weight of the polyester can be more extensive, which is not limited herein.

[0067] Further, in the process of preparing the amphiphilic block copolymer, the mass fraction of the water-soluble polymer is X, the mass fraction of the first monomer is Y, and the mass fraction of the second monomer is Z, X, Y and Z satisfy:

[0068] X = 40%-90%, the mass fraction of the water-soluble polymer can be 40%, 50%, 60%, 70%, 80%, 90%, etc.

[0069] Y = a x (100%-X), a is 10%-90%, and a can be 10%, 30%, 50%, 70%, 90%, etc., that is, the first monomer accounts for 10%-90% of the total amount of monomers.

[0070] Z = 100%-X-Y, the mass fraction of the second monomer is equal to 100% minus the mass fraction of the water-soluble polymer and the mass fraction of the first monomer.

[0071] By adjusting the mass ratio of the water-soluble polymer, the first monomer and the second monomer, the following three aspects of the prepared amphiphilic block copolymer are more ideal: (1) good stability, especially at higher temperatures (such as room temperature conditions); (2) water-solubility or self-dispersibility to form polymer micelles or nanoparticles; (3) high drug loading capacity.

[0072] Specifically, the polyester blocks are mostly amorphous, i.e. non-crystalline. The stereoregular polyester blocks include random copolymers of DLLA, LLA, DLA, CL, GA, such as P(DLLA-co-LLA), P(DLLA-co-DLA); the stereoregular polyester blocks also include block polyester copolymers, such as P(DLLA-b-LLA)-PEG-R, P(DLLA-b-DLA)-PEG-R, P(LLA-b-DLLA)-PEG-R, P(DLA-b-DLLA)-PEG-R, etc., wherein R is methyl or the same polyester block. The stereoregular polyester can also include a combination of PLLA or PDLA blocks with random copolymers having stereoregularity, such as P(DLLA-co-LLA) or P(DLLA-co-DLA).

[0073] The scheme provided by the present disclosure also includes a preparation method of the amphiphilic block copolymer, which comprises: performing a polymerization reaction of a water-soluble polymer and a first monomer and a second monomer, and the specific raw materials and mass ratio of the water-soluble polymer, the first monomer and the second monomer can refer to the above content in the specification, which is not repeated here.

[0074] In some embodiments of the present disclosure, a tri-block or penta-block copolymer can be prepared, and the preparation method comprises: after heating the water-soluble polymer MePEG or PEG, mixing with one monomer (which can be the first monomer or the second monomer) used for forming a polyester, performing a first polymerization reaction in the presence of a catalyst, and then adding another monomer used for forming a polyester to perform a second polymerization reaction, to obtain a tri-block copolymer containing MePEG or a penta-block copolymer containing PEG. By adding the first monomer and the second monomer in two times and performing the first polymerization reaction and the second polymerization reaction respectively, the tri-block copolymer containing MePEG or the penta-block copolymer containing PEG is obtained.

[0075] Further, when preparing the tri-block or penta-block copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer is controlled to be (40-90):(5-45):(5-45), and it is appropriate to control the use amount of the water-soluble polymer, the first monomer and the second monomer in the above range when preparing the tri-block or penta-block copolymer, so as to further improve the comprehensive performance of the product, especially the stability, self-dispersibility and high drug loading. The reaction temperature of the first polymerization reaction is 120-150°C, and the polymerization time is 2-72h; the reaction temperature of the second polymerization reaction is 120-150°C, and the polymerization time is 2-72h. By adjusting the polymerization temperature and time in the above range, the amphiphilic block copolymer with ideal performance in three aspects can be obtained.

[0076] Specifically, when preparing the triblock or pentablock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer can be 40:30:30, 50:30:20, 60:20:20, 70:20:10, 80:10:10, 90:5:5, etc. The reaction temperature of the first polymerization reaction can be 120°C, 130°C, 140°C, 150°C, etc., and the polymerization time can be 2h, 5h, 10h, 20h, 30h, 40h, 50h, 60h, 70h, 72h, etc.; the reaction temperature of the second polymerization reaction can be 120°C, 130°C, 140°C, 150°C, etc., and the polymerization time can be 2h, 5h, 10h, 20h, 30h, 40h, 50h, 60h, 70h, 72h, etc.

[0077] In another embodiment, the preparation method comprises: heating the water-soluble polymer, mixing it with the first monomer and the second monomer, and performing polymerization in the presence of a catalyst to obtain a diblock copolymer containing MePEG or a triblock copolymer containing PEG.

[0078] Further, when preparing the diblock or triblock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer is controlled to be (40-90):(5-45):(5-45), and the use amount of the water-soluble polymer, the first monomer and the second monomer is controlled to be within the above range when preparing the diblock copolymer, which is suitable for further improving the three aspects of the performance of the product. When preparing the diblock or triblock copolymer, the polymerization temperature is controlled to be 120°C-150°C, and the polymerization time is controlled to be 5h-72h, and the polymerization temperature and time are controlled to be within the above range, so that the block length in the product is more suitable, and the three aspects of the performance of the product are all better.

[0079] Specifically, when preparing the diblock or triblock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer can be 40:30:30, 50:30:20, 60:20:20, 70:20:10, 80:10:10, 90:5:5, etc., and the use amount of the first monomer and the second monomer can be equal or not equal. The polymerization temperature can be 120°C, 130°C, 140°C, 150°C, etc., and the polymerization time can be 5h, 10h, 20h, 30h, 40h, 50h, 60h, 70h, 72h, etc.

[0080] In some embodiments of the present disclosure, the catalyst used is selected from at least one of stannous octoate, zinc lactate, alkoxides of stannous, alkoxides of aluminum, and alkoxides of zinc, which can be any one or several of the above, such as isopropoxy aluminum. The mass ratio of the total mass of the water-soluble polymer, the first monomer, and the second monomer to the mass of the catalyst is 100:(0.02-0.5), such as 100:0.02, 100:0.05, 100:0.10, 100:0.20, 100:0.30, 100:0.40, 100:0.50, and the like.

[0081] In some embodiments of the present disclosure, after the water-soluble polymer is heated to the polymerization temperature, the raw materials are melted and then subjected to vacuum treatment to remove residual water, and then the first monomer and / or the second monomer are added for polymerization to prevent water from interfering with the reaction.

[0082] The embodiments of the present disclosure also provide a stereocomplex, which comprises at least two of the above amphiphilic block copolymers. The stability of the polymer can be further improved by forming the stereocomplex.

[0083] In some embodiments of the present disclosure, the first amphiphilic block copolymer and the second amphiphilic block copolymer are prepared, and the water-soluble polymer used in the preparation of the first amphiphilic block copolymer and the second amphiphilic block copolymer is selected from at least one of polyethylene glycol, methoxypolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide, polyamino acid, and polyacrylate, preferably, the water-soluble polymer is selected from at least one of polyethylene glycol and methoxypolyethylene glycol. The first monomer used is at least one of D, L-lactide and meso-lactide. The second monomer used in the preparation of the first amphiphilic block copolymer is L-lactide, and the second monomer used in the preparation of the second amphiphilic block copolymer is D-lactide. The inventors have found that mixing the block copolymer rich in L-lactide with the block copolymer rich in D-lactide can form a stereocomplex, thereby further improving the stability of the polymer and forming a self-dispersing colloidal micelle with high drug loading capacity.

[0084] Further, the first amphiphilic block copolymer and the second amphiphilic block copolymer are both two-block copolymers, and the mass ratio of the first amphiphilic block copolymer to the second amphiphilic block copolymer is 1:(0.8-1.2), such as 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, and the like.

[0085] The embodiments of the present disclosure also provide a preparation method of a stereocomplex, which comprises mixing two amphiphilic block copolymers in a molten or solution state. The specific parameters of the first amphiphilic block copolymer and the second amphiphilic block copolymer can refer to the above description.

[0086] In some embodiments of the present disclosure, the melting and mixing temperature is controlled to be 40-60°C, and the mixing time is 15-120 min, to obtain a homogeneous stereocomplex. Specifically, the mixing temperature can be 40°C, 50°C, 60°C, etc., the mixing time can be 15 min, 30 min, 50 min, 80 min, 100 min, 120 min, etc., and the stereocomplex can also be prepared by mixing solutions of the first and second amphiphilic block copolymers.

[0087] The present disclosure also provides the use of the above-mentioned amphiphilic block copolymer or the above-mentioned stereocomplex as a carrier in drug delivery. The amphiphilic block copolymer and the stereocomplex provided by the present disclosure have good stability, water solubility or self-dispersibility, high drug loading capacity, etc., and can be used in drug delivery, thus having very good application prospects.

[0088] In some embodiments of the present disclosure, the loaded drug is selected from at least one of cinacalcet hydrochloride, cinacalcet, nimodipine, amiodarone, posaconazole, docetaxel, paclitaxel, clarithromycin, and indomethacin, and the drug can be any one or several of the above.

[0089] In some embodiments of the present disclosure, the drug loading method is selected from at least one of preparing a freeze-dried preparation, solvent evaporation method for preparing a drug-polymer matrix, and melt mixing method for preparing a drug-polymer matrix, and ethanol solution preparation, and the drug loading method can use any one or several of the above.

[0090] Specifically, the process of preparing a freeze-dried preparation includes: dissolving the drug and the carrier, removing the solvent, then re-dissolving to form a drug-loaded micelle, and then performing liquid separation and freeze-drying. The solvent used for dissolving can be ethanol, but is not limited thereto; the solvent used for re-dissolving can be a sodium acetate aqueous solution, but is not limited thereto. During the process of dissolving, removing the solvent, and re-dissolving in a buffer, heating (~ 45°C) and stirring can be used.

[0091] Specifically, the process of preparing a drug-polymer matrix by solvent evaporation includes: dissolving the drug, the carrier, and the solvent, heating and vacuumizing to remove the solvent to obtain a drug-polymer matrix, and re-dissolving the drug-polymer matrix to form a micelle solution. The solvent used for dissolving can be ethanol, acetonitrile, etc., and the solvent used for re-dissolving can be a sodium acetate aqueous solution.

[0092] Specifically, the process of preparing a drug-polymer matrix by melt mixing includes: mixing and heating the drug and the carrier to obtain a molten material, cooling the molten material to obtain a drug-polymer solid matrix, and re-dissolving the drug-polymer solid matrix to obtain a micelle solution.

[0093] Specifically, the process of preparing the ethanol solution formulation includes: dissolving the drug and the carrier in ethanol, diluting with a water-based diluent, and forming a drug-loaded micelle.

[0094] The features and performance of the present disclosure are further described in detail below in conjunction with the examples. In these examples, the percentages are all weight percentages unless otherwise specified.

[0095] It should be noted that the main raw materials used in the following examples and comparative examples: MePEG and PEG were purchased from Merck Company in Germany, MePEG molecular weight 2000 with product number 202509, MePEG molecular weight 5000 with product number 81323, PEG molecular weight 3350 with product number 202444, PEG molecular weight 6000 with product number 81260; D, L-lactide, L-lactide, D-lactide, ε-caprolactone were purchased from Jinan Daigang Biological Technology Co., Ltd.

[0096] Comparative Example 1 - Synthesis of PDLLA-MePEG

[0097] This comparative example provides a preparation method of PDLLA-MePEG block copolymer, and the specific steps are as follows:

[0098] Into a 250 mL clean reaction flask with magnetic stirring, 75 g of MePEG with a molecular weight of 2000 was added. The flask was immersed in an oil bath at 130°C, and when the MePEG was melted, vacuum was applied for 2 hours under stirring to remove the residual water in the MePEG. Then 75 g of D, L-lactide was added, and after melting, 0.3 g of stannous octoate was added. The polymerization reaction was completed at 130°C under stirring for about 8 hours. After each feeding, a short air suction was applied before sealing. The polymerization was stopped by cooling to room temperature, and a diblock copolymer was obtained. This polymer is named PDLLA-MePEG 2000-50 / 50, indicating that the molecular weight of MePEG is 2000 and the ratio of DLLA / MePEG is 50 / 50.

[0099] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC. The GPC chromatogram of the diblock copolymer prepared in Comparative Example 1 is shown in Figure 2(a).

[0100] Example 1 - Synthesis of PLA block copolymer with stereoregularity PDLLA-PLLA-MePEG

[0101] This example provides a preparation method of an amphiphilic block copolymer, and the specific steps are as follows:

[0102] A 250 mL clean flask with magnetic stirring was charged with 50 g of MePEG with a molecular weight of 2000. The flask was immersed in an oil bath at 130 °C and, after the MePEG was melted, vacuum was applied for 3 hours with stirring to remove residual moisture in the MePEG. 15 g of L-lactide was added, after melting, 0.1 g of stannous octoate was added, and the mixture was stirred at 130 °C for about 4 hours, then 35 g of D,L-lactide was added, and the mixture was stirred at 130 °C for about 8 hours to complete the polymerization. After each addition, the flask was sealed after a short evacuation. The polymerization was stopped by cooling to room temperature to obtain a triblock copolymer. The polymer was named PDLLA-PLLA-MePEG 2000-35 / 15 / 50, indicating that the MePEG has a molecular weight of 2000 and the ratio of DLLA / LLA / MePEG is 35 / 15 / 50.

[0103] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC. The GPC chromatogram of the diblock copolymer prepared in Example 1 is shown in Figure 2(b).

[0104] Example 2 - Synthesis of stereoregular PLA block copolymer PDLLA-PDLA-MePEG

[0105] This example provides a method for preparing an amphiphilic block copolymer, and the specific steps are as follows:

[0106] A 250 mL clean flask with magnetic stirring was charged with 50 g of MePEG with a molecular weight of 2000. The flask was immersed in an oil bath at 130 °C and, after the MePEG was melted, vacuum was applied for 3 hours with stirring to remove residual moisture in the MePEG. 15 g of L-lactide was added, after melting, 0.1 g of stannous octoate was added, and the mixture was stirred at 130 °C for about 4 hours, then 35 g of D,L-lactide was added, and the mixture was stirred at 130 °C for about 8 hours to complete the polymerization. After each addition, the flask was sealed after a short evacuation. The polymerization was stopped by cooling to room temperature to obtain a triblock copolymer. The polymer was named PDLLA-PLLA-MePEG 2000-35 / 15 / 50, indicating that the MePEG has a molecular weight of 2000 and the ratio of DLLA / LLA / MePEG is 35 / 15 / 50.

[0107] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC.

[0108] Example 3 - Synthesis of stereoregular PLA block copolymer PDLA-PDLLA-MePEG

[0109] The present example provides a method for preparing an amphiphilic block copolymer, the specific steps are as follows:

[0110] A 100 mL clean flask with magnetic stirring was added with 50 g of MePEG with a molecular weight of 2000. The flask was immersed in an oil bath at 130°C, and after the MePEG was melted, vacuum was applied for 3 hours under stirring to remove the residual moisture in the MePEG. 0.1 g of stannous octoate was added and stirred for 0.5 hours, 35 g of D, L-lactide was added, and the polymerization reaction was completed at 130°C under stirring for about 15 hours. After each addition, a short air suction was applied before sealing. The polymerization reaction was stopped after cooling to room temperature to obtain a triblock copolymer. The polymer is named PDLA-PDLLA-MePEG 2000-15 / 35 / 50, indicating that the molecular weight of MePEG is 2000, and the ratio of DLA / DLLA / MePEG is 15 / 35 / 50.

[0111] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC.

[0112] Example 4 - Synthesis of a stereoregular PLA block copolymer PLLA-PDLLA-MePEG

[0113] The present example provides a method for preparing an amphiphilic block copolymer, the specific steps are as follows:

[0114] A 100 mL clean flask with magnetic stirring was added with 50 g of MePEG with a molecular weight of 2000. The flask was immersed in an oil bath at 130°C, and after the MePEG was melted, vacuum was applied for 3 hours under stirring to remove the residual moisture in the MePEG. 0.1 g of stannous octoate was added and stirred for 0.5 hours, 35 g of D, L-lactide was added, and the polymerization reaction was completed at 130°C under stirring for about 15 hours. After each addition, a short air suction was applied before sealing. The polymerization reaction was stopped after cooling to room temperature to obtain a triblock copolymer. The polymer is named PDLA-PDLLA-MePEG 2000-15 / 35 / 50, indicating that the molecular weight of MePEG is 2000, and the ratio of DLA / DLLA / MePEG is 15 / 35 / 50.

[0115] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC.

[0116] Example 5 - Synthesis of PLA random copolymer with stereoregularity PDLLA / LLA-MePEG

[0117] This example provides a method for preparing an amphiphilic block copolymer, the specific steps are as follows:

[0118] Into a 10 mL clean flask with magnetic stirring, 5 g MePEG with molecular weight of 2000 was added. The flask was immersed in a metal sand bath heated to about 130°C, after MePEG was melted, vacuum was applied for 2 hours to remove residual moisture in MePEG under stirring. 2.5 g D, L-lactide and 2.5 g L-lactide were added, after melting, 0.05 g stannous octoate was added, and the polymerization reaction was completed at about 130°C for about 7 hours under stirring. After each addition, a short air was applied before sealing. The polymerization reaction was stopped by cooling to room temperature to obtain a diblock copolymer. The polymer was named PDLLA / LLA-MePEG 2000-25 / 25 / 50, indicating that the molecular weight of MePEG was 2000, and the ratio of DLLA / LLA / MePEG was 25 / 25 / 50.

[0119] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by 1H-NMR, GPC, and RP-HPLC, respectively. 1 H-NMR, GPC, and RP-HPLC.

[0120] Example 6 - Synthesis of PLA random copolymer with stereoregularity PDLLA / DLA-MePEG

[0121] This example provides a method for preparing an amphiphilic block copolymer, the specific steps are as follows:

[0122] Into a 10 mL clean flask with magnetic stirring, 5 g MePEG with molecular weight of 2000 was added. The flask was immersed in a metal sand bath heated to about 130°C, after MePEG was melted, vacuum was applied for 2 hours to remove residual moisture in MePEG under stirring. 2.5 g D, L-lactide and 2.5 g L-lactide were added, after melting, 0.05 g stannous octoate was added, and the polymerization reaction was completed at about 130°C for about 7 hours under stirring. After each addition, a short air was applied before sealing. The polymerization reaction was stopped by cooling to room temperature to obtain a diblock copolymer. The polymer was named PDLLA / LLA-MePEG 2000-25 / 25 / 50, indicating that the molecular weight of MePEG was 2000, and the ratio of DLLA / LLA / MePEG was 25 / 25 / 50.

[0123] Table 1 shows the molecular weight, molecular weight distribution, and oligomer content determined by 1H-NMR, GPC, and RP-HPLC, respectively. 1 The 1H-NMR spectrum is shown in Figure 1.

[0124] Example 7 - Preparation of stereo-complexes

[0125] Equal proportions of PDLLA / LLA-MePEG 2000-25 / 25 / 50 and PDLLA / DLA-MePEG 2000-25 / 25 / 50 were heated to 40-60°C and mixed to obtain the stereo-complexes of the above mentioned LLA-rich and DLA-rich copolymers.

[0126] Other stereo-complexes: Equal proportions of PDLLA-PDLA-MePEG 2000-35 / 15 / 50 and PDLLA-PLLA-MePEG 2000-35 / 15 / 50 were heated to 40-60°C and mixed to obtain the stereo-complexes of the above mentioned LLA-rich and DLA-rich copolymers. The GPC chromatogram of the stereo-complexes prepared is shown in Figure 2 (c).

[0127] Example 8 - Preparation of drug-loaded lyophilized formulations

[0128] A drug / polymer / ethanol solution was prepared by mixing 1.1 g of cinacalcet hydrochloride, 4.5 g of PDLLA-PLLA-MePEG 2000-35 / 15 / 50, 4.5 g of PDLLA-PDLA-MePEG 2000-35 / 15 / 50, and 20 mL of ethanol. Vacuum was applied to remove the ethanol. 100 mL of 100 mM aqueous sodium acetate was added to dissolve the drug / polymer matrix and form drug-loaded micelles. Moderate heating (~45 degrees Celsius) and stirring can be used to aid in the dissolution of the drug / polymer in ethanol, removal of the ethanol, and reconstitution of the drug / polymer matrix in the buffer. The drug-loaded polymer micelles were filtered, aliquoted into glass vials, lyophilized to remove water, and stoppered and crimped for long-term storage. The results of the test are provided in Table 5 (Lot NB009-067).

[0129] Example 9 - Preparation of drug / polymer matrix by solvent evaporation

[0130] A solution was prepared by mixing 10 mg of cinacalcet, 90 mg of PDLLA / DLA-MePEG 2000-25 / 25 / 50, 2 mL of ethanol, and 1 mL of acetonitrile. Vacuum and moderate heating (~40°C) were applied to remove the organic solvents and obtain the drug / polymer matrix. 1.9 mL of 100 mM sodium acetate was added to the matrix to obtain a clear micellar solution, which was further diluted with 8 mL of 5% dextrose water for testing. The results are provided in Table 6 (Polymer ID NB009-177-4).

[0131] Example 10 - Preparation of drug / polymer matrix by melt mixing

[0132] 5 mg indomethacin was mixed with 95 mg of PDLLA / PDLA-MePEG 2000-35 / 15 / 50 or PDLLA / PLLA-MePEG 2000-35 / 15 / 50, heated to 160 °C and mixed for 15 minutes to obtain a molten transparent liquid. The liquid was cooled to room temperature to obtain a drug / polymer solid matrix. Water was added to reconstitute the transparent micellar solution. The test results are provided in Table 7.

[0133] The DSC thermograms of the block copolymers tested are shown as examples in Figures 3, 4 and 5, which show that the polyester blocks thereof are amorphous. Figure 6 is a plot of the change in oligomer content of the block copolymers synthesized when stored at 40 °C, which shows that the polymers with stereoregularity have good stability. Figures 7-10 are examples of the particle size distribution of the polymer micellar formulations measured by DLS.

[0134] It should be noted that the synthesis of some of the block copolymers in Tables 1-4 is not specifically given and can be synthesized according to the method of Example 1 and Example 5, the synthesis steps of the triblock copolymers in Table la refer to Example 1 and the synthesis steps of the diblock copolymers refer to Example 5. For example, PDLLA / LLA-MePEG represents a diblock copolymer and PDLLA-PDLA-MePEG represents a triblock copolymer. The synthesis steps of the diblock copolymers in Table lb refer to Example 5. The synthesis steps of the pentablock copolymers (e.g. PLLA-PDLLA-PEG-PDLLA-PLLA) in Table lc refer to Example 1 and the synthesis steps of the triblock copolymers (e.g. PDLLA / LLA-PEG-PDLLA / LLA) refer to Example 5.

[0135] Table la Molecular weight, molecular weight distribution and oligomer residue of the PLA-MePEG block copolymers synthesized

[0136] a indicates: determined by H-NMR; b indicates: the polydispersity is the ratio of the weight average molecular weight to the number average molecular weight determined by GPC; c indicates: determined by RP-HPLC; d indicates: NMR not determined, number average molecular weight determined by GPC. 1 H-NMR; b indicates: the polydispersity is the ratio of the weight average molecular weight to the number average molecular weight determined by GPC; c indicates: determined by RP-HPLC; d indicates: NMR not determined, number average molecular weight determined by GPC.

[0137] Table lb Molecular weight, molecular weight distribution and oligomer residue of the PCLLA-MePEG block copolymers synthesized

[0138] a indicates: determined by GPC, mobile phase is THF, standard is polyethylene glycol; b indicates: the polydispersity is the ratio of the weight average molecular weight to the number average molecular weight determined by GPC; c indicates: determined by RP-HPLC.

[0139] Table lc Molecular weight, molecular weight distribution, and oligomer residue of the synthesized PLA-PEG-PLA block copolymer

[0140] a indicates: THF is the mobile phase, and polyethylene glycol is the standard by GPC determination; the polydispersity is the ratio of the weight average molecular weight to the number average molecular weight determined by GPC; b indicates: determined by RP-HPLC.

[0141] Table 2a Polyester-MePEG and polyester-PEG-polyester block copolymers with water solubility or self-dispersibility a

[0142] a indicates: the polymer is added with water to a concentration of 1%. The appearance and turbidity of the solution are determined.

[0143] Table 2b Polyester-MePEG and polyester-PEG-polyester block copolymers without water solubility or self-dispersibility examples

[0144] Table 2a shows the water solubility or self-dispersibility of the polymers, forming micelles or nanoparticles. The water solubility or self-dispersibility of the polymers is affected by the hydrophobicity of the polymer, which is increased by the content of the polyester in the polymer. The water solubility or self-dispersibility of the polymers is also affected by the molecular weight of the polyester block. Table 2b shows some examples of the polymers that are not water soluble or self-dispersible. The water solubility or self-dispersibility of the polymers can be adjusted by the chemical composition and molecular weight of the amphiphilic polymers. The data shows that the polymers have good water solubility or self-dispersibility when the content of the polyester in the polymer is not more than about 50% w / w. The polymers have good water solubility or self-dispersibility when the calculated molecular weight of the polyester block is less than about 2600 (see Table 2a, entries 33 and 34). For the random polyester blocks with stereoregularity, such as PDLLA / LLA and PDLLA / DLA, the content of LLA or DLA should not be too high, otherwise the crystallization of the polyester will decrease the water solubility or self-dispersibility of the polymers. The polymers have good water solubility when the ratio of PDLLA / LLA or PDLLA / DLA is not less than about 20 / 30, and have good self-dispersibility when the ratio is about 15 / 35 (see Table 2a, entries 18-23, 29-30, 33-34, 38-39). The polymers are self-soluble in water when the content of PCL in PCL / LA is up to about 80% (see Table 2a, entries 35-37). Similarly, for the block polyester PDLLA-PLLA or PDLLA-PDLA, the content of PLLA or PDLA should not be too high, otherwise the water solubility or self-dispersibility of the polymers will decrease. The data shows that the polymers have good water solubility when the content of PDLLA in PDLLA-PLLA or PDLLA-PDLA is about 50% or less (see Table 2a, entries 11-13, 17, 26-28, 31). The turbidity of the micelles of the polymers in water increases when the polymers of the left-handed and right-handed stereoregular polyesters are mixed in equal amounts (see Table 2a, entries 7-10, 15-16).

[0145] Table 3 Melting temperature and enthalpy of the polymers

[0146] As shown in Table 3, the block copolymers with stereoregularity or stereocomplex increase the melting temperature of the MePEG block, thus increasing the storage stability.

[0147] Table 4a Stability of the polymers at 40°C

[0148] a indicates that the particle size distribution was measured by DLS. The average particle size and PDI of PDLLA / LLA-MePEG 2000-15 / 35 / 50, lot number NB009-177-5 were 22.76 nm and 0.674, respectively. The average particle size and PDI of PDLLA / DLA-MePEG 2000-15 / 35 / 50, lot number NB009-177-6 were 18.54 nm and 1.452, respectively. The few larger particles in the sub-micron range caused the turbidity.

[0149] As can be seen from Table 4a, the poly(DLLA-co-LLA) (i.e., PDLLA / LLA) or poly(DLLA-co-DLA) (i.e., PDLLA / DLA) polymers with stereocomplex are more stable under the accelerated storage condition at 40°C. Figure 6 shows that the oligomers change the least with storage time for the polymers based on PDLLA / LLA and PDLLA / PLA.

[0150] Table 4b Stability of polymers when stored at 40°C

[0151] As can be seen from Table 4b, the stereocomplex further improves the stability of the polymers. The stereocomplexes have less change in molecular weight and are more stable than the stereoregular polymers PDLLA / LLA-MePEG and PDLLA / DLA-MePEG under the accelerated storage condition at 40°C.

[0152] Table 4c Stability of 60 mg / mL polymers in 0.1% phosphoric acid water when stored at 40°C

[0153] Table 4c gives the stability of 60 mg / mL polymers in 0.1% phosphoric acid water when stored at 40°C. As can be seen, the PDLLA / LLA-PEG-R, PDLLA / DLA-PEG-R, PCL / LLA-PEG-R, PCL / DLA-PEG-R, PCL / DLLA-PEG-R random polyester polymers with stereocomplex and their stereocomplexes are generally more stable with lower oligomer increase (items 18-35, 37-38, 40).

[0154] Table 5. Cinacalcet polymer micelles - lyophilized formulation (10% drug loading) a,b

[0155] a indicates that a cinacalcet / polymer / ethanol solution (cinacalcet: polymer: ethanol = 1 :9:20 w / w / v) was prepared, then the ethanol was removed using vacuum and moderate heat (~45°C), then the cinacalcet / polymer matrix was reconstituted with diluent to a cinacalcet concentration of 10 mg / mL. b indicates that 2 mL of the reconstituted cinacalcet solution from above was added to a 7 mL glass vial and lyophilized to remove water. c indicates that the lyophilized preparation was added to 1.85 mL of water to obtain a reconstituted cinacalcet solution at a concentration of 10 mg / mL. d. The above reconstituted 10 mg / mL cinacalcet solution was diluted 5-fold with 5% dextrose in water (D5W) for turbidity and pH measurements.

[0156] Table 6a. Cinacalcet polymer micelle-matrix formulations (10% drug loading) a

[0157] a indicates: a cinacalcet / polymer / ethanol / acetonitrile solution (cinacalcet: polymer: ethanol: acetonitrile = 1 :9:200:100 w / w / v / v) was prepared, then the ethanol and acetonitrile were removed using vacuum and moderate heat (~45°C). b indicates: 1.85 mL of a 100 mM aqueous sodium acetate (NaOAc) solution was added to 100 mg of the matrix formulation to obtain a reconstituted cinacalcet solution at a concentration of 10 mg / mL. c indicates: the above reconstituted 10 mg / mL cinacalcet solution was diluted 5-fold with 5% dextrose in water (D5W) for turbidity and pH measurements.

[0158] Table 6b Clarithromycin, indomethacin polymer micelle-matrix formulations a

[0159] a indicates: formulations using polymer NB013-007, the polymer was dissolved in ethanol containing 8% acetonitrile. The drug substance was dissolved in ethanol, the drug and ethanol solutions were combined and the solvent was removed under vacuum. Formulations using polymers NB009-177-3 and NB009-177-4, the polymer and drug were dissolved in acetonitrile, then the solvent was removed under vacuum. Formulations using polymers NB009-177-1 and NB009-177-2, the drug and polymer were mixed and heated to 160°C with stirring, the liquid mixture was allowed to stand for 15 minutes, then cooled to obtain a drug / polymer matrix. b indicates: 10 mL of water was added to 100 mg of the matrix formulation to obtain a reconstituted drug solution for turbidity and pH measurements. There were no significant changes in the appearance, turbidity and pH of the solution at room temperature for at least 24 hours.

[0160] Table 7a Docetaxel, paclitaxel, cenicriviroc, clarithromycin, indomethacin polymer micelle-ethanol solution formulation a

[0161] a: the drug and polymer are dissolved in ethanol, diluted 10 times with diluent to form drug-loaded micelles. b: observe the appearance at room temperature for 0-48 hours, the time in the parentheses is the longest observation point for maintaining the micellar state.

[0162] Table 7b Docetaxel, paclitaxel, cenicriviroc, indomethacin polymer micelle-ethanol solution formulation a

[0163] a: the drug and polymer are dissolved in ethanol, diluted 10 times with diluent to form drug-loaded micelles. b: observe the appearance at room temperature for 0-25, 0-24, or 0-48 hours, the time in the parentheses is the longest observation point for maintaining the micellar state.

[0164] As can be seen from Tables 5-7, the block copolymer provided by the present disclosure can efficiently load the dissolved drug, and most of them have good stability after drug loading. Industrial applicability

[0165] The present disclosure introduces a second monomer with stereoregularity on the premise of using D, L-lactide, meso-lactide and other raw materials as the first monomer to modify the monomer forming the polyester block. The preparation process is simple and easy to operate, and is suitable for industrial application. The block copolymer prepared still maintains its water solubility or self-dispersibility, and maintains high drug loading capacity, and the stability is significantly improved.

Claims

1. An amphiphilic block copolymer, characterized in that, The application relates to a preparation method of an amphiphilic block copolymer. The block copolymer is formed by a polyester and a water-soluble polymer; The monomers used for forming the polyester comprise a first monomer and a second monomer; The first monomer is at least one of D, L-lactide and meso-lactide, and the second monomer is at least one selected from L-lactide and D-lactide; The first monomer is at least one of D, L-lactide, meso-lactide, L-lactide and D-lactide, and the second monomer is epsilon-caprolactone.

2. The amphiphilic block copolymer according to claim 1, characterized in that, In the process of preparing the amphiphilic block copolymer, the mass percentage of the water-soluble polymer is X, the mass percentage of the first monomer is Y, and the mass percentage of the second monomer is Z, and X, Y and Z satisfy: X=40%-90%; Y=a*(100%-X), and the value of a is 10%-90%; Z=100%-X-Y.

3. The amphiphilic block copolymer according to any one of claims 1-2, wherein, The water-soluble polymer is at least one selected from polyethylene glycol, methoxyl polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polysaccharide, polyamino acid and polyacrylate; preferably, the water-soluble polymer is methoxyl polyethylene glycol or polyethylene glycol. The number average molecular weight of the water-soluble polymer is 350-1000000, preferably 750-20000, and more preferably 1300-8000.

4. A process for the preparation of the amphiphilic block copolymer according to any one of claims 1 to 3, characterized in that, The application also relates to a preparation method of the amphiphilic block copolymer. The water-soluble polymer is polymerized with the first monomer and the second monomer.

5. The production method according to claim 4, characterized by, The preparation method comprises the following steps: after the water-soluble polymer PEG or MePEG is heated, one monomer used for forming the polyester is mixed, and one-polymerization is carried out in the presence of a catalyst; then another monomer used for forming the polyester is added to carry out two-polymerization, so as to obtain a MePEG-containing triblock copolymer or a PEG-containing pentablock copolymer.

6. The production method according to claim 5, wherein In the preparation of the triblock or pentablock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer is controlled to be (40-90):(5-45):(5-45). The reaction temperature of the one-polymerization is 120-150 DEG C, and the polymerization time is 2-72 hours. The reaction temperature of the two-polymerization is 120-150 DEG C, and the polymerization time is 2-72 hours.

7. The preparation method according to claim 4, characterized in that, The preparation method comprises the following steps: after the water-soluble polymer is heated, the first monomer and the second monomer are mixed, and polymerization is carried out in the presence of a catalyst to obtain a MePEG-containing diblock copolymer or a PEG-containing triblock copolymer.

8. The preparation method according to claim 7, characterized in that, In the preparation of the diblock or triblock copolymer, the mass ratio of the water-soluble polymer, the first monomer and the second monomer is controlled to be (40-90):(5-45):(5-45). In the preparation of the diblock or triblock copolymer, the polymerization temperature is controlled to be 120-150 DEG C, and the polymerization time is 5-72 hours.

9. The production method according to any one of claims 5 to 8, characterized by, The catalyst is at least one selected from stannous octoate, zinc lactate, alkoxide of stannous, alkoxide of aluminum and alkoxide of zinc. And / or, the mass ratio of the water-soluble polymer, the first monomer and the second monomer to the catalyst is 100:(0.02-0.5).

10. The production method according to any one of claims 5 to 9, characterized by, After the water-soluble polymer is heated to the polymerization temperature, the raw materials are melted and then vacuum treated to remove residual moisture, and then the first monomer and / or the second monomer are added for polymerization.

11. A stereocomplex characterized in that, The amphiphilic block copolymer comprises at least two amphiphilic block copolymers, wherein the amphiphilic block copolymer is the amphiphilic block copolymer of any one of claims 1-3 or the amphiphilic block copolymer prepared by the preparation method of any one of claims 4-10.

12. The stereocomplex according to claim 11, characterized in that, The amphiphilic block copolymer comprises a first amphiphilic block copolymer and a second amphiphilic block copolymer, The water-soluble polymer used in the preparation of the first amphiphilic block copolymer and the second amphiphilic block copolymer is at least one selected from polyethylene glycol, methoxypolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide, polyamino acid and polyacrylate, and the first monomer used is at least one of D, L-lactide and meso-lactide.

13. The structural composite according to claim 12, wherein, The second monomer used in the preparation of the first amphiphilic block copolymer is L-lactide, and the second monomer used in the preparation of the second amphiphilic block copolymer is D-lactide; And / or, the water-soluble polymer is at least one selected from polyethylene glycol and methoxypolyethylene glycol; And / or, the mass ratio of the first amphiphilic block copolymer to the second amphiphilic block copolymer is 1:(0.8-1.2).

14. A process for the preparation of a stereocomplex according to any one of claims 11-13, characterized in that, The amphiphilic block copolymer comprises: The two amphiphilic block copolymers are mixed in a molten or solution state.

15. The method of claim 14, wherein, The melting mixing temperature is controlled to be 40-60°C, and the mixing time is 15-120 min.

16. Use of the amphiphilic block copolymer of any one of claims 1-3 or the amphiphilic block copolymer prepared by the preparation method of any one of claims 4-10 or the stereocomplex of any one of claims 11-13 or the stereocomplex prepared by the preparation method of any one of claims 14-15 as a carrier in drug delivery.

17. Use according to claim 16, characterized in that, The loaded drug is at least one selected from cinacalcet hydrochloride, cinacalcet, nimodipine, amiodarone, posaconazole, docetaxel, paclitaxel, clarithromycin and indomethacin.

18. Use according to claim 16 or 17, characterized in that, The drug loading method is at least one selected from preparation of a freeze-dried preparation, solvent evaporation method for preparing a drug-polymer matrix, melt mixing method for preparing a drug-polymer matrix and ethanol solution preparation; The process of preparing a freeze-dried preparation comprises: dissolving the drug and the carrier, removing the solvent, then dissolving again to form a drug-loaded micelle, and then separating, freezing and drying; The process of preparing a drug-polymer matrix by solvent evaporation method comprises: dissolving the drug, the carrier and the solvent, heating to remove the solvent to obtain a drug-polymer matrix, and dissolving the drug-polymer matrix again to form a micelle solution; The process for preparing the drug-polymer matrix by melt mixing comprises: mixing and heating the drug and the carrier to obtain a molten material, cooling the molten material to obtain a drug-polymer solid matrix, and re-dissolving the drug-polymer solid matrix to obtain a micellar solution. The process for preparing the ethanol solution preparation comprises: dissolving the drug and the carrier in ethanol, and diluting with an aqueous diluent to form a drug-loaded micelle.

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