Preparation method of particle size controllable multi-arm polycaprolactone microspheres for injection

Abstract

The invention provides a preparation method of particle-controllable multi-arm polycaprolactone microspheres for injection, which comprises the following steps of: synthesizing multi-arm polycaprolactone with narrow molecular weight distribution through epsilon-caprolactone ring-opening polymerization reaction under the action of an organic tin catalyst by adopting an initiator gluconic acid; the multi-arm polycaprolactone microspheres with concentrated particle size distribution can be obtained in the microsphere preparation process; the multi-arm polycaprolactone microspheres are prepared by using a solvent evaporation method, rhamnolipid is used as a surfactant, the microspheres prepared by matching with an ultrasonic technology are uniform in particle size, the polycaprolactone composite gel prepared from the polycaprolactone microspheres is good in storage stability, and the microspheres cannot be adhered and aggregated after being stored for 6 months, and can still be smoothly injected.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for preparing multi-arm polycaprolactone microspheres with controllable particle size for injection. Background Art

[0002] Minimally invasive cosmetic injections have become increasingly popular with patients seeking facial rejuvenation in recent years due to their advantages of less trauma and quick recovery. Ideal soft tissue fillers should have long-lasting effects, be safe, biocompatible, biodegradable, and not cause inflammatory reactions.

[0003] Polycaprolactone (PCL) is a new type of biocompatible and biodegradable polymeric polyester. It can be used as a soft tissue filler by changing its structure and morphology and micronization technology. Mixing polycaprolactone with a suitable gel or other preparation and injecting it into the skin surface or depression can effectively fill wrinkles, repair scars, increase facial three-dimensionality, etc. This filler has good biocompatibility and plasticity, and gradually degrades and is metabolized in the body. For example, a method for preparing polycaprolactone microspheres disclosed in patent CN113769164B includes: contacting a hydroxypropyl methylcellulose aqueous solution and a dichloromethane solution of polycaprolactone and simultaneously shearing and emulsifying to form a shear emulsified mixed solution; contacting and mixing a polyvinyl alcohol aqueous solution with the shear emulsified mixed solution and heating it until the dichloromethane is completely volatilized; filtering to obtain microspheres of 28μm-100μm. Patent CN115531607B discloses a method for preparing mixed biodegradable material microspheres and a composite preparation, wherein the composite preparation comprises the following raw materials: microspheres and gel; the materials of the microspheres are any two of PLLA, PLGA, and PCL; the components of the gel include one or more of sodium hyaluronate, collagen, sodium carboxymethyl cellulose, chitosan, and sodium alginate; the mass fraction of the microspheres in the composite preparation is 10-100%.

[0004] Although polycaprolactone microspheres in the above technologies have many advantages such as biodegradability, biocompatibility, promotion of cell growth and tissue regeneration, they generally have wide and uneven particle size distribution, and larger particles will settle and be unevenly distributed in the tissue, affecting the filling effect, resulting in local depressions or lumps, and in severe cases, they cannot be injected smoothly. Therefore, it is necessary to develop a polycaprolactone microsphere with controllable particle size for injection. Summary of the invention

[0005] In order to solve the defects of the wide distribution and uneven particle size distribution of polycaprolactone microspheres in the prior art, which lead to poor filling effect, the present invention provides a preparation method and application of multi-arm polycaprolactone microspheres with controllable particle size for injection. The present invention uses gluconic acid as an initiator, and synthesizes multi-arm polycaprolactone with a narrow molecular weight distribution through the ring-opening polymerization reaction of ε-caprolactone under the action of an organic tin catalyst, which helps to obtain multi-arm polycaprolactone microspheres with concentrated particle size distribution during the microsphere preparation process; multi-arm polycaprolactone microspheres are prepared by solvent evaporation method, and rhamnolipid is used as a surfactant, and the microspheres prepared by ultrasonic technology have uniform particle size.

[0006] In order to achieve the above objectives, the following technical solutions are adopted:

[0007] A method for preparing controllable multi-arm polycaprolactone microspheres for injection comprises the following steps:

[0008] 1) adding gluconic acid, an organotin catalyst solution and ε-caprolactone into a reaction kettle, evacuating the air to remove the air, filling the reaction kettle with an inert gas, then closing the reaction kettle under vacuum, heating the reaction kettle for reaction, cooling the reaction kettle to room temperature after the reaction is completed, redissolving the solid product, reprecipitating, filtering, washing and drying the solid product to obtain polycaprolactone;

[0009] 2) dissolving polycaprolactone in an organic solvent to obtain an oil phase, dispersing rhamnolipid in water to obtain an aqueous phase, dropping the oil phase into the aqueous phase, ultrasonically dispersing, heating, continuing ultrasonication, filtering, washing, and freeze-drying to obtain polycaprolactone microspheres.

[0010] Step 1) The organic tin catalyst solution is mixed with organic tin and a solvent, the organic tin is selected from one or a combination of stannous octoate and stannous acetate, and the solvent is selected from one or a combination of toluene and benzene. The concentration of the organic tin catalyst solution is 5-10mmol / L. The temperature is raised to 120-150°C, the reaction time is 4-24h, preferably 4.5-7h, and the number of vacuum-filling inert gas is 1-5 times. The redissolution is to dissolve the solid product in a solvent, and the solvent is selected from one or a combination of two or more of dichloromethane, chloroform, toluene, and benzene. The vacuum condition is 10-20Pa. The reprecipitation is to pour the mixture obtained by redissolution into a precipitation solvent, and the precipitation solvent is selected from one or a combination of two or more of ether, methanol, and ethanol. The washing is 1-3 times with ethanol. The drying is dried at 60-100°C to constant weight. The molar ratio of gluconic acid, organotin and ε-caprolactone is 3-5: 0.1-0.3: 100. The weight average molecular weight of the polycaprolactone is 10000-30000, and the molecular weight distribution coefficient is 1.08-1.20.

[0011] Step 2) The organic solvent is selected from one or a combination of two or more of dichloromethane, chloroform, ethyl acetate, acetone, and tetrahydrofuran. The mass fraction of polycaprolactone in the oil phase is 10-15wt%. The mass fraction of rhamnolipid in the water phase is 1-2wt%. The volume ratio of the oil phase to the water phase is 1:7-10. The oil phase is dripped into the water phase within 20-60min. The ultrasonic dispersion is ultrasonic for 10-60min under the conditions of power 1000-2000W and frequency 50-60kHz. The temperature is raised to 30-40°C, and the continued ultrasonic power is 800-1500W, frequency 50-60kHz, and time is 1-2h. The washing is washed with water 1-3 times. The freeze-drying conditions are to freeze at -50°C to -15°C for 6-24h, put it in a freeze dryer, and dry it at a vacuum degree of 5-80Pa for 20-28h. The HLB value of the rhamnolipid is 10-15.

[0012] The present invention uses rhamnolipid as a dispersant, which is a non-toxic biosurfactant with good chemical stability, good biocompatibility and biodegradability. Its hydrophilic-lipophilic balance value, i.e., HLB value, is 10-15, which shows lower hydrophilicity than polyethylene glycol. Although it can prepare a more stable polycaprolactone emulsion system with fine droplets, it is not suitable for preparing small and uniform polycaprolactone microspheres by conventional solvent evaporation method.

[0013] Because in the process of preparing polycaprolactone microspheres by solvent evaporation, as the small molecular organic solvent in the small droplets evaporates, the low hydrophilicity of rhamnolipid causes the interface of its oil-water phase to become unstable, the droplets aggregate and merge, and small bubbles are formed. Ordinary mechanical stirring cannot overcome the problem of droplet aggregation and merging, and may even aggravate the aggregation and merging, resulting in uneven particle size of the prepared microspheres.

[0014] Ultrasonic waves can produce a strong cavitation effect, which is manifested in the formation, growth and rupture of cavitation microbubbles in the solution. The cavitation microbubbles burst instantly to produce extremely short strong pressure pulses, local hot spots and strong microjets. The present invention adopts ultrasonic dispersion and rhamnolipid to prepare polycaprolactone microspheres in coordination, which can not only make the bubbles on the surface of polycaprolactone microspheres burst and increase the surface coverage of rhamnolipid on the microspheres, but also help to cooperate with rhamnolipid to form smaller polycaprolactone microspheres with more uniform particle size. If a highly hydrophilic dispersant such as polyethylene glycol and carboxymethyl cellulose is used, it will cause excessive aggregation of polycaprolactone microspheres in the aqueous phase, thereby failing to form stable and uniform small droplets. Although ultrasound helps to disperse, the coverage of highly hydrophilic polyethylene glycol on the surface of polycaprolactone microspheres is low, and the span value of the prepared polycaprolactone microspheres is large, and the particle size distribution is still wide.

[0015] The present invention also provides a polycaprolactone composite gel for injection, comprising the following raw materials: 12.5-17.5 parts by mass of the above-mentioned polycaprolactone microspheres, 1-2 parts by mass of a gelling agent, 8-20 parts by mass of a phosphate buffer and an osmotic pressure regulator; the osmotic pressure of the polycaprolactone composite gel for injection is 250-400mOsmol / kg.

[0016] The polycaprolactone microspheres have a D50 of 25-40 μm and a span value of 0.5-0.8.

[0017] The phosphate buffer has a pH of 7.0-7.4 and an osmotic pressure of 250-350 mOsmol / kg. The phosphate buffer can be commercially available or homemade, and is specifically prepared by mixing sodium phosphate dodecahydrate and disodium hydrogen phosphate dodecahydrate, adding water to dissolve and dilute, and adjusting the pH with phosphoric acid or sodium hydroxide solution.

[0018] The osmotic pressure of the polycaprolactone composite gel for injection is adjusted by adding an osmotic pressure regulator solution, wherein the osmotic pressure regulator solution is a mixture of an osmotic pressure regulator and water, wherein the osmotic pressure regulator accounts for 0.7-1.35wt%, and the osmotic pressure regulator is selected from one or a combination of two or more of potassium chloride, sodium chloride, and glycerol.

[0019] The gel is selected from one or a combination of two or more of sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium hyaluronate, chitosan and sodium alginate.

[0020] The present invention also provides a method for preparing the above-mentioned polycaprolactone composite gel for injection, comprising the following steps:

[0021] The gelling agent and phosphate buffer are mixed evenly, polycaprolactone microspheres are added and mixed evenly, and an osmotic pressure regulator is added to adjust the osmotic pressure to obtain a polycaprolactone composite gel for injection.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The invention adopts gluconic acid as an initiator, and synthesizes multi-arm polycaprolactone with narrow molecular weight distribution through ring-opening polymerization of ε-caprolactone under the action of an organic tin catalyst, which is helpful to obtain multi-arm polycaprolactone microspheres with concentrated particle size distribution in the process of microsphere preparation; the multi-arm polycaprolactone microspheres are prepared by a solvent volatilization method, and rhamnolipid is used as a surfactant, and the microspheres prepared by ultrasonic technology have uniform particle size.

[0024] The inventors found that using gluconic acid as an initiator can increase the polymerization reaction rate of ε-caprolactone, and it is speculated that gluconic acid helps the organotin catalyst to form a highly active substance that initiates polymerization. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific embodiments, but is not limited to the contents of the specification. Unless otherwise specified, the "parts" described in the embodiments of the present invention are all parts by weight. The reagents used are all commercially available reagents in the art.

[0026] Rhamnolipid was purchased from Ruijie Biotechnology with an HLB value of 11.2 and model 6FA.

[0027] Phosphate buffer was purchased from Wuhan Pronosai Life Science Co., Ltd., with a pH of 7.2, an osmotic pressure of 280 mOsmol / kg, and phosphate components of sodium phosphate dodecahydrate and disodium hydrogen phosphate dodecahydrate.

[0028] Polyethylene glycol with a number average molecular weight of 400 was purchased from Jiangsu Yutong Biotechnology Co., Ltd.

[0029] Example 1

[0030] 1) 5 mol of gluconic acid, 20 L of 5 mmol / L stannous octoate solution (solvent: toluene), and 100 mol of ε-caprolactone were added to a reaction kettle, and the air was removed by vacuum and nitrogen was filled for 3 times. Then, the reaction kettle was closed under a vacuum degree of 20 Pa, and the temperature was raised to 120° C. to react for 4.5 hours. After the reaction was completed, the reaction kettle was cooled to room temperature, and the solid product was redissolved in dichloromethane. The redissolved mixture was poured into ether for reprecipitation, filtered, washed with ethanol 3 times, and dried at 60° C. to constant weight to obtain polycaprolactone;

[0031] 2) The polycaprolactone obtained in step 1) was dissolved in dichloromethane to obtain an oil phase with a polycaprolactone concentration of 15 wt%, and rhamnolipid was dispersed in water to obtain an aqueous phase with a rhamnolipid concentration of 2 wt%. The oil phase was dripped into the aqueous phase at a volume ratio of 1:10 for 30 min. The mixture was first ultrasonicated at 2000 W and a frequency of 60 kHz for 60 min, and then heated to 40° C., and then ultrasonicated at a power of 1000 W and a frequency of 50 kHz for 1 h. The mixture was filtered and washed with water for 3 times. After freezing at -50° C. for 24 h, the mixture was placed in a freeze dryer and dried at a vacuum degree of 40 Pa for 24 h to obtain polycaprolactone microspheres.

[0032] 3) 2 g of sodium carboxymethyl cellulose and 20 g of phosphate buffer were mixed evenly, 17.5 g of the polycaprolactone microspheres obtained in step 2) were added and mixed evenly, and 1000 g of a 1.35 wt % osmotic pressure regulator solution prepared by mixing glycerol and water was added to adjust the osmotic pressure to obtain a polycaprolactone composite gel for injection with an osmotic pressure of 400 mOsmol / kg.

[0033] Example 2

[0034] The rest is the same as Example 1, except that in step 1), the amount of gluconic acid used is 3 mol.

[0035] Example 3

[0036] The rest is the same as Example 1, except that, step 2) is to dissolve the polycaprolactone obtained in step 1) in dichloromethane to obtain an oil phase with a polycaprolactone concentration of 15wt%, disperse rhamnolipid in water to obtain an aqueous phase with a rhamnolipid concentration of 2wt%, and drip the oil phase into the aqueous phase at a volume ratio of 1:10 for 30 minutes. First, ultrasonicate at 1500W and a frequency of 50kHz for 50 minutes, heat to 40°C, continue ultrasonicate at a power of 800W and a frequency of 50kHz for 2h, filter, wash with water 3 times, freeze at -50°C for 24h, put into a freeze dryer, and dry at a vacuum degree of 40Pa for 24h to obtain polycaprolactone microspheres.

[0037] Example 4

[0038] The rest is the same as Example 1, except that, step 2) is to dissolve the polycaprolactone obtained in step 1) in dichloromethane to obtain an oil phase with a polycaprolactone concentration of 10wt%, disperse rhamnolipid in water to obtain an aqueous phase with a rhamnolipid concentration of 1wt%, and drip the oil phase into the aqueous phase at a volume ratio of 1:7 for 30 minutes. The mixture is ultrasonicated at 2000W and a frequency of 50kHz for 60 minutes, heated to 40°C, and ultrasonicated at 800W and a frequency of 60kHz for 2 hours. The mixture is filtered and washed with water three times, frozen at -50°C for 24 hours, and then placed in a freeze dryer and dried at a vacuum degree of 40Pa for 24 hours to obtain polycaprolactone microspheres.

[0039] Example 5

[0040] The rest is the same as Example 1, except that, in step 2), the oil phase is dropped into the water phase at a volume ratio of 1:5.

[0041] Example 6

[0042] 1) 3 mol of gluconic acid, 20 L of 5 mmol / L stannous octoate solution (solvent: toluene), and 100 mol of ε-caprolactone were added to a reactor, and the air was removed by vacuum and nitrogen was filled for 3 times. Then, the reactor was closed under a vacuum degree of 20 Pa, and the temperature was raised to 120° C. to react for 4.5 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solid product was redissolved in dichloromethane. The redissolved mixture was then poured into ether for reprecipitation, filtered, and dried at 60° C. to constant weight to obtain polycaprolactone;

[0043] 2) The polycaprolactone obtained in step 1) was dissolved in dichloromethane to obtain an oil phase with a polycaprolactone concentration of 10 wt%, and rhamnolipid was dispersed in water to obtain an aqueous phase with a rhamnolipid concentration of 2 wt%. The oil phase was dripped into the aqueous phase at a volume ratio of 1:7 for 60 min, and ultrasonicated at 2000 W and a frequency of 60 kHz for 10 min, and then ultrasonicated at 1500 W and a frequency of 60 kHz for 30 min, and the temperature was raised to 40° C., and ultrasonicated at a power of 1000 W and a frequency of 50 kHz for 1 h, filtered, washed with water 3 times, frozen at -50° C. for 24 h, placed in a freeze dryer, and dried at a vacuum degree of 40 Pa for 24 h to obtain polycaprolactone microspheres.

[0044] 3) 2 g of sodium hyaluronate and 10 g of phosphate buffer were mixed evenly, 12.5 g of the polycaprolactone microspheres obtained in step 2) were added and mixed evenly, and 1500 g of a 0.7 wt % osmotic pressure regulator solution prepared by mixing glycerol and water was added to adjust the osmotic pressure to obtain a polycaprolactone composite gel for injection with an osmotic pressure of 250 mOsmol / kg.

[0045] Comparative Example 1

[0046] The rest is the same as Example 1, except that in step 2), mechanical stirring at 200 r / min for 12 h is used instead of ultrasound.

[0047] Specifically, step 2) the polycaprolactone obtained in step 1) is dissolved in dichloromethane to obtain an oil phase with a polycaprolactone concentration of 15wt%, rhamnolipid is dispersed in water to obtain an aqueous phase with a rhamnolipid concentration of 2wt%, the oil phase is dripped into the aqueous phase at a volume ratio of 1:10 for 30 minutes, mechanically stirred at a speed of 200r / min for 12 hours, filtered, washed with water 3 times, frozen at -50°C for 24 hours, placed in a freeze dryer, and dried at a vacuum degree of 40Pa for 24 hours to obtain polycaprolactone microspheres.

[0048] Comparative Example 2

[0049] The rest is the same as Example 1, except that in step 2), an equal mass of polyethylene glycol (number average molecular weight 400) is used to replace rhamnolipid.

[0050] Comparative Example 3

[0051] The rest is the same as Example 1, except that in step 1), an equimolar amount of sorbitol is used instead of gluconic acid.

[0052] Comparative Example 4

[0053] The rest is the same as Example 1, except that in step 1), an equimolar amount of sorbitol is used to replace gluconic acid, and the reaction time is 8 h at 120°C.

[0054] The polycaprolactone prepared in step 1) of the above embodiment and comparative example was subjected to 1 performance test; the microspheres prepared in step 2) were subjected to the following 2 performance tests; the composite gel prepared in step 3) was subjected to 3 performance tests:

[0055] 1. GPC method for determining molecular weight: sample mass concentration is 2.5 mg / mL, mobile phase is DMF, flow rate is 1 mL / min, PMMA is used as standard, and a differential refractometer is used to detect the relative molecular mass and polydispersity index PDI of polycaprolactone. The larger the PDI, the wider the molecular weight distribution, and the smaller the PDI, the more uniform the molecular weight distribution.

[0056] 2. Particle size analysis of microspheres: Take 50 mg of microspheres and two drops of glycerol and mix them evenly. Use a laser particle size analyzer to measure D10, D50, and D90, and calculate the span value = (D90-D10) / D50. The smaller the span value, the narrower the particle size distribution and the more uniform the microspheres.

[0057] 3. Storage stability test: Place the composite gel at 40°C for 0 and 6 months, draw the sample with a 1 mL syringe, put on a 27G needle, push the sample out of the needle, and check the needleability. The number of attempts is 50, and the number of complete passes is recorded.

[0058] Table 1 Performance test results

[0059]

[0060] It can be seen from Table 1 that Example 1 and Comparative Examples 3-4 use gluconic acid as a small molecule polyol and can significantly shorten the reaction time and reduce the molecular weight distribution coefficient. Although no further verification has been done, it can be inferred from the catalytic mechanism of organotin catalysts that the structure of gluconic acid helps the organotin catalyst to form a highly active substance that initiates polymerization.

[0061] The polycaprolactone prepared by the present invention has a narrow molecular weight distribution, and the polycaprolactone microspheres have uniform particle sizes, narrow particle size distribution, and a small span value. After the composite gel is stored for 6 months, the microspheres will not adhere and aggregate, and the number of complete passes of a 27G needle is high.

[0062] It can be seen from Example 1 and Comparative Example 2 that the higher hydrophilicity of polyethylene glycol will lead to its excessive aggregation in the aqueous phase, thereby failing to form stable, uniform small droplets. The prepared polycaprolactone microspheres have a larger D50, a larger span value, and a wider particle size distribution.

[0063] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing controllable multi-arm polycaprolactone microspheres for injection, characterized in that: The method comprises the following steps: 1) adding gluconic acid, an organic tin catalyst solution and ε-caprolactone into a reaction kettle, evacuating the air to remove the air, filling the reaction kettle with an inert gas, then closing the reaction kettle under vacuum conditions, heating the reaction kettle for reaction, cooling the reaction kettle to room temperature after the reaction is completed, re-dissolving the solid product, re-precipitating, filtering, washing and drying the solid product to obtain polycaprolactone; 2) dissolving polycaprolactone in an organic solvent to obtain an oil phase, dispersing rhamnolipid in water to obtain an aqueous phase, dropping the oil phase into the aqueous phase, ultrasonically dispersing, heating, continuing ultrasonication, filtering, washing, and freeze-drying to obtain polycaprolactone microspheres.

2. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 1), the organotin catalyst solution is prepared by mixing organotin with a solvent, the organotin is selected from stannous octoate and stannous acetate or a combination of two, and the solvent is selected from toluene and benzene or a combination of two; the concentration of the catalyst solution is 5-10 mmol / L.

3. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 1), the temperature is raised to 120-150° C., and the reaction time is 4-24 h, preferably 4.5-7 h.

4. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 1), the molar ratio of gluconic acid, organotin and ε-caprolactone is 3-5:0.1-0.3:

100.

5. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 1), the weight average molecular weight of the polycaprolactone is 10000-30000, and the molecular weight distribution coefficient is 1.08-1.

20.

6. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 2), the ultrasonic dispersion is carried out at a power of 1000-2000 W and a frequency of 50-60 kHz for 10-60 min; the temperature is raised to 30-40° C., and the ultrasonic power is continued at 800-1500 W, a frequency of 50-60 kHz, and a time of 1-2 h.

7. The method for preparing the controllable multi-arm polycaprolactone microspheres for injection according to claim 1, characterized in that: In step 2), the HLB value of the rhamnolipid is 10-15; the mass fraction of polycaprolactone in the oil phase is 10-15wt%; the mass fraction of rhamnolipid in the water phase is 1-2wt%; and the volume ratio of the oil phase to the water phase is 1:7-10.

8. A polycaprolactone composite gel for injection, characterized in that: The invention comprises the following raw materials: 12.5-17.5 parts by weight of the polycaprolactone microspheres according to any one of claims 1 to 7, 1-2 parts by weight of a gelling agent, 8-20 parts by weight of a phosphate buffer and an osmotic pressure regulator; and the osmotic pressure of the polycaprolactone composite gel for injection is 250-400 mOsmol / kg.

9. The polycaprolactone composite gel for injection according to claim 8, characterized in that: The D50 of the polycaprolactone microspheres is 25-40 μm, and the span value is 0.5-0.8; the pH of the phosphate buffer is 7.0-7.4, and the osmotic pressure is 250-350 mOsmol / kg.

10. The method for preparing the polycaprolactone composite gel for injection according to claim 8, characterized in that: The steps include: The gelling agent and phosphate buffer are mixed evenly, polycaprolactone microspheres are added and mixed evenly, and an osmotic pressure regulator is added to adjust the osmotic pressure to obtain a polycaprolactone composite gel for injection.

Images