A polycaprolactone-polyethylene glycol copolymer gel and its preparation method and application

Abstract

The invention discloses a polycaprolactone-polyethylene glycol copolymer gel and its preparation method and application, including: adding a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, a low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and an additive into water, dissolving to obtain a milky white polycaprolactone-polyethylene glycol copolymer gel; the mass ratio of high and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is (2-5):1; the additive is hydroxyapatite or tricalcium phosphate, the particle size of the additive is not more than 20 μm, and the mass of the additive accounts for 1% to 5% of the mass of the polycaprolactone-polyethylene glycol copolymer gel. The present invention can prolong the degradation cycle of the product, increase the efficacy, and obtain a polycaprolactone-polyethylene glycol copolymer gel with a long-lasting effect by compounding and controlling the mass ratio of high and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymers.

Description

Technical Field

[0001] The invention belongs to the technical field of biomaterials, and in particular relates to a polycaprolactone-polyethylene glycol copolymer gel and a preparation method and application thereof. Background Art

[0002] With the development of technology, several products using biodegradable polymers for tissue repair and treatment have been developed. These products mainly use biocompatible polymers as pharmaceutical carriers, or process water-insoluble polymers into microparticles and then disperse them in a medium to prepare tissue repair or pharmaceutical preparations. However, these existing products have problems such as rapid degradation and needle clogging during injection in actual use.

[0003] Based on the above problems, PCT / KR2020 / 016617 discloses an amphiphilic polymer mPEG-PCL. Due to the linear structure of the amphiphilic polymer mPEG-PCL, the degradation cycle of the product is too fast, and multiple injections are required to maintain the effect, which brings pain to patients and increases the cost of treatment. CN107383377B discloses a cyclic polycaprolactone-polyethylene glycol amphiphilic block copolymer and a preparation method. The cyclic copolymer has better drug loading capacity and a longer degradation cycle than linear copolymers. However, due to the biological toxicity of Cu ions in its reaction, the application range of the product is limited. In addition, the degradation product of polycaprolactone is 6-hydroxycaproic acid, which is not easily metabolized in vivo. With the continuous degradation of polycaprolactone, 6-hydroxycaproic acid accumulates and aggregates, resulting in local acidity inside the skin tissue, increasing the probability of late nonspecific tissue inflammation. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a polycaprolactone-polyethylene glycol copolymer gel and a preparation method and application thereof in view of the above-mentioned deficiencies in the prior art. The method can obtain a polycaprolactone-polyethylene glycol copolymer gel preparation with a long-lasting effect by compounding and controlling the mass ratio of high-molecular-weight and low-molecular-weight cyclic polycaprolactone-polyethylene glycol copolymers.

[0005] In order to solve the above technical problems, the technical scheme adopted by the present invention is: a method for preparing a polycaprolactone-polyethylene glycol copolymer gel, characterized in that it comprises: adding a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, a low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and an additive into water, and dissolving them to obtain a milky white polycaprolactone-polyethylene glycol copolymer gel; the mass ratio of the high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer to the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is (2-5):1; the additive is hydroxyapatite or tricalcium phosphate, the particle size of the additive is not more than 20 μm, and the mass of the additive accounts for 1% to 5% of the mass of the polycaprolactone-polyethylene glycol copolymer gel.

[0006] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that the high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is made of high molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl and high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH as main raw materials; the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is made of low molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl and low molecular weight bis-mercapto polyethylene glycol HS-PEG-SH as main raw materials.

[0007] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that a high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is prepared by using a polycaprolactone with a molecular weight of 4000 to 20000, and a low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is prepared by using a polycaprolactone with a molecular weight of less than 4000; a high molecular weight bis-thiol polyethylene glycol HS-PEG-SH is prepared by using a polyethylene glycol with a molecular weight of 4000 to 20000, and a low molecular weight bis-thiol polyethylene glycol HS-PEG-SH is prepared by using a polyethylene glycol with a molecular weight of less than 4000.

[0008] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that the method for synthesizing a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer comprises: placing a high molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl, a high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH and a photoinitiator in a solvent, performing a polymerization reaction under ultraviolet light irradiation, removing the solvent after the polymerization reaction is completed, adding dichloromethane until completely dissolved, then adding ether for precipitation purification, filtering, and drying to obtain a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer.

[0009] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that the molar ratio of the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl to the high molecular weight bis-thiol polyethylene glycol HS-PEG-SH is 1:(1-4), the solvent is optionally selected from one of DMF, 1,4-dioxane, dichloromethane, chloroform and DMSO, and the mass of the solvent is 5-20 times the sum of the masses of the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl and the high molecular weight bis-thiol polyethylene glycol HS-PEG-SH; the photoinitiator is optionally selected from one of DMPA, DEAP and 2-hydroxy-2-methylpropiophenone, and the molar ratio of the photoinitiator to the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is (0.1-1.5):1; and the polymerization reaction time is 30min-200min.

[0010] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that the method for synthesizing a low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer comprises: placing a low molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl, a low molecular weight bis-thiol polyethylene glycol HS-PEG-SH and a photoinitiator in a solvent, performing a polymerization reaction under ultraviolet light irradiation, removing the solvent after the polymerization reaction is completed, adding dichloromethane until completely dissolved, then adding ether for precipitation purification, filtering, and drying to obtain a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer.

[0011] The above-mentioned method for preparing a polycaprolactone-polyethylene glycol copolymer gel is characterized in that the molar ratio of the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl to the low molecular weight bis-thiol polyethylene glycol HS-PEG-SH is 1:(1-4), the solvent is optionally selected from one of DMF, 1,4-dioxane, dichloromethane, chloroform and DMSO, and the mass of the solvent is 5-20 times the sum of the masses of the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl and the low molecular weight bis-thiol polyethylene glycol HS-PEG-SH; the photoinitiator is optionally selected from one of DMPA, DEAP and 2-hydroxy-2-methylpropiophenone, and the molar ratio of the photoinitiator to the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is (0.1-1.5):1; and the polymerization reaction time is 30min-200min.

[0012] Furthermore, the present invention provides a polycaprolactone-polyethylene glycol copolymer gel prepared by the above preparation method.

[0013] Furthermore, the present invention provides an application of the above-mentioned polycaprolactone-polyethylene glycol copolymer gel in the preparation of pharmaceutical products, characterized in that the pharmaceutical products include one or more of antibacterial pharmaceutical products, antihistamine pharmaceutical products, anti-inflammatory pharmaceutical products, immunosuppressant pharmaceutical products, anti-metabolism pharmaceutical products, anesthetic pharmaceutical products, analgesic pharmaceutical products, anticoagulant pharmaceutical products, muscle relaxant pharmaceutical products, protein pharmaceutical products and peptide pharmaceutical products.

[0014] The above application is characterized in that the preparation method of the pharmaceutical product comprises: adding at least one effective dose of pharmaceutical agent, high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and additives into water and mixing them evenly.

[0015] Compared with the prior art, the present invention has the following advantages:

[0016] 1. The present invention can improve the stability of the gel and prolong the degradation cycle by compounding high and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymers. High molecular weight cyclic polycaprolactone-polyethylene glycol copolymers cannot obtain high-concentration preparations due to solubility problems, and excessive addition of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymers will lead to excessive molecular weight and poor thermal stability. The present invention can prolong the degradation cycle of the product by compounding and controlling the mass ratio of high and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymers, and obtain a long-acting polycaprolactone-polyethylene glycol copolymer gel.

[0017] 2. The present invention preferably synthesizes a cyclic amphiphilic polymer through a safer thiol-alkyne addition reaction in a click chemistry reaction, and synthesizes high and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymers by controlling the molecular weight and molar ratio of PCL / PEG and the amount of photoinitiator added, thereby solving the problem of biological toxicity of Cu ions in the CuAAC reaction in the prior art. The synthesized cyclic copolymer has stronger stability. Compared with linear polycaprolactone-polyethylene glycol copolymers, the cyclic polycaprolactone-polyethylene glycol copolymers synthesized by the present invention have a longer degradation cycle, a longer effect maintenance time, high biosafety, and can be used as a sustained-release carrier for many pharmaceutical preparations.

[0018] 3. The present invention can effectively neutralize 6-hydroxycaproic acid in the degradation product of polycaprolactone-polyethylene glycol copolymer by adding hydroxyapatite or tricalcium phosphate, improve the acidic environment in the skin tissue, reduce the probability of inflammatory reaction in the late degradation process of the product, and solve the problem of late nonspecific tissue inflammatory reaction caused by accumulation of 6-hydroxycaproic acid in the degradation process of polycaprolactone-polyethylene glycol copolymer.

[0019] 4. The polycaprolactone-polyethylene glycol copolymer gel prepared by the present invention reduces the possibility of needle blocking during use. Compared with its linear structure, cyclic polycaprolactone-polyethylene glycol has a smaller hydrodynamic volume, a slower degradation rate, and better stability. In addition, the added hydroxyapatite or tricalcium phosphate with a particle size of no more than 20 μm does not increase the risk of needle blocking in the product due to its extremely small particle size. The addition of an appropriate amount of hydroxyapatite or tricalcium phosphate and cyclic polycaprolactone-polyethylene glycol can further enhance the anti-degradation property of the gel product while neutralizing the 6-hydroxycaproic acid produced by the polycaprolactone-polyethylene glycol copolymer during the degradation process, thereby avoiding the problem of late nonspecific tissue inflammatory response.

[0020] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The nuclear magnetic hydrogen spectrum of the polycaprolactone-polyethylene glycol copolymer synthesized in Example 1 of the present invention ( 1 1H NMR).

[0022] Figure 2 This is a graph of pH change rates during the degradation process of the gel products prepared in Examples 1-3 of the present invention and Comparative Examples 1-4.

[0023] Figure 3 The cell morphology after injection of the gel prepared in Example 1 of the present invention and Comparative Example 5 is shown.

[0024] Figure 4 This is the injection distribution diagram of the rat back in the inflammation experiment.

[0025] Figure 5 HE sections without injection, after injection of the gel products of Example 1 of the present invention and Comparative Example 3 were observed under an optical microscope. DETAILED DESCRIPTION

[0026] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the embodiments. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments, unless otherwise specified, can be obtained from commercial channels.

[0027] The present invention is specifically described below in conjunction with embodiments, but the following description is not intended to limit the present invention.

[0028] The synthesis of alkynyl polycaprolactone 1-PCL-2alkynyl of the present invention specifically comprises the following steps:

[0029] a. Synthesis of acetylenic anhydride: 9.3 g (93.0 mmol) of succinic anhydride and 2.6 g (21.4 mmol) of 4-dimethylaminopyridine (DMAP) were dissolved in 20 mL of dry dichloromethane (DCM) to obtain a suspension solution. 6.0 g (107.0 mmol) of propargyl alcohol was dissolved in 10 mL of dry DCM and slowly added dropwise to the above suspension solution. The mixture was stirred at 25°C for 36 h under argon protection. After the reaction was completed, 50 mL of DCM was added for dilution, and the mixture was washed three times with 10% NaHSO4 aqueous solution (3×20 mL) and three times with 10% NaHCO3 aqueous solution (3×20 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and rotary evaporated to obtain a white solid powder (Compound 1). 8.0 g (51.3 mmol) of Compound 1 was dissolved in 40 mL of dry DCM and cooled to 0°C in an ice-salt bath. Take 5.5g (26.6mmol) of dicyclohexylcarbodiimide (DCC) and dissolve it in 20mL of DCM, then slowly drop it into the above solution. After reacting at 0℃ for 1h, remove the ice-salt bath, and continue stirring the reaction at 25℃ for 24h under argon protection. After the reaction is completed, remove the solid produced by the reaction by suction filtration, remove DCM by rotary evaporation, and then dissolve it in 10mL of ethyl acetate (EA), freeze it in the lower layer of the refrigerator, remove the solid by suction filtration, and repeat three times. Remove EA by rotary evaporation to obtain a white waxy solid compound, which is acetylenic anhydride.

[0030] bl-PCL-2alkynyl: Add a stirrer to the ampoule, heat it on a double-row tube under vacuum, cool it with argon three times, and put it in a glove box. Add different molecular weights of ε-CL (ε-caprolactone) and initiator ethylene glycol to the ampoule at a molar ratio of 52:1. Then add 0.8 mol / L toluene solution of catalyst Sn(Oct)2 (the molar ratio of ε-CL (ε-caprolactone) to Sn(Oct)2 is 560:1). Seal it with a rubber tube and stir the reaction at 100°C for 2h. After the reaction is completed, take it out of the glove box, cool it immediately, add THF to dissolve it, precipitate it with ice anhydrous ether, filter it, and dry the filter cake in a vacuum oven at 25°C overnight to obtain a white powder, which is hydroxylated polycaprolactone (l-PCL-2OH).

[0031] l-PCL-2OH of different molecular weights, acetylenic anhydride, DMAP, triethylamine (TEA) in a molar ratio of 1:12:0.6:12 and 15mL DCM were added to a 25mL Schlenk tube with a stirrer. Freeze-evacuate-thaw cycles were performed on the double-row tube for 3 times, and the reaction was stirred at 25°C for 24h. After the reaction was completed, 100mL DCM was added for dilution, and the mixture was washed with saturated NaHSO4 solution, saturated NaHCO3 solution and water in turn. The organic layer was collected, dried with anhydrous Na2SO4, filtered, and the filtrate was rotary evaporated to remove the solvent, then dissolved with THF, precipitated with ice anhydrous ether, filtered, and the filter cake was dried in a vacuum oven at 25°C overnight to obtain a white powder, which was acetylenic polycaprolactone (l-PCL-2alkynyl).

[0032] The synthesis of HS-PEG-SH specifically includes: adding polyethylene glycol of different molecular weights to a 50mL three-necked flask equipped with a stirrer and pre-filled with toluene. The system is evacuated at 80°C for 30 minutes. Toluene flows back into the flask to maintain a constant volume. The flask is heated to 125°C in an oil bath. Then, thioglycolic acid (the molar ratio of thioglycolic acid to polyethylene glycol is 2:1) and concentrated sulfuric acid are added, wherein the mass ratio of concentrated sulfuric acid to polyethylene glycol is 0.01:1. The reaction is carried out for 2 hours. The product is precipitated in ether three times, filtered, and then left overnight under vacuum at 40°C. A white powder is obtained, which is HS-PEG-SH.

[0033] The pharmaceutical agents suitable for incorporation into the polycaprolactone-polyethylene glycol copolymer gel of the present invention may be water-soluble, slightly water-soluble and water-insoluble pharmaceutical agents, including, but not limited to:

[0034] Antimicrobial substances, such as beta-lactam antibiotics, e.g. cefoxitin, tetracycline, chloramphenicol, neomycin, carbenicillin, polymyxin, penicillin G, polymyxin B, gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics and their analogues;

[0035] Antihistamines, such as chlorpheniramine, tetrahydrozoline, antazoline decongestants, and similar medicines;

[0036] anesthetics, such as etidocaine cocaine, henoxinate, cinchocaine hydrochloride, dyclonine hydrochloride, nadicaine, phenacaine, piperocaine, proparacaine hydrochloride, tetracaine hydrochloride, hexicaine, bupivacaine, lidocaine, mepivacaine, and prilocaine;

[0037] Peptides and proteins, such as luteinizing hormone, releasing hormone, vasoactive intestinal peptide, antidiuretic hormone, cyclosporine, botulinum toxin, interferon, substance P enkephalin, epidermal growth factor, ocular growth factor, fibronectin, collagen, mussel mucin, insulin-like growth factor, and mesodermal growth factor;

[0038] Those skilled in the art will appreciate that the pharmaceutical compounds listed above are merely exemplary. Because the pharmaceutical composition of the present invention is particularly suitable for subcutaneous injection, a wide variety of pharmaceutical agents may be incorporated therein. Accordingly, the pharmaceutical products listed above in the present invention are not limited to this scope, and are merely exemplary.

[0039] Example 1

[0040] In this example, high molecular weight acetylenic polycaprolactone 1-PCL was prepared according to the above method. 10000 -2alkynyl, low molecular weight alkynyl polycaprolactone 1-PCL 1000 -2alkynyl, high molecular weight bis-thiol polyethylene glycol HS-PEG 10000 -SH and low molecular weight bis-thiol polyethylene glycol HS-PEG 1000 -SH.

[0041] Step 1: Synthesis of high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 5 mmol high molecular weight acetylened polycaprolactone 1-PCL 10000 -2alkynyl, 15mmol high molecular weight bis-thiol polyethylene glycol HS-PEG 10000 -SH, 5mmolDMPA (DEAP or 2-hydroxy-2-methylpropiophenone can also be used instead) and 2000mL DMF solvent (1,4-dioxane, dichloromethane, chloroform or DMSO can also be used instead) are added to a three-necked flask, stirring is started, the ultraviolet lamp is turned on, and the polymerization reaction is carried out by continuous stirring and irradiation for 120min. After the polymerization reaction is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle. Ice ether is used for precipitation purification, filtration, and the dry solid is collected to obtain a white solid powder high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 10000 -CPCL 10000 -PEG 10000 (175.9 g, yield: 92.6%);

[0042] Synthesis of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 50 mmol of low molecular weight acetylenic polycaprolactone 1-PCL 1000 -2alkynyl, 100mmol low molecular weight bis-thiol polyethylene glycol HS-PEG 1000-SH, 50mmol DMPA (DEAP or 2-hydroxy-2-methylpropiophenone may also be used instead) and 1500mL DMF solvent (1,4-dioxane, dichloromethane, chloroform or DMSO may also be used instead) are added to a three-necked flask, stirring is started, the UV lamp is turned on, stirring and irradiation are continued for 120min for polymerization, after the polymerization is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle, and ice ether is used for precipitation purification, filtration, and the dry solid is collected to obtain a white solid powder low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 1000 -CPCL 1000 -PEG 1000 (130.7 g, yield: 93.4%);

[0043] Step 2: Add 1.5 g of hydroxyapatite (particle size range not greater than 20 μm), 24 g of high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, 6 g of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and 18.5 g of ultrapure water into a beaker, stir to swell and dissolve to obtain a milky white gel with 60% copolymer.

[0044] Example 2

[0045] In this example, high molecular weight acetylenic polycaprolactone 1-PCL was prepared according to the above method. 20000 -2alkynyl, low molecular weight alkynyl polycaprolactone 1-PCL 2000 -2alkynyl, high molecular weight bis-thiol polyethylene glycol HS-PEG 20000 -SH and low molecular weight bis-thiol polyethylene glycol HS-PEG 400 -SH.

[0046] Step 1: Synthesis of high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 5 mmol high molecular weight acetylened polycaprolactone 1-PCL 20000 -2alkynyl, 5mmol high molecular weight bis-thiol polyethylene glycol HS-PEG 20000 -SH, 7.5mmolDEAP (DMPA or 2-hydroxy-2-methylpropiophenone may also be used instead) and 1000mL chloroform solvent (DMF, 1,4-dioxane, dichloromethane or DMSO may also be used instead) are added to a three-necked flask, stirring is started, the ultraviolet lamp is turned on, and the polymerization reaction is carried out by continuous stirring and irradiation for 200 minutes. After the polymerization reaction is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle. Ice ether is used for precipitation purification, filtration, and the dry solid is collected to obtain a white solid powder high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 20000 -CPCL 20000 -PEG20000 (377.2 g, yield: 88.6%);

[0047] Synthesis of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 50 mmol of low molecular weight acetylenic polycaprolactone 1-PCL 2000 -2alkynyl, 50mmol low molecular weight bis-thiol polyethylene glycol HS-PEG 400 -SH, 75mmolDMPA (DEAP or 2-hydroxy-2-methylpropiophenone can also be used instead) and 600mL DMF solvent (1,4-dioxane, dichloromethane, chloroform or DMSO can also be used instead) are added to a three-necked flask, stirring is started, the ultraviolet lamp is turned on, and the polymerization is carried out by continuous stirring and irradiation for 200 minutes. After the polymerization is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle. Ice ether is used for precipitation and purification, and the dried solid is collected by filtration to obtain a white solid powder low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 400 -CPCL 2000 -PEG 400 (1278.6, yield: 89.3%);

[0048] Step 2: Add 2.5 g of tricalcium phosphate (particle size range not greater than 20 μm), 27 g of high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, 5.4 g of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and 15.1 g of ultrapure water into a beaker, stir to swell and dissolve to obtain a milky white gel with 65% copolymer.

[0049] Example 3

[0050] In this example, high molecular weight acetylenic polycaprolactone 1-PCL was prepared according to the above method. 4000 -2alkynyl, low molecular weight alkynyl polycaprolactone 1-PCL 400 -2alkynyl, high molecular weight bis-thiol polyethylene glycol HS-PEG 4000 -SH and low molecular weight bis-thiol polyethylene glycol HS-PEG 400 -SH.

[0051] Step 1: Synthesis of high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 5 mmol high molecular weight acetylened polycaprolactone 1-PCL 4000 -2alkynyl, 20mmol high molecular weight bis-thiol polyethylene glycol HS-PEG 4000-SH, 0.5mmol 2-hydroxy-2-methylpropiophenone (DMPA or DEAP may also be used instead) and 2000mL 1,4-dioxane solvent (DMF, dichloromethane, chloroform or DMSO may also be used instead) are added to a three-necked flask, stirring is started, and the ultraviolet lamp is turned on. The polymerization reaction is carried out by continuous stirring and irradiation for 30 minutes. After the polymerization reaction is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle. Ice ether is used for precipitation purification, filtration, and the dry solid is collected to obtain a white solid powder high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 4000 -CPCL 4000 -PEG 4000 (85.2 g, yield: 85.9%);

[0052] Synthesis of low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer: 50 mmol of low molecular weight acetylenic polycaprolactone 1-PCL 400 -2alkynyl, 200mmol low molecular weight bis-thiol polyethylene glycol HS-PEG 400 -SH, 5mmolDMPA (DEAP or 2-hydroxy-2-methylpropiophenone can also be used instead) and 2000mL DMSO solvent (DMF, 1,4-dioxane, dichloromethane or chloroform can also be used instead) are added to a three-necked flask, stirring is started, and the ultraviolet lamp is turned on. Stirring and irradiation are continued for 30 minutes to polymerize. After the polymerization is completed, the solvent is removed by a rotary evaporator, and a small amount of dichloromethane is added to completely dissolve the solid in the bottle. Ice ether is used for precipitation and purification, and the dried solid is collected by filtration to obtain a white solid powder low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 400 -CPCL 400 -PEG 400 (74.1 g, yield: 74.2%);

[0053] Step 2: Add 0.5 g hydroxyapatite (particle size range not greater than 20 μm), 15 g high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, 7.5 g low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and 27 g ultrapure water into a beaker, stir to swell and dissolve to obtain a milky white gel with 45% copolymer.

[0054] Example 4

[0055] The following is the preparation of a medical gel for antihistamine treatment.

[0056] Take 1g of hydroxyapatite (particle size range is not more than 20μm), 20g of the high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer prepared in Example 1, 5g of the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer prepared in Example 1 and 3.3g of chlorpheniramine and add them into a beaker, add 21g of ultrapure water and stir for 24h to obtain chlorpheniramine medical gel with a drug loading rate of 13%.

[0057] Example 5

[0058] The following is the preparation of a medical gel for promoting collagen regeneration.

[0059] Take 0.5g of hydroxyapatite (particle size range is not more than 20μm), 25g of the high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer prepared in Example 1, 6.5g of the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer prepared in Example 1, 1.0g of recombinant collagen, and 0.15g of licadoglycan into a beaker, add 16.9g of ultrapure water and stir for 24h to obtain a medical gel for promoting collagen regeneration with a drug loading rate of 3.6%.

[0060] Comparative Example 1

[0061] This comparative example adopts the method of Example 1 without adding low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 1000 -CPCL 1000 -PEG 1000 , high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 10000 -CPCL 10000 -PEG 10000 The dosage is 30g. After stirring and swelling, it cannot be completely dissolved and the product appears as white granules.

[0062] Comparative Example 2

[0063] This comparative example adopts the method of Example 1, and the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 1000 -CPCL 1000 -PEG 1000 and high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 10000 -CPCL 10000 -PEG 10000 The dosage was 15 g, and a milky white gel was obtained by stirring, swelling and dissolving. However, due to the excessive low molecular weight doping amount, the molecular weight of the compatible copolymer was too wide, the thermal stability was poor, thermal degradation occurred, and the pH value decreased.

[0064] Comparative Example 3

[0065] This comparative example adopts the method of Example 1, without adding hydroxyapatite, low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG1000 -CPCL 1000 -PEG 1000 The dosage is 5g, high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 10000 -CPCL 10000 -PEG 10000 The dosage is 25 g, and the mixture is stirred, swollen and dissolved to obtain a milky white gel with 60% copolymer.

[0066] Comparative Example 4

[0067] This comparative example uses a linear copolymer PCL-PEG-PCL

[0068] Preparation of high molecular weight linear copolymer PCL 10000 -PEG 10000 -PCL 10000 : Add 2.5mmol PEG10000 and 1.56mmol ε-CL10000 into the sealed tube, add a drop of Sn(Oct)2 with a syringe, evacuate, pass nitrogen, replace 5 times, and exhaust oxygen. After the tube is sealed with a spray gun, place it in a 120℃ oil bath and stir to react for 24h. After the reaction is completed, dissolve the product in dichloromethane, precipitate and purify it twice with petroleum ether, vacuum dry overnight, seal it and store it in a refrigerator at 4℃;

[0069] Preparation of low molecular weight linear copolymer PCL 1000 -PEG 1000 -PCL 1000 :Use low molecular weight PEG and ε-CL to prepare according to the preparation method of high molecular weight linear copolymer;

[0070] 24 g of high molecular weight linear copolymer PCL 10000 -PEG 10000 -PCL 10000 , 6g low molecular weight linear copolymer PCL 1000 -PEG 1000 -PCL 1000 (mass ratio of high molecular weight to low molecular weight is 5:1), 1.5 g hydroxyapatite (particle size range is less than 20 μm) and 18.5 g ultrapure water are added into a beaker, stirred, swollen and dissolved to obtain a milky white gel with 60% copolymer.

[0071] Comparative Example 5

[0072] This comparative example synthesizes high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG according to "CN107383377B-Cyclic polycaprolactone-polyethylene glycol amphiphilic block copolymer and its preparation and application" 10000 -CPCL 10000 -PEG 10000and low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer PEG 1000 -CPCL 1000 -PEG 1000 , and then prepare the gel according to the method of Example 1.

[0073] 24 g high molecular weight PEG 10000 -CPCL 10000 -PEG 10000 , 6g low molecular weight PEG 1000 -CPCL 1000 -PEG 1000 , 1.5 g of hydroxyapatite (3%) (particle size range less than 20 μm) and 18.5 g of ultrapure water were added to a beaker, stirred, swollen and dissolved to obtain a milky white gel with 60% copolymer.

[0074] Performance Evaluation

[0075] 1. Structural characterization: Using H NMR spectroscopy ( 1 H NMR) was used to characterize the structure of the polycaprolactone-polyethylene glycol copolymer synthesized in Example 1. The results are shown in Figure 1 , the ratio of n and m corresponding to PCL and PEG in the figure is 1:(0.3~3). The proton assignments corresponding to each absorption peak are as follows: δ4.36 (peak a), δ2.41 (peak b), δ1.83 (peak c), δ1.51 (peak d), δ4.01 (peak e), δ2.69 (peak f), δ5.48 (peak g), δ3.15 (peak h), δ4.63 (peak i), δ3.63 (peak j). The results show that all proton hydrogens can find corresponding assignments. This indicates that an efficient thiol-alkyne reaction has occurred.

[0076] 2. Investigate the thermal stability of different ratios of high and low molecular weight

[0077] 10 mL of each gel prepared in Example 1-3 and Comparative Example 1-4 was poured into a 20 mL glass bottle, and then 2 μg of NaN3 was added, and the bottles were sealed with rubber stoppers and aluminum-plastic caps. The glass bottles containing the gel products of Example 1-3 and Comparative Example 1-4 were placed in a 37°C stabilization box at the same time, and 2 mL was taken before (0 month), 1 month, 3 months and 5 months after being placed in the stabilization box, and the pH was tested after diluting 10 times with purified water. The pH results are shown in Table 1, and the pH changes are shown in Table 1. Figure 2 As shown. The degradation rate of the gel can be evaluated by pH changes. The greater the pH drop, the faster the degradation, and the shorter the efficacy maintenance time.

[0078] Table 1 pH of Examples 1-3 and Comparative Examples 1-4 at different times

[0079]

[0080]

[0081] Through Table 1 and Figure 2 It can be seen that Examples 1-3 can all obtain high-concentration milky white gel preparations, and the pH drop rate of the gel products prepared in Examples 1-3 is slow in the in vitro degradation experiment, indicating that the gel prepared in Examples 1-3 has a longer degradation cycle, thereby maintaining the efficacy for a longer time.

[0082] Comparative Examples 1-4 are compared with the performance of Example 1, and the above results show that:

[0083] In Comparative Example 1, since no low molecular weight copolymer PEG was added 1000 -CPCL 1000 -PEG 1000 , resulting in the high molecular weight polymer block being too long, wherein the polycaprolactone block mainly grows accordingly, and polycaprolactone is a hydrophobic segment, so Comparative Example 1 cannot be completely dissolved in the aqueous solution and cannot form a gel, resulting in the product being unusable.

[0084] The pH of the gel product prepared in Comparative Example 2 decreased rapidly during the period of 0-3 months, and then increased rapidly during the period of 3 to 5 months. This is because the low molecular weight copolymer PEG in Comparative Example 2 1000 -CPCL 1000 -PEG 1000 If the addition amount is too high and the block is too short, the gel will be more easily degraded and a large amount of 6-hydroxyhexanoic acid will be produced, resulting in a rapid decrease in pH. The hydroxyapatite in Comparative Example 2 begins to degrade during 3-5 months to produce calcium ions and phosphate ions, which can react with 6-hydroxyhexanoic acid to neutralize, so that the pH of the system begins to rise again during 3-5 months.

[0085] During the long-term storage of the gel product prepared in Comparative Example 3, the pH change rate was slow during the period of 0-3 months, while the pH of the system dropped rapidly during the period of 3-5 months. This is because the accumulation of 6-hydroxycaproic acid, a degradation product of the copolymer in the system, was not large during the period of 0-3 months, and therefore, the impact on the pH was not very large. However, during the period of 3-5 months, as the storage time increased, the accumulation of 6-hydroxycaproic acid in the system increased, and no hydroxyapatite was added in Comparative Example 3, and the accumulated 6-hydroxycaproic acid could not be neutralized, resulting in a rapid drop in the pH of the system.

[0086] The pH of the gel product prepared in Comparative Example 4 decreased fastest during the period of 0-3 months, and then increased significantly during the period of 3-5 months. This is because the linear structure of PCL in Comparative Example 4 10000 -PEG 10000-PCL 10000 and linear structured PCL 1000 -PEG 1000 -PCL 1000 The degradation rate of the prepared linear copolymer was much higher than that of the cyclic copolymer during the period of 0-3 months. Therefore, a large amount of 6-hydroxyhexanoic acid accumulated in the system during the period of 0-3 months. At 3-5 months, the hydroxyapatite in the system began to degrade, and the generated calcium ions and phosphate ions neutralized the accumulated 6-hydroxyhexanoic acid. Therefore, the pH in the system increased significantly again.

[0087] In summary, the pH change rate diagram during the degradation process of the gel products prepared in Examples 1-3 and Comparative Examples 1-4 can prove that the copolymer with a ring structure has better anti-degradation performance than the copolymer with a linear structure, and the ratio of high molecular weight to low molecular weight copolymers in Examples 1-3 is 2:1 to 5:1. Within this range, a gel of a high concentration preparation can be obtained, and the copolymer concentration range is 45% to 65%. Therefore, the products prepared in Examples 1-3 have a longer action time than the products prepared in other comparative examples. In addition, hydroxyapatite is added in Examples 1-3, which can effectively neutralize 6-hydroxyhexanoic acid in the later stage of injection, greatly reducing the probability of late nonspecific tissue inflammation.

[0088] 3. Cytotoxicity Evaluation

[0089] The cytotoxicity of the products prepared in Examples 1-3 and Comparative Examples 1-5 was evaluated.

[0090] Mouse fibroblasts (NCTC Clone 929, L cell, L-929, derivative of Strain L) were cultured in MEM medium containing antibiotics and 10% serum at 37°C and 5% CO2 incubator. When the cell density reached 80%, they were digested with trypsin and collected for counting. The cell concentration was adjusted to 1×10 5 The above cell suspension was added to a 96-well plate, 100 μL per well, for a total of 1×10 4cells / well, cultured at 37°C, 5% CO2 for 24 hours. After the culture was completed, the culture medium in the culture plate was discarded, and the extract, negative control, positive control and blank control were added in groups, with 8 wells in each group, and cultured in a 37°C, 5% CO2 incubator for 24 hours. Subsequently, the cell culture plate was taken out, the culture medium was discarded, 50 μL (1 mg / mL) of MTT stain was added to each well, and the plate was cultured in a 37°C, 5% CO2 saturated humidity incubator for 2 hours; after the culture was completed, the liquid in the culture plate was discarded, 100 μL of isopropanol was added to each well, the plate was shaken to mix, and the plate was placed in a microplate reader, and the reading was read at 570 nm. For each concentration group and the positive control group, the relative cell survival rate was calculated by the OD value of the blank control group;

[0091] Relative cell survival rate (%) = (average OD value of the test group / average OD value of the blank control group), calculate the cell proliferation rate of each group, and the results are shown in Table 2.

[0092] Table 2 Cell proliferation rate of Examples 1-3 and Comparative Examples 1-5

[0093] Grouping Cell proliferation rate Example 1 99％ Example 2 98％ Example 3 96％ Comparative Example 1 95％ Comparative Example 2 96％ Comparative Example 3 97％ Comparative Example 4 94％ Comparative Example 5 59％

[0094] The cell morphology of each group was observed under an inverted microscope. The cell morphology of Example 1, Comparative Example 5, negative control group and positive control group was as follows: Figure 3 shown.

[0095] The results showed that the cell proliferation rates of Example 1, Comparative Example 5, negative control group and positive control group were 99%, 59%, 100% and 3%, respectively. The cell morphology of the negative control group was similar to that of Example 1, with almost no cell lysis and decreased cell proliferation. There was a significant decrease in cell lysis and cell proliferation in Comparative Example 5, which was due to the introduction of Cu ions into the cyclic copolymer synthesized in Comparative Example 5, resulting in a decrease in cell survival rate. The cell proliferation rates of other Examples 2-3 and Comparative Examples 1-4 were close to those of Example 1, all between 94% and 99%, and the cell morphology was similar to that of Example 1. Therefore, based on the comprehensive cell proliferation rate and cell morphology, it can be determined that the gel preparation prepared by the present invention has no cytotoxicity, indicating that it has high biosafety.

[0096] 4. Tissue Inflammation Test

[0097] Animal experiments were carried out on the gel products prepared in Example 1 and Comparative Example 3.

[0098] The control group was not injected, and the experimental groups were Example 1 (hydroxyapatite was added) and Comparative Example 3 (hydroxyapatite was not added). The experiment used 6-week-old SD rats as the research subjects. After the rat model was prepared, the back skin was shaved, and injections were performed in the 5cm*6cm area (marked by tattooing) on ​​both sides of the spine according to the injection distribution diagram in Table 3, with 200μL injected at each point. The sampling points were March, June and September, and two rats were taken from each sampling point, and two rats were reserved, for a total of eight rats. The breeding temperature was 24±2℃, the humidity was 50±10%, and the light / dark cycle was 12h. The injection point arrangement diagram is shown in the figure Figure 4 shown.

[0099] The animals were killed at 3, 6, and 9 months after injection, and the uninjected skin tissues from the back and the tissues from the test group (Example 1 and Comparative Example 3) were fixed with 10% neutral buffered formalin, then embedded in paraffin and cut into 5 μm thickness for HE staining, and scored according to the inflammatory response scoring table. The therapeutic effect of hydroxyapatite on late specific inflammatory response was evaluated by inflammation. The tissue sections were observed at 100 times using an optical microscope. The results are shown in Figure 2. Figure 5 And as shown in Table 3.

[0100] Table 3 Inflammation score results

[0101]

[0102] exist Figure 5 In, we observed that Comparative Example 3 had dense inflammatory cells (purple) at 6 months and 9 months of injection, which was due to excessive accumulation of 6-hydroxycaproic acid, a degradation product of polycaprolactone, indicating that a significant late nonspecific tissue inflammatory reaction occurred. It can be seen from the scoring results of Table 3 that Comparative Example 3 was scored as 2 points at 6 months and 3 points at 9 months, indicating that the inflammatory reaction in September was more serious than that in June. These inflammatory reactions may cause adverse reactions such as redness and swelling to occur at the injection site in the later stage. However, in Example 1, due to the addition of hydroxyapatite, inflammatory cells did not occur, and according to the scoring results of Table 3, the inflammation score of Example 1 was 0 points in March, June and September, which was due to the hydroxyapatite in Example 1 being degraded into calcium ions and phosphate ions in vivo, which can be neutralized with the degradation product 6-hydroxycaproic acid, reducing the phenomenon of avoiding excessive acid in skin tissue, and solving the probability of occurrence of late nonspecific tissue inflammation.

[0103] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent structural change made to the above embodiment according to the technical essence of the invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing a polycaprolactone-polyethylene glycol copolymer gel, characterized in that: include: A high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, a low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and an additive are added into water and dissolved to obtain a milky white polycaprolactone-polyethylene glycol copolymer gel; the mass ratio of the high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer to the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is (2-5):1; the additive is hydroxyapatite or tricalcium phosphate, the particle size of the additive is not greater than 20 μm, and the mass of the additive accounts for 1% to 5% of the mass of the polycaprolactone-polyethylene glycol copolymer gel.

2. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 1, characterized in that: The high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is prepared from high molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl and high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH as main raw materials; the low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer is prepared from low molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl and low molecular weight bis-mercapto polyethylene glycol HS-PEG-SH as main raw materials.

3. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 2, characterized in that: High molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is prepared by using polycaprolactone with a molecular weight of 4000-20000, and low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is prepared by using polycaprolactone with a molecular weight of less than 4000; high molecular weight bis-thiol polyethylene glycol HS-PEG-SH is prepared by using polyethylene glycol with a molecular weight of 4000-20000, and low molecular weight bis-thiol polyethylene glycol HS-PEG-SH is prepared by using polyethylene glycol with a molecular weight of less than 4000.

4. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 2, characterized in that: The method for synthesizing a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer comprises: placing a high molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl, a high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH and a photoinitiator in a solvent, performing a polymerization reaction under ultraviolet light irradiation, removing the solvent after the polymerization reaction is completed, adding dichloromethane until the mixture is completely dissolved, then adding ether for precipitation purification, filtering and drying to obtain a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer.

5. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 4, characterized in that: The molar ratio of the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl to the high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH is 1:(1-4); the solvent is selected from one of DMF, 1,4-dioxane, dichloromethane, chloroform and DMSO, and the mass of the solvent is 5-20 times the sum of the mass of the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl and the high molecular weight bis-mercapto polyethylene glycol HS-PEG-SH; the photoinitiator is selected from one of DMPA, DEAP and 2-hydroxy-2-methylpropiophenone, and the molar ratio of the photoinitiator to the high molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is (0.1-1.5):1; and the polymerization reaction time is 30 min to 200 min.

6. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 2, characterized in that: The method for synthesizing a low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer comprises: placing a low molecular weight alkynylated polycaprolactone 1-PCL-2alkynyl, a low molecular weight bis-mercapto polyethylene glycol HS-PEG-SH and a photoinitiator in a solvent, performing a polymerization reaction under ultraviolet light irradiation, removing the solvent after the polymerization reaction is completed, adding dichloromethane until the mixture is completely dissolved, then adding ether for precipitation purification, filtering and drying to obtain a high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer.

7. The method for preparing a polycaprolactone-polyethylene glycol copolymer gel according to claim 6, characterized in that: The molar ratio of the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl to the low molecular weight bis-mercapto polyethylene glycol HS-PEG-SH is 1:(1-4); the solvent is selected from one of DMF, 1,4-dioxane, dichloromethane, chloroform and DMSO, and the mass of the solvent is 5-20 times the sum of the mass of the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl and the low molecular weight bis-mercapto polyethylene glycol HS-PEG-SH; the photoinitiator is selected from one of DMPA, DEAP and 2-hydroxy-2-methylpropiophenone, and the molar ratio of the photoinitiator to the low molecular weight alkynyl polycaprolactone 1-PCL-2alkynyl is (0.1-1.5):1; and the polymerization reaction time is 30 min to 200 min.

8. A polycaprolactone-polyethylene glycol copolymer gel prepared by the preparation method as claimed in claim 1.

9. Use of the polycaprolactone-polyethylene glycol copolymer gel according to claim 8 in the preparation of pharmaceutical products, characterized in that: The pharmaceutical products include one or more of antibacterial pharmaceutical products, antihistamine pharmaceutical products, anti-inflammatory pharmaceutical products, immunosuppressant pharmaceutical products, anti-metabolism pharmaceutical products, anesthetic pharmaceutical products, analgesic pharmaceutical products, anticoagulant pharmaceutical products, muscle relaxant pharmaceutical products, protein pharmaceutical products and peptide pharmaceutical products.

10. The use according to claim 9, characterized in that: The preparation method of the pharmaceutical product comprises: adding at least one effective dose of pharmaceutical agent, high molecular weight cyclic polycaprolactone-polyethylene glycol copolymer, low molecular weight cyclic polycaprolactone-polyethylene glycol copolymer and additives into water and mixing them evenly.

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