Polyamino acid high polymer material, preparation method and application

Abstract

The invention provides a polyamino acid high polymer material, a preparation method and application, the polyamino acid high polymer material takes sarcosine as a raw material, and the sarcosine is configured to have an adjustable polymerization degree. Aiming at the defects and deficiencies of vitamin E polyethylene glycol succinate as a pharmaceutical adjuvant in the prior art, polysarcosine (PSar) is taken as a raw material and has excellent biocompatibility, a degradation product of the PSar is completely physiologically harmless and has good biological safety, and the PSar is not charged and has good hydrophilicity and hidden effect, and in addition, the vitamin E polyethylene glycol succinate is taken as a medicinal adjuvant, so that the vitamin E polyethylene glycol succinate can be applied to the preparation of the pharmaceutical adjuvant and the preparation method of the vitamin E polyethylene glycol succinate and the preparation method of the vitamin E polyethylene glycol succinate and the preparation method of the vitamin E polyethylene glycol succinate and the preparation method of the vitamin E polyethylene glycol succinate and the preparation method thereof. The product disclosed by the invention shows excellent effects in the aspects of emulsifying property, heat resistance, solubilization, nano-drug crystal dispersity, stability and the like.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to the preparation of polyamino acid macromolecular materials. Background Art

[0002] It is reported that more than 70% of chemically synthesized drugs have poor solubility problems, and about 40% of new chemical entities (NCEs) cannot enter clinical trials due to their poor solubility, which greatly limits their application. Therefore, how to improve the solubility of poorly soluble drugs has very important research value and practical significance, and is a difficult problem that the pharmaceutical industry needs to overcome urgently.

[0003] Traditional methods for improving the solubility of poorly soluble drugs are divided into chemical and physical methods. Chemical methods mainly involve structural modification of drug molecules, such as introducing hydrophilic groups (hydroxyl, carboxyl, amino, etc.) into drug molecules. For weak acid or weak base drugs, the water solubility of the drug can be increased by salt formation. The main problem with chemical methods is that the chemical structure of the drug is changed, and its activity may change. Physical methods include solubilization, solubilization, latent solubilization, inclusion complexes, solid dispersions, and drug cocrystals. Solubilization mainly relies on the action of surfactants to increase the apparent solubility of the drug by forming micelles. Its disadvantages are that the solubilization effect is limited and it is easily affected by the ionic strength in water. Solubilization relies on the formation of complexes and composites between cosolvents and poorly soluble drugs to improve the water solubility of the drug. Its solubilization effect is limited, and it is not easy to find a suitable cosolvent. Latent solubilization uses mixed solvents to improve the solubility of the drug. It often requires the addition of organic solvents, and the solvent composition changes after the system is diluted with water or body fluids, resulting in the easy precipitation of the drug. Crystallization. Inclusion complexes are compounds that embed drug molecules into the cavities of molecules of another substance. They have low drug loading, long preparation time, high energy consumption in the later spray drying, and high cost. Solid dispersions are compounds that disperse drugs in carrier materials in the form of molecules, amorphous or microcrystals. They have a significant effect on improving drug solubility, but they have poor physical stability and are prone to drug crystallization during drug storage. Drug cocrystals designed based on crystal engineering theory are a new strategy that can improve drug stability, solubility and bioavailability without changing the chemical structure of the drug. Drug cocrystals are multi-component systems composed of active pharmaceutical ingredients (API) and cocrystal formers (CCF) in a fixed stoichiometric ratio through non-covalent bonds. However, drug cocrystal systems also have limitations in the selection of cocrystal ligands, the cocrystals are prone to dissociation in solution, and large-scale production.

[0004] In recent years, with the development of new drug formulation technologies, the use of drug-loaded nanoparticles and drug nanocrystals has, to a certain extent, solved the problems of poor absorption and low bioavailability of poorly soluble drugs. However, due to the differences in the physical and chemical properties of poorly soluble drugs, there is currently a lack of high-performance pharmaceutical polymer excipients for improving the solubility and bioavailability of poorly soluble drugs, resulting in the need for a large number of prescriptions to screen for suitable pharmaceutical excipients. However, the solubilization effect of the preferred pharmaceutical excipients is often not satisfactory.

[0005] At present, polymer excipients based on polyethylene glycol (PEG) are widely used in pharmaceutical preparations. They are mainly divided into PEG materials with different molecular weights and PEG block copolymer materials. The former are mainly used as solvents or dispersion carrier materials for drugs, while the latter are often amphiphilic block copolymers, which play the role of solubilizing, stabilizing, and dispersing drugs (or drugs dispersed in carrier materials). PEG materials have many advantages as pharmaceutical excipients, such as effectively improving the physical dispersion stability of drug-loaded nanoparticles, increasing the long circulation time of nanoparticles in the body, better biocompatibility and safety, and lower immunogenicity. However, due to the widespread use of PEG materials, PEG antibodies (or pre-existing PEG antibodies) exist in the body to a greater or lesser extent, resulting in a reduction in the advantages of PEG materials as pharmaceutical excipients, such as accelerated blood clearing (ABC). Therefore, it is urgent to develop PEG to replace pharmaceutical polymer excipients, while retaining the advantages of PEG materials and reducing their defects such as immunogenicity. D-α-Tocopherylpolyethylene glycol 1000 succinate (TPGS) is a kind of common PEG-derived polymer excipient, which is composed of vitamin E and PEG1000 connected by a succinate bond. It has an amphiphilic structure and has certain emulsification, solubilization and dispersion functions of drug-loaded nanoparticles or drug nanocrystals. However, TPGS has some disadvantages as a pharmaceutical excipient: 1) Pharmaceutical excipients are generally physiologically inert polymer materials, which mainly play the role of assisting drug molding. However, TPGS has physiological activities such as P-gp inhibition, which may change the in vivo behavior of certain drugs and produce unexpected side effects; 2) The inherent defects of PEG materials, namely immunogenicity; 3) Due to the fixed length of PEG blocks, its effects in solubilization, emulsification, nanodispersion, etc. are limited.

[0006] Therefore, there is an urgent need to develop a universal high-performance polymer pharmaceutical excipient mainly for the application of formulation technologies such as solubilization, emulsification, and dispersion of poorly soluble drugs. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a polyamino acid polymer material, a preparation method and an application thereof, aiming to solve the defective problems of existing materials in the background technology.

[0008] The technical solution adopted by the present invention to solve the above technical problems is:

[0009] In the first aspect of the present invention, the present invention provides a polyamino acid polymer material, the chemical formula of which is shown below:

[0010] , where n=10~70.

[0011] Furthermore, the polyamino acid polymer material uses sarcosine as a raw material, and the sarcosine is configured to have an adjustable degree of polymerization. By adjusting the degree of polymerization of the sarcosine at the hydrophilic end of TPSS, the polyamino acid polymer material of the present invention can meet the requirements of different prescription processes.

[0012] Furthermore, the polymerization degree of the sarcosine is preferably 10-70.

[0013] Furthermore, the raw materials of the polyamino acid polymer material include: N-phenoxycarbonylsarcosine (SarNPC), neopentylamine, N,N-diisopropylethylamine (DIPEA), succinic anhydride, vitamin E (VE), dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). In the present invention, the raw materials refer to substances that directly participate in chemical reactions as reactants, and new compounds are generated through chemical reactions between the raw materials, among which neopentylamine acts as an initiator in the reaction.

[0014] Furthermore, the N-phenoxycarbonylsarcosine (SarNPC), N,N-diisopropylethylamine (DIPEA), neopentylamine, succinic anhydride, vitamin E (VE), dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) are in a ratio of (10.0-70.0): (3.0-8.0): 1.0: (1.0-25.0): (1.0-2.0): (1.0-2.0): (0.05-1.0), calculated by equivalent ratio.

[0015] Preferably, the equivalent ratio is: 14:5:1:1.5:1.2:1.2:0.5, or 25:5:1:1.5:1.2:1.2:0.5.

[0016] Preferably, the auxiliary material of the polyamino acid polymer material includes an organic solvent, and the organic solvent is configured to assist the polymerization reaction. In the present invention, the auxiliary material and raw material are relative. As mentioned above, the raw material directly participates in the chemical reaction, while the auxiliary material is a substance that provides reaction conditions such as possibility and convenience for the chemical reaction, such as solvents, catalysts, etc.

[0017] Preferably, the organic solvent is selected from at least one of DMSO, DMF, DMAc, dichloromethane, ethyl ether, tert-methyl ether, and isopropyl ether. In the present invention, different steps in the overall process of preparing the compound can select different organic solvents according to actual conditions and reaction conditions to achieve the optimization effect of the present invention.

[0018] Preferably, the synthesis route of the polyamino acid polymer material is as follows:

[0019] , where n=10~70.

[0020] In a second aspect of the present invention, the present invention provides a method for preparing a polyamino acid polymer material, wherein the method is configured to prepare the polyamino acid polymer material according to the first aspect of the present invention, and the preparation process is as follows:

[0021] (1) Synthesis of intermediate PSar n S:

[0022] (1.1) Dissolution: taking the raw materials N-phenoxycarbonylsarcosine (SarNPC) and N,N-diisopropylethylamine (DIPEA) according to the ratio described in the first aspect of the present invention, placing them in a reaction container, adding an organic solvent, stirring and dissolving to obtain a solution;

[0023] (1.2) Polymerization: taking the raw material neopentylamine according to the ratio described in the first aspect of the present invention and adding it to the solution of step (1.1) to carry out a polymerization reaction;

[0024] (1.3) Amidation: dissolving succinic anhydride in an organic solvent according to the ratio described in the first aspect of the present invention, and adding the solution to the reaction system for amidation reaction to obtain a reaction solution;

[0025] (1.4) Add organic solvent to the reaction solution, centrifuge and filter to obtain the solid intermediate product PSar. n S;

[0026] (2) Synthetic product TPSS:

[0027] (2.1) Synthesis reaction: Take the intermediate product PSar obtained in step (1) n S, vitamin E (VE), dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) are placed in a reaction container, an organic solvent is added, stirred for reaction, and then filtered to obtain a filtrate;

[0028] (2.2) Centrifugation: Add an organic solvent to the filtrate of step (2.1) and centrifuge to precipitate a solid. Repeat the centrifugation operation until the organic solvent layer is clear. The solid is vacuum dried to obtain the product TPSS.

[0029] Preferably, the organic solvent in step (1.1) and step (1.3) is selected from at least one of DMSO, DMF and DMAc.

[0030] Preferably, the organic solvent in step (2.1) is selected from at least one of dichloromethane, DMSO, DMF and DMAc.

[0031] Preferably, the organic solvents in step (1.4) and step (2.2) are respectively selected from at least one of diethyl ether, tertiary methyl ether, isopropyl ether, n-heptane, n-hexane and petroleum ether.

[0032] Preferably, in the preparation process, the polymerization degree can be adjusted by changing the equivalent weight of the sarcosine monomer so that it can meet the requirements of different formulation processes.

[0033] In the third aspect of the present invention, the present invention provides an application of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention in the preparation of medicines and cosmetics. The application described in this aspect refers to applying the polyamino acid polymer material of the present invention to the process of preparing medicines and cosmetics as a pharmaceutical excipient.

[0034] In the fourth aspect of the present invention, the present invention provides an application of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention in dissolving compounds. The application described in this aspect refers to the application of the polyamino acid polymer material of the present invention to the dissolution of compounds. This dissolution can be in the field of compound pharmaceuticals or in other fields of compound synthesis. For those skilled in the art, according to the contents described in the present invention, it can be known that the polyamino acid polymer material provided by the present invention has the technical feature of good solubility performance. Based on this, it can be imagined that the present invention is applied to the dissolution of compounds in different industries. Without creative work, this application should be regarded as a part of the protection required by the present invention.

[0035] In the fifth aspect of the present invention, the present invention provides an application of a polyamino acid polymer material as described in the first aspect of the present invention, or a polyamino acid polymer material prepared by the method according to the second aspect of the present invention in solubilizing and dispersing poorly soluble drugs. The application described in this aspect refers to applying the polyamino acid polymer material of the present invention to solve the dissolution problem of poorly soluble drugs, such as using the present invention for dissolution operations in a preparation process or a research process, or testing the dissolution process of a drug. The present invention does not limit the specific application method. What the present invention intends to protect is the properties of the polyamino acid polymer material that can increase the volume and disperse poorly soluble drugs.

[0036] In the sixth aspect of the present invention, the present invention provides an application of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention in terms of heat resistance. The application described in this aspect refers to the use of the heat resistance of the polyamino acid polymer material of the present invention to carry out related production and research and other technical research and development or product production activities.

[0037] In the seventh aspect of the present invention, the present invention provides an application of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention in terms of sterilizability. The sterilizability described in this aspect means that the polyamino acid polymer material of the present invention has some characteristics of its own, for example, the polyamino acid polymer material of the present invention has good heat resistance and can be sterilized at high temperature. Therefore, the feasibility, convenience and sterilization effect of sterilizing the material are better than other materials. This characteristic makes the polyamino acid polymer material of the present invention have a wider adaptability.

[0038] In the eighth aspect of the present invention, the present invention provides a use of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention as an emulsifier. The polyamino acid polymer material of the present invention has good emulsifying properties and can be used alone or in combination with other emulsifiers for the preparation of emulsions. Such emulsions are not limited to submicron emulsions, ordinary emulsions, creams and other cosmetic or pharmaceutical preparations.

[0039] In the ninth aspect of the present invention, the present invention provides a polyamino acid polymer material as described in the first aspect of the present invention, or a polyamino acid polymer material prepared by the method according to the second aspect of the present invention, for use as a wetting agent. The polyamino acid polymer material of the present invention has a wide hydrophilic-lipophilic balance (HLB value) because it is configured with an adjustable sarcosine polymerization degree, and therefore has the performance of a wetting agent within a certain sarcosine polymerization degree range, and this performance can improve the wettability of materials, for example, in the wetting and dispersion of materials in the preparation of solid preparations such as tablets, granules, etc., and liquid preparations such as suspensions.

[0040] In the tenth aspect of the present invention, the present invention provides a use of the polyamino acid polymer material as described in the first aspect of the present invention, or the polyamino acid polymer material prepared by the method according to the second aspect of the present invention as a detergent. The polyamino acid polymer material of the present invention has a wide hydrophilic-lipophilic balance (HLB value) because it is configured with an adjustable sarcosine polymerization degree, and therefore has the performance of a detergent within a certain sarcosine polymerization degree range. This property allows it to be used alone or in combination with other detergents in the formulation of detergent products.

[0041] The beneficial effects of the present invention are:

[0042] (1) The present invention aims at the defects and shortcomings of vitamin E polyethylene glycol succinate (TPGS) as a pharmaceutical excipient in the prior art, replaces the hydrophilic segment of TPGS with a polysarcosine segment, and uses polysarcosine (PSar) as a raw material, which has excellent biocompatibility. Its degradation products are completely physiologically harmless and have good biosafety. Moreover, polysarcosine is uncharged and has good hydrophilicity and stealth effect. In addition, polysarcosine has the functions of enhancing the dispersion of nanoparticles, stealth effect, and improving the physical stability of nanomedicines, and can effectively improve the performance of the product.

[0043] (2) The product TPSS synthesized by the present invention is an amphiphilic block copolymer, that is, vitamin E is a lipophilic segment, and polysarcosine with different polymerization degrees is a hydrophilic segment. The amphiphilic structure enables it to have the common properties of common amphiphilic materials such as solubilization, emulsification, drug-loaded nanoparticle stabilizer, drug nanocrystal dispersion stabilizer, decontamination, wetting, and defoaming.

[0044] (3) Due to the improvement of raw materials and compound structure, the product TPSS of the present invention has similar or better physical and chemical properties than existing PEG-derived polymer materials (such as TPGS), namely, the hiding effect of nano-drugs, excellent physical dispersibility and stability, good mucosal permeability, etc. Moreover, TPSS can also overcome the immunogenicity caused by pre-existing PEG antibodies in the body.

[0045] (4) Experiments have shown that the product TPSS of the present invention exhibits superior effects in terms of emulsification performance, heat resistance, solubilization, drug nanocrystal dispersibility and stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 It is the chemical structural formula of the polyamino acid polymer material of the present invention.

[0047] Figure 2 It is a synthetic route map of the polyamino acid polymer material of the present invention.

[0048] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product TPSS (PSar: n=14) in Example 8 of the present invention.

[0049] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the product TPSS (PSar: n=25) in Example 8 of the present invention.

[0050] Figure 5This is the hydrogen nuclear magnetic resonance spectrum of the product TPSS (PSar: n=70) in Example 8 of the present invention.

[0051] Figure 6 It is a comparative diagram of the determination of the critical micelle concentration of TPGS and TPSS (PSar: n=14, 25, 70) in Example 9 of the present invention.

[0052] Figure 7 It is the particle size and distribution diagram of micelles formed in water by TPSS with different polymerization degrees in Example 9 of the present invention.

[0053] Figure 8 1 is an experimental result graph showing the change in turbidity of TPGS and TPSS (PSar: n=14) with temperature in Example 10 of the present invention.

[0054] Fig. 9 This is a graph showing the experimental results of the solubilization effect of TPGS and TPSS (PSar: n=14) on the poorly soluble drugs MOMIPP and paclitaxel in Example 11 of the present invention.

[0055] Fig.10 This is a graph showing the emulsification performance test results of TPSS (PSar: n=14) in Example 12 of the present invention.

[0056] Fig.11 This is a sample appearance picture of the nanocrystalline suspension of MOMIPP, aprepitant and sirolimus prepared by TPSS (PSar: n=14) in Example 13 of the present invention.

[0057] Fig.12 1 is a comparison chart of the particle size distribution and storage stability of MOMIPP nanocrystals prepared by TPGS and TPSS (PSar: n=14) in Example 13 of the present invention.

[0058] Fig.13 1 is a comparison chart of the particle size distribution of aprepitant and sirolimus nanocrystals prepared by TPGS and TPSS (PSar: n=14) in Example 13 of the present invention.

[0059] Fig.14 This is a comparison chart of the particle size distribution of MOMIPP nanocrystals prepared from TPSS with different sarcosine polymerization degrees in Example 13 of the present invention.

[0060] Fig.15 This is a transmission electron microscope photograph of MOMIPP nanocrystals prepared by TPGS and TPSS (PSar: n=14) in Example 13 of the present invention.

[0061] Fig.161 is a transmission electron micrograph of sirolimus nanocrystals prepared by TPGS and TPSS (PSar: n=14) in Example 13 of the present invention.

[0062] Fig.17 This is a verification experiment of the in vitro drug release behavior of MOMIPP and aprepitant nanocrystals prepared by TPGS and TPSS (PSar: n=14) in Example 14 of the present invention. DETAILED DESCRIPTION

[0063] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is specifically, clearly and completely described in the following embodiments in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Moreover, based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work, any modifications, equivalent substitutions, improvements, etc., should be included in the protection scope of the present invention.

[0064] In order to enable those skilled in the art to better understand the technical solution of the present invention, some technical terms of the present invention are first explained. In the text of the present invention, these explanations are mainly to help those skilled in the art understand and implement the technical solution of the present invention, rather than to limit the present invention. In addition, there may be other technical understandings of these technical terms in other disclosures outside the present invention. In order to avoid technical ambiguity, when understanding the present invention, these explanations of the present invention should be based on them.

[0065] Pharmaceutical excipients

[0066] The pharmaceutical excipients referred to in the present invention refer to excipients and additives used in the production of drugs or preparation of prescriptions. They are substances other than active drugs that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations.

[0067] Solubilization and solubilization

[0068] In the process of drug preparation research and development, many poorly soluble drugs such as some volatile oils, fat-soluble vitamins, steroid hormones, etc. have very low solubility in water and cannot reach the concentration required for treatment. At this time, the method of adding surfactants is often used to increase the solubility of drugs in water. This surfactant that plays a solubilization role is called a solubilizer.

[0069] Nanocrystal

[0070] Nanocrystals, also known as nanosuspensions, are pure drug submicron colloid dispersions with a particle size of less than 1 μm formed by dispersing drug particles in a liquid medium using surfactants or polymers as stabilizers.

[0071] Surfactant

[0072] Surfactant refers to a substance that can significantly reduce the surface tension of a liquid. It is called the surfactant of the liquid. Its structure contains polar hydrophilic groups and non-polar hydrophobic groups.

[0073] Emulsions

[0074] An emulsion is a heterogeneous liquid dispersion system formed by mixing two immiscible liquids, in which one liquid is dispersed in the other liquid in the form of droplets.

[0075] Critical micelle concentration (CMC)

[0076] ‌‌Critical micelle concentration (CMC) is a characteristic property of amphiphilic polymer materials, that is, when the amphiphilic polymer material reaches a certain concentration in water, further increasing the material concentration can form micelles. Critical micelle concentration (‌CMC) is the minimum concentration of surfactant molecules in solution to associate and form micelles. When the surfactant reaches a certain concentration in aqueous solution, the solubility of some water-insoluble or slightly soluble drugs in the micelle solution formed by it can be significantly increased and a transparent micelle solution can be formed. At this time, the concentration of the surfactant is called the critical micelle concentration. Its formation mechanism is that the surfactant molecule usually has an amphiphilic structure, that is, one end is hydrophilic and the other end is hydrophobic. At low concentrations, the surfactant molecule exists in water as a single molecule. As the concentration increases, the molecule will be enriched on the water surface to form a monolayer. When the surface adsorption reaches saturation, the excess molecules will aggregate to form micelles. The hydrophobic groups inside the micelles aggregate with each other, and the hydrophilic groups are outwardly in contact with water. In the present invention, the critical micelle concentration can be used to verify the solubility of polymer materials.

[0077] Example 1, an amino acid polymer material.

[0078] Refer to the attached Figure 1 and Figure 2 This embodiment provides a polyamino acid polymer material, the chemical formula of which is shown below:

[0079] , where n=10~70.

[0080] Preferably, the synthetic raw materials of the above-mentioned polyamino acid polymer material include: N-phenoxycarbonylsarcosine (SarNPC), N,N-diisopropylethylamine (DIPEA), neopentylamine, succinic anhydride, vitamin E (VE), dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). In the present invention, the raw materials refer to substances that directly participate in chemical reactions as reactants, and new compounds are generated through chemical reactions between the raw materials, among which neopentylamine acts as an initiator in the reaction.

[0081] Preferably, the sarcosine SarNPC, N,N-diisopropylethylamine (DIPEA), neopentylamine, succinic anhydride, vitamin E (VE), dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) are in a ratio of (10.0-70.0): (3.0-8.0): 1.0: (1.0-25.0): (1.0-2.0): (1.0-2.0): (0.05-1.0), calculated by equivalent ratio.

[0082] Preferably, the auxiliary material of the polyamino acid polymer material includes an organic solvent, and the organic solvent is configured to assist the polymerization reaction. In the present invention, the auxiliary material and raw material are relative. As mentioned above, the raw material directly participates in the chemical reaction, while the auxiliary material is a substance that provides reaction conditions such as possibility and convenience for the chemical reaction, such as solvents, catalysts, etc.

[0083] Preferably, the organic solvent is selected from at least one of DMSO, DMF, DMAc, dichloromethane, ethyl ether, tert-methyl ether, and isopropyl ether. In the present invention, different steps in the overall process of preparing the compound can select different organic solvents according to actual conditions and reaction conditions, so as to achieve the optimization effect of the present invention.

[0084] Preferably, the synthesis route of the polyamino acid polymer material is as follows:

[0085] , n=10~70.

[0086] The polysarcosine vitamin E succinate (TPSS) synthesized by the present invention is a material with a target degree of polymerization synthesized by a relatively mild and easily scalable polyamino acid synthesis process. The product has significant advantages in emulsification, solubilization, as a nano drug dispersion stabilizer, heat resistance and sterilization performance.

[0087] Sarcosine (N-methylglycine) is a kind of non-protein amino acid. As an intermediate in the natural metabolism of choline to glycine, it plays an important role in the human body. There are four main sources of sarcosine: self-synthesis by the human body, chemical synthesis, plant extraction, and food sources. Sarcosine has many beneficial physiological functions for the human body. It can improve human intelligence, increase muscle anaerobic strength and explosive power, and prevent damage caused by brain damage. The polymer with sarcosine as a repeating unit, namely polysarcosine (PSar), has excellent biocompatibility, and its degradation products are completely physiologically harmless. In addition, polysarcosine is uncharged and has good hydrophilicity and stealth effect. The properties of polysarcosine are very similar to those of PEG, and it has the functions of enhancing the dispersion of nanoparticles, stealth effect, and improving the physical stability of nanomedicines. As described in the background art, vitamin E polyethylene glycol succinate (TPGS) has some defects and deficiencies as a pharmaceutical excipient. The present invention replaces the hydrophilic segment of TPGS with a polysarcosine segment, and a series of amphiphilic polymer materials that meet different needs can be obtained by adjusting the length of the polysarcosine segment. In addition, the polyamino acid polymer material provided by the present invention can synthesize hydrophilic polysarcosine segments of different molecular weights by adjusting the polymerization degree of sarcosine to meet different formulation requirements.

[0088] Example 2, a method for preparing a polyamino acid polymer material.

[0089] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0090] The preparation process is as follows:

[0091] (1) Synthesis of intermediate PSar 14 S:

[0092] (1.1) Dissolution: Add 30.00 g (143.4 mmol, 14 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 250 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 6.61 g (51.2 mmol, 5 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 75 mL of dimethyl sulfoxide (DMSO) into the reaction bottle and stir until dissolved.

[0093] (1.2) Polymerization: Weigh 0.89 g (10.24 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0094] (1.3) Amidation: Weigh 1.53 g (15.36 mmol, 1.5 eq.) of succinic anhydride and dissolve it in DMSO. Add the succinic anhydride into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h to obtain a reaction solution.

[0095] (1.4) Add tertiary methyl ether to the reaction solution and centrifuge to filter. Repeat the centrifugation for 3 times and vacuum dry to obtain solid PSar. 14 S.

[0096] (2) Synthetic product TPSS:

[0097] (2.1) Synthesis reaction: Weigh PSar 14 S 4.61 g (3.9 mmol, 1 eq.), vitamin E (VE) 2.52 g (5.85 mmol, 1.5 eq.), dicyclohexylcarbodiimide (DCC) 0.97 g (4.68 mmol, 1.2 eq.), and 4-dimethylaminopyridine (DMAP) 0.24 g (1.95 mmol, 0.5 eq.) were all added into a 100 mL single-necked reaction bottle, and then 40 mL of dichloromethane (DCM) was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0098] (2.2) Centrifugation: The filtrate from step (2.1) was added to a 500-mL centrifuge bottle, and 240 mL of tert-methyl ether was added and centrifuged to precipitate the solid. The solid was precipitated after the first centrifugation. The centrifugation operation was repeated three times. The solid was vacuum dried to obtain 4.67 g of product TPSS (PSar: n=14) with a yield of 75%.

[0099] Example 3, a method for preparing a polyamino acid polymer material.

[0100] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0101] The preparation process is as follows:

[0102] (1) Synthesis of intermediate PSar 25 S:

[0103] (1.1) Dissolution: Add 60.00 g (284 mmol, 25 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 500 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 7.41 g (56.8 mmol, 5 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 150 mL of dimethyl sulfoxide (DMSO) into the reaction bottle and stir until dissolved.

[0104] (1.2) Polymerization: Weigh 0.99 g (11.36 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0105] (1.3) Amidation: Weigh 1.71 g (17.04 mmol, 1.5 eq.) of succinic anhydride and dissolve it in DMSO. Add the succinic anhydride into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h.

[0106] (1.4) Add tertiary methyl ether to the reaction solution and centrifuge to filter. Repeat the centrifugation for 3 times and vacuum dry to obtain solid PSar. 25 S.

[0107] (2) Synthetic product TPSS:

[0108] (2.1) Synthesis reaction: Weigh PSar 25 S 7.66 g (3.9 mmol, 1 eq.), vitamin E (VE) 2.52 g (5.85 mmol, 1.5 eq.), dicyclohexylcarbodiimide (DCC) 0.97 g (4.68 mmol, 1.2 eq.), and 4-dimethylaminopyridine (DMAP) 0.24 g (1.95 mmol, 0.5 eq.) were all added into a 100 mL single-necked reaction bottle, and then 40 mL of dichloromethane (DCM) was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0109] (2.2) Centrifugation: The filtrate from step (2.1) was added to a 500-mL centrifuge bottle, and 240 mL of tert-methyl ether was added and centrifuged to precipitate the solid. The solid was precipitated after the first centrifugation. The centrifugation operation was repeated three times. The solid was vacuum dried to obtain 7.14 g of product TPSS (PSar: n=25) with a yield of 77%.

[0110] Example 4, a method for preparing a polyamino acid polymer material.

[0111] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0112] The preparation process is as follows:

[0113] (1) Synthesis of intermediate PSar 70 S:

[0114] (1.1) Dissolution: Add 49.79 g (238 mmol, 70 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 250 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 2.20 g (17 mmol, 5 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 125 mL of dimethyl sulfoxide (DMSO) into the reaction bottle and stir until dissolved.

[0115] (1.2) Polymerization: Weigh 0.30 g (3.4 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0116] (1.3) Amidation: Weigh 0.51 g (5.1 mmol, 1.5 eq.) of succinic anhydride and dissolve it in DMSO. Add the succinic anhydride into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h.

[0117] (1.4) Add ether to the reaction solution and centrifuge to filter. Repeat the centrifugation three times and vacuum dry to obtain solid PSar. 70 S.

[0118] (2) Synthetic product TPSS:

[0119] (2.1) Synthesis reaction: Weigh PSar 70 S 6.71 g (1.3 mmol, 1 eq.), vitamin E (VE) 0.84 g (1.95 mmol, 1.5 eq.), dicyclohexylcarbodiimide (DCC) 0.32 g (1.56 mmol, 1.2 eq.), and 4-dimethylaminopyridine (DMAP) 0.08 g (0.65 mmol, 0.5 eq.) were all added into a 100 mL single-necked reaction bottle, and then 15 mL of dichloromethane (DCM) was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0120] (2.2) Centrifugation: Add the filtrate from step (2.1) into a 100-mL centrifuge tube, add 90 mL of tert-methyl ether and centrifuge to precipitate the solid. Repeat the centrifugation operation three times to precipitate the solid. The solid was vacuum dried to obtain 4.49 g of product TPSS (PSar: n=70) with a yield of 62%.

[0121] Example 5, a method for preparing a polyamino acid polymer material.

[0122] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0123] The preparation process is as follows:

[0124] (1) Synthesis of intermediate PSar 10 S:

[0125] (1.1) Dissolution: Add 10.00 g (47.8 mmol, 10 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 250 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 4.94 g (38.24 mmol, 8 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 80 mL of N,N-dimethylacetamide (DMAc) into the reaction bottle and stir until dissolved.

[0126] (1.2) Polymerization: Weigh 0.42 g (4.78 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0127] (1.3) Amidation: Weigh 11.96 g (119.5 mmol, 25 eq.) of succinic anhydride and dissolve it in DMAc. Add it into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h.

[0128] (1.4) Add ether to the reaction solution and centrifuge to filter. Repeat the centrifugation three times and vacuum dry to obtain solid PSar. 10 S.

[0129] (2) Synthetic product TPSS:

[0130] (2.1) Synthesis reaction: Weigh PSar 10S 1.35 g (1.5 mmol, 1 eq.), vitamin E (VE) 1.29 g (3 mmol, 2 eq.), dicyclohexylcarbodiimide (DCC) 0.62 g (3 mmol, 2 eq.), and 4-dimethylaminopyridine (DMAP) 0.18 g (1.5 mmol, 1 eq.) were all added into a 100 mL single-necked reaction bottle, and then 15 mL of dichloromethane (DCM) was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0131] (2.2) Centrifugation: Add the filtrate from step (2.1) into a 100-mL centrifuge tube, add 90 mL of ether and centrifuge to precipitate the solid. Repeat the centrifugation operation three times to precipitate the solid. The solid was dried under vacuum to obtain 1.34 g of product TPSS (PSar: n=10) with a yield of 68%.

[0132] Example 6, a method for preparing a polyamino acid polymer material.

[0133] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0134] The preparation process is as follows:

[0135] (1) Synthesis of intermediate PSar 50 S:

[0136] (1.1) Dissolution: Add 35.56 g (170 mmol, 50 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 250 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 1.32 g (10.2 mmol, 3 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 90 mL of dimethyl sulfoxide (DMSO) into the reaction bottle and stir until dissolved.

[0137] (1.2) Polymerization: Weigh 0.30 g (3.4 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0138] (1.3) Amidation: Weigh 3.40 g (34 mmol, 10 eq.) of succinic anhydride and dissolve it in DMSO. Add the succinic anhydride into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h.

[0139] (1.4) Add isopropyl ether to the reaction solution and centrifuge to filter. Repeat the centrifugation for 3 times and vacuum dry to obtain solid PSar. 50 S.

[0140] (2) Synthetic product TPSS:

[0141] (2.1) Synthesis reaction: Weigh PSar 50 S 5.61 g (1.5 mmol, 1 eq.), vitamin E (VE) 0.65 g (1.5 mmol, 1 eq.), dicyclohexylcarbodiimide (DCC) 0.31 g (1.5 mmol, 1 eq.), and 4-dimethylaminopyridine (DMAP) 9.2 mg (0.075 mmol, 0.05 eq.) were all added into a 50 mL single-necked reaction bottle, and then N,N-dimethylformamide (DMF) 10 mL was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0142] (2.2) Centrifugation: Add the filtrate from step (2.1) into a 100-mL centrifuge tube, add 90 mL of isopropyl ether and centrifuge to precipitate the solid. Repeat the centrifugation operation three times to precipitate the solid. The solid is dried under vacuum to obtain 3.12 g of product TPSS (PSar: n=50) with a yield of 50%.

[0143] Example 7, a method for preparing a polyamino acid polymer material.

[0144] This embodiment provides a method for preparing a polyamino acid polymer material. According to the preparation method of this embodiment, the polyamino acid polymer material described in Example 1, namely TPSS, can be prepared.

[0145] The preparation process is as follows:

[0146] (1) Synthesis of intermediate PSar 14 S:

[0147] (1.1) Dissolution: Add 10 g (47.8 mmol, 14 eq.) of N-phenyloxycarbonylsarcosine (SarNPC) into a 100 mL double-necked reaction bottle. Use a double-row tube to replace the nitrogen three times. Use a syringe to weigh 2.20 g (17 mmol, 5 eq.) of N,N-diisopropylethylamine (DIPEA) and inject it into the reaction bottle while turning on the nitrogen. Continue to use a syringe to draw 50 mL of N,N-dimethylformamide (DMF) into the reaction bottle and stir until dissolved.

[0148] (1.2) Polymerization: Weigh 0.30 g (3.4 mmol, 1 eq.) of neopentylamine and pour it into a reaction bottle. Perform the polymerization reaction at 60 °C for 24 h.

[0149] (1.3) Amidation: Weigh 6.80 g (68 mmol, 20 eq.) of succinic anhydride and dissolve it in DMF. Add it into the polymerization reaction and carry out the amidation reaction at room temperature for 24 h.

[0150] (1.4) Add ether to the reaction solution and centrifuge to filter. Repeat the centrifugation three times and vacuum dry to obtain solid PSar. 14 S.

[0151] (2) Synthetic product TPSS:

[0152] (2.1) Synthesis reaction: Weigh PSar 14 S 4.61 g (3.9 mmol, 1 eq.), vitamin E (VE) 2.02 g (4.68 mmol, 1.2 eq.), dicyclohexylcarbodiimide (DCC) 1.21 g (5.85 mmol, 1.5 eq.), and 4-dimethylaminopyridine (DMAP) 0.24 g (1.95 mmol, 0.5 eq.) were all added into a 100 mL single-necked reaction bottle, and then 50 mL of dichloromethane (DCM) was added, stirred at room temperature for 24 h, and then filtered to obtain the filtrate.

[0153] (2.2) Centrifugation: The filtrate from step (2.1) was added to a 500 mL centrifuge bottle, and 400 mL of ether was added and centrifuged to precipitate the solid. The solid was precipitated after the first centrifugation. The centrifugation operation was repeated 3 times. The solid was vacuum dried to obtain 3.67 g of product TPSS (PSar: n=14) with a yield of 59%.

[0154] Example 8, structural confirmation and HLB value determination of the product TPSS.

[0155] In this example, nuclear magnetic resonance hydrogen spectrum was used to confirm the structure of the synthesized TPSS. The specific method was as follows: the product TPSS materials obtained in Example 2, Example 3 and Example 4 were dissolved in DMSO-d6 respectively, and measured using a Bruker 600MHz magnetic resonance hydrogen spectrometer to obtain nuclear magnetic resonance hydrogen spectra of TPSS with different polysarcosine chain segment lengths, as shown in FIG. Figure 3 , Figure 4 , Figure 5 As shown in the figure, it can be seen that the product TPSS is amphiphilic.

[0156] The hydrophile-lipophile balance (HLB) value of amphiphilic polymer materials is calculated using the relative volume of hydrophilic protons in the hydrogen nuclear magnetic resonance spectrum.

[0157] Depend on Figure 3It can be calculated that the hydrophilic protons of TPSS with n=14 (with δ=2.5 as the dividing point) are 84.64, and the lipophilic protons are 54. The HLB value is further calculated according to the following formula:

[0158] HLB = ,

[0159] Wherein, H is the relative volume of hydrophilic protons in the NMR spectrum, and the calculated value of H is 0.6105. Substituting the H value into the formula, the HLB value of TPSS (PSar: n=14) calculated is 14.03.

[0160] Compared with the HLB value of TPGS reported in the prior art literature of 13.2 (Zhiping Zhang et al., Vitamin ETPGS as a molecular biomaterial for drug delivery), the hydrophile-lipophile balance value of TPSS (PSar: n=14) is comparable to that of TPGS.

[0161] Similarly, the HLB values ​​of the other two sarcosine polymerization degrees of TPSS can be calculated based on the H NMR spectra of TPSS (PSar: n=25) and TPSS (PSar: n=70). Figure 4 and Figure 5 )The calculated HLB value of TPSS (PSar: n=25) is 15.61, while the HLB value of TPSS (PSar: n=70) is 17.86, which provides a reference for its application in solubilization, emulsification, nano-drug dispersion stabilization, etc.

[0162] Example 9, determination of the critical micelle concentration value of the product TPSS.

[0163] In this embodiment, the critical micelle concentration (CMC) of TPSS is determined by the pyrene fluorescence method. Pyrene is the most commonly used fluorescent probe molecule for determining the CMC value. Its solubility in water is very small, and the inner core of the polymer micelle formed by TPSS is a hydrophobic region, so pyrene can be solubilized into the TPSS polymer micelle through hydrophobic action. When the concentration of TPSS is less than its critical micelle concentration, TPSS molecules exist on the surface of the solution, that is, on the gas-liquid interface, and pyrene is not solubilized in the micelle; when the solubility of TPSS in the solution reaches its CMC, the gas-liquid interface can no longer accommodate TPSS molecules, and the excess TPSS molecules enter the solution to form micelles, that is, the lipophilic end of vitamin E of TPSS is inside the micelle, and the hydrophilic chain of polysarcosine is on the surface of the micelle. When the concentration of TPSS in the solution increases further, that is, >CMC, more and more TPSS micelles will be formed, which will cause the poorly soluble pyrene to be solubilized into the inside of the micelle. After excitation at 335 nm, pyrene has five electron vibration peaks in its fluorescence emission spectrum in solution, among which the intensity of the first and third vibration peaks is much higher than that of I 1 / I 3 It strongly depends on the polarity of the environment in which pyrene is located. Therefore, the polarity of the two environments of pyrene in solution and in TPSS micelles is very different, so I 1 / I 3 The value of will change greatly, which can be 1 / I 3 The ratio and TPSS concentration are plotted, and the CMC value of TPSS can be obtained by the tangent method ( Figure 6 ). According to the inflection point tangency, the critical micelle concentrations of TPSS (PSar: n=14, 25, 70) were calculated to be 27.167 ± 4.428 μg / mL, 43.583 ± 1.563 μg / mL, and 33.431 ± 3.214 μg / mL. At the same time, the CMC value of TPGS was also determined by this method to be 1.593 ± 0.233 μg / mL. Therefore, TPSS has similar critical micelle concentration values ​​to TPGS, indicating that it can form micelles and solubilize drugs at specific concentrations.

[0164] This example verifies that the product TPSS of the present invention has the solubilizing property for drugs.

[0165] When the concentration of TPSS in water is higher than the CMC value, micelles can be formed. The particle sizes of micelles formed by TPSS with three different sarcosine polymerization degrees in Examples 2, 3 and 4 were measured using a Malvern particle size analyzer. The results are shown in Table 1. Figure 7 The results show that with the increase of the polymerization degree of sarcosine, the particle size of the formed micelles increases. From the particle size distribution diagram, it can be seen that the micelles formed in water may have different assembly forms.

[0166] Example 10, determination of turbidity (tan point) of product TPSS.

[0167] The solution of some amphiphilic polymer materials, such as TPGS, will become turbid as the temperature rises. This is because as the temperature rises, the hydrophilicity of the hydrophilic end of the amphiphilic polymer becomes weaker, resulting in turbidity of the solution. In this embodiment, the turbidity of TPGS and TPSS is verified by experiments.

[0168] Add 3 mL of 2% TPSS (PSar: n=14) solution to a 5 mL vial, then heat to a specific temperature and observe whether the solution becomes turbid ("cloudy"). Figure 8 shown. Figure 8 The comparison of TPGS and TPSS at 70℃, 80℃, 90℃ and 100℃ with room temperature is shown respectively. It can be seen from the results that when the temperature is heated to 70℃, TPGS begins to become turbid (dark spots), and this turbidity gradually increases with the increase in temperature. However, no turbidity is found in the TPSS solution even when it is heated to 100℃, indicating that the hydrophilicity of the hydrophilic end polysarcosine of TPSS is significantly stronger than that of PEG, allowing it to withstand higher temperatures.

[0169] The experiment of Tan Dian in this embodiment proves that TPSS has higher high temperature resistance and can be sterilized by high temperature, thus overcoming the defect that TPGS in the prior art cannot be sterilized by high temperature.

[0170] Example 11, solubilization experiment of the product TPSS on poorly soluble drugs.

[0171] This example verifies the solubilization effect of TPSS on poorly soluble drugs. Two poorly soluble drugs were selected. One is 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one, MOMIPP), a poorly soluble small molecule anti-tumor drug that can induce giant vesicular death in tumors, with a solubility of 0.003 ± 0.0003 mg / mL, and the other is paclitaxel (PTX).

[0172] The specific method of the solubilization experiment in this example is: put an excess of MOMIPP and paclitaxel into a vial containing TPSS (PSar: n=14) or TPGS aqueous solution, and then put it into a constant temperature incubation shaker and shake it at 60 rpm for 24 hours to fully dissolve the drug. Then the sample is centrifuged at high speed, and the supernatant is taken and the drug content in the supernatant is determined by high performance liquid chromatography (HPLC). The results are shown in Fig. 9. It can be seen from the figure that the solubility of MOMIPP and paclitaxel in water is extremely low, and the concentration in the supernatant is lower than the quantitative limit of HPLC for the two drugs. For MOMIPP, TPGS and TPSS have similar solubilization effects, and both can improve the solubility of MOMIPP in water to a certain extent. However, for paclitaxel, TPGS has no obvious solubilization effect, that is, paclitaxel is still not detected in the TPGS supernatant, while for TPSS, we can see that it can significantly solubilize paclitaxel, indicating that it is significantly better than TPGS in solubilizing certain drugs.

[0173] Example 12, emulsification performance experiment of product TPSS.

[0174] In Example 8, it has been verified that the product TPSS of the present invention has an amphiphilic structure, namely vitamin E at the lipophilic end and a polysarcosine segment at the hydrophilic end, so it has the structural characteristics of an emulsifier. This example further verifies the potential of TPSS as an emulsifier.

[0175] In this example, commonly used vegetable oils were selected, including safflower seed oil, olive oil, medium-chain oil, etc. 1 mL of TPSS (PSar: n=14) aqueous solution was taken in a vial, and then 100 μL of each vegetable oil was added to the vial. Due to the separation of oil and water, the state is as follows: Fig.10 As shown in Figure A, the added vegetable oil floats on the interface of the TPSS solution. Insert the probe of the ultrasonic cell disruptor under the surface of the above solution, set the ultrasonic parameters to ultrasonic power 100 W, ultrasonic for 1 s, stop for 2 s, and ultrasonic for a total of 2 min to form a stable emulsion ( Fig.10 The prepared emulsion was placed in a 4°C refrigerator for 1 week without obvious oil-water separation, indicating that TPSS can stably form emulsion droplets, that is, TPSS has a good emulsifying effect and can be used as an effective emulsifier alone or in combination.

[0176] Example 13, performance test of the product TPSS as drug nanocrystal dispersion and stability.

[0177] In this example, the application potential of TPSS with a sarcosine polymerization degree of 14 in the preparation of drug nanocrystals was tested.

[0178] In this example, several representative insoluble drugs, namely MOMIPP, aprepitant and sirolimus, were selected and prepared into nanocrystals. The particle size, PDI and stability of the nanocrystals were used as evaluation indicators to examine their advantages as dispersants / stabilizers for drug nanocrystals.

[0179] First, MOMIPP nanocrystals were prepared, and the dispersion and stability of TPGS and TPSS in nanocrystals were compared. The preparation method is as follows: MOMIPP was dissolved in DMSO (30 mg / mL), TPGS / TPSS (PSar: n=14) was dissolved in water, and the DMSO solution of MOMIPP was slowly injected into the aqueous solution of TPGS / TPSS (PSar: n=14) using a syringe pump, while maintaining high-speed magnetic stirring (1200 rpm). With the injection of the DMSO solution of MOMIPP, uniform nanoparticles were formed in the aqueous solution. After the preparation, ultrasonic cell disruptor was used for 15 min, working for 2 s, and stopping for 2 s. The nanocrystal suspension after ultrasound was subjected to ultracentrifugation at 20,000×g for 30 min. After the centrifugation, the supernatant was discarded, and the nanocrystal precipitate was resuspended by vortexing with a small amount of water, and then ultrasonic cell disruptor was used for 15 min, working for 2 s, and stopping for 2 s. The prepared MOMIPP nanocrystal suspension ( Fig.11 ) was diluted and the particle size of the nanocrystals was measured using a Malvern particle size potentiometer. The results were ( Fig.12 A picture in and Fig.12 Figure B): The particle size of the nanocrystals prepared by TPSS is 179.6 ± 11.17 nm, and the PDI is 0.310 ± 0.001. The particle size of the nanocrystals prepared by TPGS is 399.5 ± 33.2, and the PDI is 0.559 ± 0.044. From the results, it can be seen that the particle size of the MOMIPP nanocrystals prepared by TPSS is smaller, and the nanocrystal particles are more uniform (generally speaking, the nanocrystal particle size is preferably around 200, and the stability is better), indicating that TPSS is better than TPGS in dispersing and stabilizing nanocrystals.

[0180] The stability of the prepared MOMIPP nanocrystals was further investigated over time. The MOMIPP nanocrystals prepared by TPGS were unstable in a short period of time and the particles increased significantly, while the MOMIPP nanocrystals prepared by TPSS remained stable after being stored at 4°C for 21 days, and the particle size and PDI did not change significantly ( Fig.12 The above results show that TPSS not only has a better dispersion effect (small particle size and PDI) than TPGS in the preparation of MOMIPP nanocrystals, but also can effectively stabilize drug nanocrystals and improve the physical stability of their dispersion.

[0181] The same method as above was used to investigate the nanocrystals of aprepitant and sirolimus prepared by TPGS and TPSS (PSar: n=14), and the application of TPSS in broad-spectrum drugs has been confirmed. Fig.11) After dilution, the particle size and distribution of each nanocrystal suspension were measured using a Malvern particle size potentiometer. The results are as follows Fig.13 As shown. The results show that compared with TPGS, the nanocrystals prepared by TPSS (PSar: n=14) have smaller particle size and more uniform dispersion (smaller PDI), indicating that the dispersion effect of TPSS is better than that of TPGS when preparing aprepitant nanocrystals. When preparing sirolimus nanocrystals, both TPGS and TPSS can prepare nanocrystal suspensions with smaller particle size and uniform particle size dispersion, and both show the same dispersion effect.

[0182] In addition, this example further uses MOMIPP as a model drug to investigate the differences in the preparation of nanocrystals using TPSS with different sarcosine polymerization degrees. The specific method is: prepare TPSS solutions of the same concentration (0.1%~0.5%, w / v), and then prepare MOMIPP drug nanocrystal suspensions according to the above method, and use a Malvern particle size potentiometer to measure the particle size and distribution of nanocrystals prepared from different polymer materials. The results are shown in Fig.14 The results show that the MOMIPP nanocrystals prepared by TPSS with a sarcosine polymerization degree of 14 (MW≈1000) and a polymer of 25 (MW≈2000) (from the right) have a smaller particle size (<200 nm) and a more uniform particle size distribution. The particle size of TPSS with a sarcosine polymerization degree of 70 (MW≈5000) is larger, indicating that its ability to disperse drug nanocrystals is weaker than that of the first two sarcosine polymerization degrees of TPSS.

[0183] To further verify the dispersion effect, we used transmission electron microscopy to observe the morphology of the drug nanocrystals prepared according to the above method. The drug nanocrystals were appropriately diluted, and then 10 μL of the sample was dropped on the copper mesh and dried naturally. Then 10 μL of 2% phosphotungstic acid was added for negative staining. After negative staining for 2 minutes, the phosphotungstic acid was removed by aspiration. Wash twice with 10 μL of ultrapure water, each for 2 minutes, and complete the sample preparation after natural drying, and then take photos with a transmission electron microscope. Transmission electron microscope photos of MOMIPP nanocrystals are shown in Fig.15 As can be seen from the figure, the nanocrystals prepared by TPGS have poor dispersion due to the aggregation of drug nanocrystals (easy to agglomerate) caused by the sample drying process during the sample preparation process; however, the nanocrystals prepared by TPSS (PSar: n=14) can still maintain a good nanoscale dispersion state after sample preparation, which is consistent with the particle size value measured by the Malvern particle size analyzer, indicating that TPSS has a better dispersion effect than TPGS in the preparation of MOMIPP nanocrystals.

[0184] In addition, we also used transmission electron microscopy to characterize the appearance of sirolimus nanocrystals. Fig.16. As can be seen from the figure, the sirolimus nanocrystals prepared by TPGS have a slightly larger particle size than the particle size measured by the Malvern particle size analyzer due to treatments such as drying during the sample preparation process, although its dispersibility is good. The sirolimus nanocrystals prepared by TPSS (PSar: n=14) can still maintain a smaller particle size after transmission electron microscopy sample preparation, and its size is consistent with the data of Malvern particle size measurement, and its dispersibility is good. It can be clearly seen from the experiments in this embodiment that the drug nanocrystals prepared by TPSS have a better dispersion effect than TPGS, and in the drying process of drug nanocrystals (such as transmission electron microscopy sample preparation), the nanocrystals prepared by TPSS can better maintain a better dispersion and stability effect, while the nanocrystals prepared by TPGS will cause the particle size of the drug nanocrystals to become larger or agglomerate.

[0185] Example 14, in vitro drug release behavior experiment.

[0186] This example further verifies the in vitro drug release of drug nanocrystals prepared by the TPSS of the present invention on the basis of Example 13. Two model drugs, namely MOMIPP and aprepitant, were selected in this example. Since the solubility of the two drugs in water is very low, in order to meet the detection requirements and sink conditions, a 2% SDS PBS solution was selected as the release medium, and the volume of the release medium was 20 mL. Take an appropriate amount of MOMIPP nanocrystal suspension and aprepitant suspension and put them into a dialysis bag (MWCO: 8000-14000), then immerse the dialysis bag in a centrifuge tube containing the above-mentioned release medium, and put it into a constant temperature oscillator for experiment. The setting parameters of the constant temperature oscillator are: temperature of 37°C, oscillation speed of 60 rpm, sampling at preset time points and replacing all release media. The methodologically validated high performance liquid chromatography (HPLC) was used to detect the amount of drug in the release medium at different time points, and the cumulative drug release was calculated. The results are shown in Fig.17 The results show that the nanocrystals of the two drugs prepared by TPGS and TPSS have similar in vitro drug release behaviors. This example verifies the feasibility of the product of the present invention in pharmaceutical preparation.

[0187] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A polyamino acid polymer material, It is characterized in that The chemical formula of the polymer material is shown below: , where n=10~70.

2. A polyamino acid polymer material according to claim 1, It is characterized in that The polyamino acid polymer material uses sarcosine as a raw material, and the sarcosine is configured to have an adjustable polymerization degree.

3. A polyamino acid polymer material according to claim 2, It is characterized in that The polymerization degree of the sarcosine is preferably 10-70.

4. A polyamino acid polymer material according to claim 1, It is characterized in that The raw materials of the polyamino acid polymer material include: N-phenoxycarbonylsarcosine, neopentylamine, N,N-diisopropylethylamine, succinic anhydride, vitamin E, dicyclohexylcarbodiimide and 4-dimethylaminopyridine.

5. A polyamino acid polymer material according to claim 4, It is characterized in that The N-phenoxycarbonylsarcosine, N,N-diisopropylethylamine, neopentylamine, succinic anhydride, vitamin E, dicyclohexylcarbodiimide and 4-dimethylaminopyridine are mixed in a ratio of (10.0-70.0): (3.0-8.0): 1.0: (1.0-25.0): (1.0-2.0): (1.0-2.0): (0.05-1.0), calculated by equivalent ratio.

6. A polyamino acid polymer material according to claim 4, It is characterized in that The auxiliary materials of the polyamino acid polymer material include organic solvents.

7. A polyamino acid polymer material according to claim 6, It is characterized in that The organic solvent includes, but is not limited to, DMSO, DMF, DMAc, dichloromethane, ethyl ether, tert-methyl ether, isopropyl ether, n-heptane, n-hexane and petroleum ether.

8. A polyamino acid polymer material according to claim 1, It is characterized in that The synthetic route of the polyamino acid polymer material is as follows: , where n=10~70.

9. A method for preparing a polyamino acid polymer material, It is characterized in that The preparation method is configured to prepare the polyamino acid polymer material according to any one of claims 1 to 8, and the preparation process is as follows: (1) Synthesis of intermediate PSar n S: (1.1) Dissolution: Place the raw materials N-phenoxycarbonylsarcosine and N,N-diisopropylethylamine in a reaction vessel according to the ratio, add an organic solvent, stir and dissolve to obtain a solution; (1.2) Polymerization: neopentylamine is added to the solution of step (1.1) according to the ratio to carry out polymerization reaction; (1.3) Amidation: After dissolving succinic anhydride in an organic solvent according to the ratio, add it into the reaction system to carry out an amidation reaction to obtain a reaction solution; (1.4) Add organic solvent to the reaction solution, centrifuge and filter to obtain the solid intermediate product PSar. n S; (2) Synthetic product TPSS: (2.1) Synthesis reaction: Take the intermediate product PSar obtained in step (1) n S, vitamin E, dicyclohexylcarbodiimide and 4-dimethylaminopyridine are placed in a reaction container, an organic solvent is added, stirred for reaction, and then filtered to obtain a filtrate; (2.2) Centrifugation: Add an organic solvent to the filtrate from step (2.1) and centrifuge to precipitate a solid. Repeat the centrifugation operation until the organic solvent layer is clear. The solid is vacuum dried to obtain the product TPSS.

10. The method for preparing a polyamino acid polymer material according to claim 9, It is characterized in that The organic solvents in the step (1.1) and the step (1.3) are respectively selected from at least one of DMSO, DMF, and DMAc.

11. The method for preparing a polyamino acid polymer material according to claim 9, It is characterized in that The organic solvent in the step (2.1) is selected from at least one of dichloromethane, DMSO, DMF and DMAc.

12. The method for preparing a polyamino acid polymer material according to claim 9, It is characterized in that The organic solvents in step (1.4) and step (2.2) are respectively selected from at least one of diethyl ether, tertiary methyl ether, isopropyl ether, n-heptane, n-hexane and petroleum ether.

13. The method for preparing a polyamino acid polymer material according to claim 9, It is characterized in that During the preparation process, the addition ratio and polymerization degree of sarcosine can be adjusted.

14. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material prepared according to the method according to any one of claims 9 to 13 in the preparation of medicines and cosmetics.

15. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material obtained by the method according to any one of claims 9 to 13 in dissolving compounds.

16. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material prepared according to the method according to any one of claims 9 to 13 in solubilizing and dispersing poorly soluble drugs.

17. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material prepared according to the method according to any one of claims 9 to 13 in terms of heat resistance.

18. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material obtained by the method according to any one of claims 9 to 13 in terms of bactericidal properties.

19. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material obtained by the method according to any one of claims 9 to 13 as an emulsifier.

20. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material obtained by the method according to any one of claims 9 to 13 as a wetting agent.

21. Use of the polyamino acid polymer material according to any one of claims 1 to 8, or the polyamino acid polymer material prepared according to the method according to any one of claims 9 to 13 as a detergent.

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