Sterilization process of polycaprolactone copolymer solution

Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to a sterilization process of a polycaprolactone copolymer solution, which comprises the following steps: S1, dispersing a polycaprolactone copolymer in a buffer salt system, heating and stirring to obtain a homogeneous solution; s2, adding the homogeneous solution into a filling container, placing the filling container in a sterilization chamber, raising the temperature to 111-114 DEG C, raising the pressure to 0.1-0.15 MPa, ensuring that F0 is greater than 12, continuously reacting, and then reducing the temperature and the pressure to normal temperature and normal pressure to obtain a polycaprolactone copolymer solution; and the polycaprolactone copolymer is a block copolymer and comprises a polycaprolactone-methoxy polyethylene glycol diblock copolymer or a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, and the weight-average molecular weight ratio of polycaprolactone to polyethylene glycol chain segments is (1: 4)-(5: 1). The mass percentage of the polycaprolactone copolymer is 5-50% of the mass percentage of the polycaprolactone copolymer solution.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and particularly relates to a sterilization process of a polycaprolactone copolymer solution. Background Art

[0002] Polycaprolactone copolymers, due to their excellent biocompatibility, biodegradability, and controlled drug release, are widely used in biopharmaceutical applications such as drug carriers and soft tissue fillers. However, the clinical application of these materials is highly dependent on the safety of sterilization processes, which require thorough microbial sterilization while maintaining the structural stability and functional activity of the copolymer solution.

[0003] The current mainstream sterilization methods include irradiation sterilization, filtration sterilization, high temperature and high pressure steam sterilization (moist heat sterilization), etc. However, these methods all have significant defects due to the characteristics of polycaprolactone copolymer solutions:

[0004] (1) Irradiation sterilization: Copolymers are easily oxidized and degraded under high-energy radiation, and have a significant impact on the stability of materials containing polyethylene glycol segments. The subsequent solution preparation process must ensure the sterility of the process, which places strict requirements on the production environment; (2) Filtration sterilization: Limited by the micelle particle size (needed to be less than 0.22 μm), larger micelles are prone to interception loss or filter membrane clogging, and viruses cannot be removed; (3) High-temperature and high-pressure steam sterilization: At conventional sterilization temperature (121°C), the microphase separation of the hydrophobic and hydrophilic segments of the copolymer is disturbed, the micelles disintegrate, the particle size increases or aggregates, and the dispersibility deteriorates rapidly.

[0005] Polycaprolactone copolymer solutions are significantly temperature-sensitive. During high-temperature sterilization, polycaprolactone copolymers with low glass transition temperatures enter a viscous flow state, with highly mobile molecular chains and a disrupted balance between hydrophobic and hydrophilic segments. This leads to a dramatic dynamic reorganization of the micelle structure, which is the core reason for micelle aggregation after moist heat sterilization. To address this problem, the existing technologies have attempted to improve the following solutions: (1) adding stabilizers: for example, CN 114699554A and CN 115531608A add stabilizing substances such as sodium hyaluronate and sodium carboxymethyl cellulose to the micelle solution to inhibit micelle aggregation, but this significantly increases the complexity of the formula and the production cost; (2) existing low-temperature sterilization solutions: for example, CN 119303123 A performs sterilization in a low-temperature range (110-114°C & 15-60min), but F0≤12. According to the national requirements for excessive sterilization of injections by wet heat sterilization, F0≥12 is required. Obviously, this solution cannot meet the sterility requirements, and the entire sterilization process relies on high pressure (0.2-0.3MPa) to inhibit micelle expansion, which has problems such as low safety and strong equipment dependence.

[0006] Therefore, how to overcome the defects caused by the temperature sensitivity of polycaprolactone copolymers during the sterilization process is a technical problem that urgently needs to be solved in this field.

[0007] It should be noted that the above information disclosed in this background technology section is only used to understand the background technology of the present application concept, and therefore, the above description is not considered to constitute information of the prior art. Summary of the Invention

[0008] The embodiments of the present disclosure at least provide a sterilization process for a polycaprolactone copolymer solution.

[0009] In a first aspect, an embodiment of the present disclosure provides a sterilization process for a polycaprolactone copolymer solution, comprising the following steps: S1, dispersing the polycaprolactone copolymer in a buffer salt system, heating and stirring to obtain a homogeneous solution; S2, adding the homogeneous solution to a filling container, placing it in a sterilization chamber, heating to 111-114°C, increasing the pressure to 0.1-0.15 MPa, ensuring that F0>12, continuing the reaction, and then cooling and reducing the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution; and, the polycaprolactone copolymer is a block copolymer, including a polycaprolactone-methoxypolyethylene glycol diblock copolymer or a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, wherein the ratio of the weight-average molecular weight of the polycaprolactone to the polyethylene glycol segment is 1:4-5:1; the mass percentage of the polycaprolactone copolymer is 5-50% of the polycaprolactone copolymer solution.

[0010] In an optional embodiment, the weight average molecular weight of the polycaprolactone copolymer is 10 to 40 kDa; wherein the weight average molecular weight of the polycaprolactone segment is 2 to 30 kDa, and the weight average molecular weight of the polyethylene glycol segment is 5 to 10 kDa.

[0011] In an optional embodiment, the heating temperature of the heating and stirring in step S1 is 60-105° C., the stirring speed is 500-1000 rpm, and the reaction time is 30-120 min.

[0012] In an optional embodiment, the buffer salt system includes any one of water for injection, phosphate buffer, citrate buffer, sodium chloride solution, or a combination thereof.

[0013] In an optional embodiment, the filling container in step S2 includes a prefilled syringe or a vial.

[0014] In a second aspect, the embodiments of the present disclosure also provide a polycaprolactone copolymer solution, which is prepared using the sterilization process as described above.

[0015] In an optional embodiment, the polycaprolactone copolymer in the solution includes large-particle micelles with a particle size D90 ≥ 220 nm.

[0016] In an optional embodiment, the pH value of the solution ranges from 7.0 to 7.5.

[0017] In an optional embodiment, the osmotic pressure of the solution is in the range of 300 mOsmol / kg to 350 mOsmol / kg.

[0018] In a third aspect, embodiments of the present disclosure further provide a polycaprolactone copolymer solution prepared by the aforementioned process or the use of the aforementioned polycaprolactone copolymer solution in the fields of drug carriers, soft tissue fillers, and the like.

[0019] The beneficial effect of the present invention is that the sterilization process of the polycaprolactone copolymer solution is based on the temperature-sensitive properties of the polycaprolactone copolymer and its phase change mechanism. By precisely controlling the copolymer segment ratio, polymer solution concentration and moist heat sterilization parameters, the hydrophilic-hydrophobic interaction is balanced and crystal aggregation is inhibited, thereby achieving the technical goal of uniform dispersion, no sedimentation and long-term stable preservation of the solution after sterilization; the process avoids the disintegration or aggregation of micelles and ensures that the solution after sterilization is uniformly dispersed and stable for a long time, and there is no need to add stabilizers. It also uses mild pressure to adapt conventional equipment while taking into account large-particle micelles, which is suitable for large-scale production.

[0020] Other features and advantages of the present invention will be described in the following description, and in part will become apparent from the description, or understood by practicing the present invention. The purpose and other advantages of the present invention are realized and obtained by the structures particularly pointed out in the description and the drawings.

[0021] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, preferred embodiments are given below and described in detail with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0023] Figure 1 The F0 value thermodynamic diagram under different temperature-time combinations provided in the embodiment of the present disclosure is used to calibrate the effective sterilization zone (F0 ≥ 12);

[0024] Figure 2 Macroscopic photos and microscopic morphology images of Example 21 provided in the embodiments of the present disclosure;

[0025] Figure 3Macroscopic photos and microscopic morphology images of Control Example 4 provided for the embodiments of the present disclosure. DETAILED DESCRIPTION

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0027] As used herein, the phrases "in one embodiment," "according to one embodiment," "in some embodiments," and the like generally refer to the fact that the particular feature, structure, or characteristic following the phrase may be included in at least one embodiment of the present disclosure. Thus, a particular feature, structure, or characteristic may be included in more than one embodiment of the present disclosure, such that these phrases do not necessarily refer to the same embodiment. As used herein, the terms "example," "exemplary," and the like are used to "serve as an example, instance, or illustration." Any implementation, aspect, or design described herein as "example" or "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations, aspects, or designs. Instead, the use of the terms "example," "exemplary," and the like is intended to present concepts in a concrete manner.

[0028] Herein, example embodiments of the present disclosure will be described in more detail with reference to the accompanying drawings. As used herein, expressions such as "at least one of..." when following a list of elements modify the entire list of elements, rather than modifying individual elements in the list. For example, the expression "at least one of a, b, and c" should be understood to include only a, only b, only c, both a and b, both a and c, both b and c, or all of a, b, and c.

[0029] The terms used herein are only used to describe specific exemplary configurations and are not intended to be limiting. As used herein, the singular articles "a", "an" and "the" may also be intended to include plural forms, unless otherwise clearly indicated herein. The terms "comprise", "include" and "have" are inclusive and therefore specify the presence of features, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components and / or combinations thereof. The method steps, processes and operations described herein should not be interpreted as necessarily requiring them to be performed in the particular order discussed or shown, unless specifically identified as an execution order. Additional or alternative steps may be adopted.

[0030] In this application, if Figure 1As shown in the figure, the F0 value is the standard sterilization time, which is the equivalent sterilization time given to a product at 121°C during the sterilization process. In this way, during the sterilization process, as long as the temperature and time of the sterilized items are recorded, the F0 value can be calculated using the formula.

[0031] During the existing high-temperature and high-pressure sterilization process, the hydrogen bonding between the hydrophilic segments and water molecules weakens during the heating process, and the hydrophobic segments dominate the aggregation, resulting in a sol-gel phase transition. At the same time, the increase in temperature exacerbates the hydrophobicity and crystallization tendency of the polycaprolactone block, prompting the formation of dense crystalline domains within / between molecules, destroying the stability of the hydration network.

[0032] In addition, high solution concentration further accelerates network collapse by strengthening the aggregation of hydrophobic segments and the growth of crystalline domains.

[0033] Therefore, under conventional high-temperature and high-pressure sterilization conditions, the synergistic effects of hydrophobic enhancement, crystallization induction, and concentration-dependent aggregation lead to micelle dehydration and system sedimentation.

[0034] The defects in the above solutions are the results obtained by the inventors after practice and careful research. Therefore, the process of discovering the above problems and the solutions proposed by this disclosure for the above problems below should be the contributions made by the inventors to this disclosure during the disclosure process.

[0035] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not need to be further defined or explained in subsequent drawings.

[0036] The following embodiments of the present invention are described in detail with reference to the accompanying drawings. In the absence of conflict, the following embodiments and features therein may be combined with each other.

[0037] An embodiment of the present disclosure provides a sterilization process for a polycaprolactone copolymer solution, comprising the following steps: S1, dispersing the polycaprolactone copolymer in a buffer salt system, heating and stirring to obtain a homogeneous solution; S2, adding the homogeneous solution to a filling container, placing the container in a sterilization chamber, heating to 111-114°C, increasing the pressure to 0.1-0.15 MPa, ensuring that F0>12, continuing the reaction, and then cooling and reducing the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution; and, the polycaprolactone copolymer is a block copolymer, comprising a polycaprolactone-methoxypolyethylene glycol diblock copolymer or a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, wherein the ratio of the weight-average molecular weight of the polycaprolactone to the polyethylene glycol segment is 1:4-5:1; and the mass percentage of the polycaprolactone copolymer is 5-50% of the polycaprolactone copolymer solution.

[0038] In some embodiments, specifically, the weight average molecular weight of the polycaprolactone copolymer is 10-40 kDa, wherein the weight average molecular weight of the polycaprolactone segment is 2-30 kDa, and the weight average molecular weight of the polyethylene glycol segment is 5-10 kDa.

[0039] In some embodiments, specifically, the heating temperature of the heating and stirring in step S1 is 60-105° C., the stirring speed is 500-1000 rpm, and the reaction time is 30-120 min.

[0040] In some embodiments, specifically, the buffer salt system includes any one of water for injection, phosphate buffer, citrate buffer, sodium chloride solution, or a combination thereof.

[0041] In some embodiments, specifically, the filling container in step S2 includes a prefilled syringe or a vial.

[0042] The presently disclosed embodiment also provides a polycaprolactone copolymer solution, which is prepared using the sterilization process described above.

[0043] The embodiments of the present disclosure also provide a polycaprolactone copolymer solution prepared by the process described above, or the use of the polycaprolactone copolymer solution described above in the fields of drug carriers, soft tissue fillers, etc.

[0044] Example 1

[0045] Accurately weigh 4 g of PCL2k-mPEG8k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 90°C and stir at 500 rpm for 30 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0046] Example 2

[0047] Accurately weigh 5 g of PCL2k-mPEG8k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 90°C and stir at 500 rpm for 30 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0048] Example 3

[0049] Accurately weigh 3 g of PCL2k-PEG8k-PCL2k, add 10 mL of citric acid buffer, and stir thoroughly until completely dispersed; heat the dispersion to 90°C and stir at 1000 rpm for 120 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0050] Example 4

[0051] Accurately weigh 4 g of PCL2k-PEG8k-PCL2k, add 10 mL of citric acid buffer, and stir thoroughly until completely dispersed; heat the dispersion to 90°C and stir at 1000 rpm for 120 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0052] Example 5

[0053] Accurately weigh 2.5 g of PCL5k-mPEG5k, add 10 mL of water for injection, and stir thoroughly until completely dispersed; heat the dispersion to 80°C and stir at 500 rpm for 40 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 112°C, 0.12 MPa for 96 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0054] Example 6

[0055] Accurately weigh 3 g of PCL5k-mPEG5k, add 10 mL of water for injection, and stir thoroughly until completely dispersed; heat the dispersion to 80°C and stir at 500 rpm for 40 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 112°C, 0.12 MPa for 96 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0056] Example 7

[0057] Accurately weigh 4 g of PCL5k-mPEG5k, add 10 mL of water for injection, and stir thoroughly until completely dispersed; heat the dispersion to 80°C and stir at 500 rpm for 40 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 112°C, 0.12 MPa for 96 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0058] Example 8

[0059] Accurately weigh 4.5 g of PCL5k-mPEG5k, add 10 mL of water for injection, and stir thoroughly until completely dispersed; heat the dispersion to 80°C and stir at 500 rpm for 40 min; fill the resulting micelle solution into a vial, place it in a high-temperature and high-pressure sterilizer, sterilize it at 112°C, 0.12 MPa for 96 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0060] Example 9

[0061] Accurately weigh 2.5 g of PCL5k-PEG10k-PCL5k, add 10 mL of water for injection, and stir thoroughly until completely dispersed; heat the dispersion to 85°C and stir at 700 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 112°C, 0.13 MPa for 96 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0062] Example 10

[0063] Accurately weigh 1.5 g of PCL10k-mPEG5k, add 10 mL of 0.9% sodium chloride solution, and stir thoroughly until completely dispersed. Heat the dispersion to 65°C and stir at 800 rpm for 60 min. Fill the resulting micellar solution into a vial, place it in a high-temperature and high-pressure sterilizer, and sterilize it at 114°C, 0.11 MPa for 61 min. Cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0064] Example 11

[0065] Accurately weigh 2 g of PCL10k-mPEG5k, add 10 mL of 0.9% sodium chloride solution, and stir thoroughly until completely dispersed. Heat the dispersion to 65°C and stir at 800 rpm for 60 min. Fill the resulting micellar solution into a vial, place it in a high-temperature and high-pressure sterilizer, and sterilize it at 114°C, 0.11 MPa for 61 min. Cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0066] Example 12

[0067] Accurately weigh 3 g of PCL10k-mPEG5k, add 10 mL of 0.9% sodium chloride solution, and stir thoroughly until completely dispersed. Heat the dispersion to 65°C and stir at 800 rpm for 60 min. Fill the resulting micellar solution into a vial, place it in a high-temperature and high-pressure sterilizer, and sterilize it at 114°C, 0.11 MPa for 61 min. Cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0068] Example 13

[0069] Accurately weigh 4 g of PCL10k-mPEG5k, add 10 mL of 0.9% sodium chloride solution, and stir thoroughly until completely dispersed. Heat the dispersion to 65°C and stir at 800 rpm for 60 min. Fill the resulting micellar solution into a vial, place it in a high-temperature and high-pressure sterilizer, and sterilize it at 114°C, 0.11 MPa for 61 min. Cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0070] Example 14

[0071] Accurately weigh 2.5 g of PCL5k-PEG5k-PCL5k, add 10 mL of 0.9% sodium chloride solution, and stir thoroughly until completely dispersed; heat the dispersion to 65°C and stir at 800 rpm for 60 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 114°C, 0.11 MPa for 61 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0072] Example 15

[0073] Accurately weigh 1 g of PCL30k-mPEG10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 105°C and stir at 600 rpm for 45 minutes; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 114°C, 0.15 MPa for 61 minutes, and then cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0074] Example 16

[0075] Accurately weigh 2 g of PCL30k-mPEG10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 105°C and stir at 600 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 114°C, 0.15 MPa for 61 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0076] Example 17

[0077] Accurately weigh 3 g of PCL30k-mPEG10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 105°C and stir at 600 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 114°C, 0.15 MPa for 61 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0078] Example 18

[0079] Accurately weigh 3.5 g of PCL30k-mPEG10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 105°C and stir at 600 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 114°C, 0.15 MPa for 61 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0080] Example 19

[0081] Accurately weigh 1 g of PCL20k-mPEG5k and add it to 10 mL of phosphate buffer, stirring thoroughly until completely dispersed. Heat the dispersion to 60°C and stir at 900 rpm for 45 min. Fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C and 0.11 MPa for 121 min, and then cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0082] Example 20

[0083] Accurately weigh 2 g of PCL20k-mPEG5k and add it to 10 mL of phosphate buffer, stirring thoroughly until completely dispersed. Heat the dispersion to 60°C and stir at 900 rpm for 45 min. Fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and then cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0084] Example 21

[0085] Accurately weigh 3 g of PCL20k-mPEG5k and add it to 10 mL of phosphate buffer, stirring thoroughly until completely dispersed. Heat the dispersion to 60°C and stir at 900 rpm for 45 min. Fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and then cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution. Figure 2 The macroscopic properties and microscopic morphology of Example 21 are shown.

[0086] Example 22

[0087] Accurately weigh 3.5 g of PCL20k-mPEG5k and add 10 mL of phosphate buffer, stirring thoroughly until completely dispersed. Heat the dispersion to 60°C and stir at 900 rpm for 45 min. Fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and then cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0088] Example 23

[0089] Accurately weigh 0.5 g of PCL10k-PEG5k-PCL10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0090] Example 24

[0091] Accurately weigh 1 g of PCL10k-PEG5k-PCL10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and then cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0092] Example 25

[0093] Accurately weigh 1.5 g of PCL10k-PEG5k-PCL10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0094] Example 26

[0095] Accurately weigh 2 g of PCL10k-PEG5k-PCL10k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.11 MPa for 121 min, and cool and reduce the pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0096] Example 27

[0097] Accurately weigh 0.5 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 85°C and stir at 800 rpm for 60 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0098] Example 28

[0099] Accurately weigh 1 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 85°C and stir at 800 rpm for 60 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0100] Example 29

[0101] Accurately weigh 2 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 85°C and stir at 800 rpm for 60 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0102] Example 30

[0103] Accurately weigh 3 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 85°C and stir at 800 rpm for 60 min; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 111°C, 0.1 MPa for 121 min, and cool and reduce the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution.

[0104] Specifically, the macroscopic properties of Examples 1 to 30 are shown in Table 1 below.

[0105] Table 1 Macroscopic properties of each embodiment after sterilization (cooled to room temperature)

[0106]

[0107] Example 31

[0108] The polycaprolactone copolymer solution obtained in Example 20 was placed in a constant temperature incubator at 40° C., and the macroscopic properties, particle size, pH, and osmotic pressure of the samples were regularly tested for a total of 12 weeks. The results are shown in Table 2.

[0109] Table 2

[0110]

[0111] Specifically, as shown in Table 2, the polycaprolactone copolymer solution obtained in Example 20 remained uniform from week 0 to week 12, with no observed precipitation or stratification. The solution particle size varied by less than 2%, while the pH fluctuated by less than 0.02 and the osmotic pressure varied by less than 0.1%. This consistent and stable data demonstrates that the present invention, through precise control of the PCL / PEG segment ratio, optimized solution concentration, and matching moist heat sterilization parameters, effectively inhibits the high-temperature crystallization and aggregation of the polycaprolactone hydrophobic segments while thoroughly inactivating microorganisms (F0 > 12). This allows the micelle self-assembly structure to maintain thermodynamic equilibrium for a long period of time without the intervention of exogenous stabilizers. This achieves the triple technical goals of post-sterilization solution dispersion uniformity, micelle structural integrity, and storage stability at the molecular level, overcoming the industry bottleneck of moist heat sterilization, which inevitably leads to the dissociation or aggregation of temperature-sensitive micelles.

[0112] Example 32

[0113] The polycaprolactone copolymer solutions obtained in Examples 27 to 30 were tested for pushing force using 30G, 31G, 32G, and 34G needles, respectively. The pushing speed was 30 mm / min, the displacement distance was 15 mm, and the average pushing force was recorded. The results are shown in Table 3.

[0114] Table 3

[0115] Example 30G 31G 32G 34G Example 27 1.276N 2.188N 4.562N 11.942N Example 28 2.275N 5.016N 6.388N 15.421N Example 29 4.103N 5.975N 8.092N 21.322N Example 30 8.323N 11.801N 18.661N 35.869N

[0116] The polycaprolactone copolymer solutions of Examples 27-30 in Table 3 exhibited push forces measured at various polymer concentrations (5-30 wt%) and needle gauges (30G-34G) that were strictly below 36N. This key data demonstrates the core advantage of the present invention: the sterilization process achieves long-term micelle stability while fully preserving the clinical performance of the formulation. Specifically, while increasing polymer concentration or reducing needle diameter (34G is an extremely fine needle) objectively increases solution push resistance, the synergistically controlled PCL / PEG segment ratio optimizes hydrophilic layer coverage, avoiding polymer chain entanglement or micelle aggregation thickening caused by high-temperature sterilization, ensuring that the solution rheological properties are consistently optimized for injection. Precise control of moist heat sterilization parameters maintains low shear viscosity without disrupting the micelle structure, ultimately ensuring that the push forces for all tested combinations fall within the safe range of the human body's acceptable injection force threshold. This result directly supports the technical benefits of the aforementioned "applications in drug carriers, soft tissue fillers, and other fields," confirming that the process successfully achieves sterilization stability and formulation applicability.

[0117] Comparative Example 1

[0118] Accurately weigh 0.5 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; filter the resulting micellar solution through a 0.22 μm sterile filter membrane.

[0119] Comparative Example 2

[0120] Accurately weigh 1 g of PCL25k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 min; filter the resulting micellar solution through a 0.22 μm sterile filter membrane.

[0121] Comparative Example 3

[0122] Accurately weigh 2 g of PCL20k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 minutes; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 121°C, 0.1 MPa for 15 minutes, and then cool and reduce the pressure to room temperature and pressure.

[0123] Comparative Example 4

[0124] Accurately weigh 3 g of PCL20k-mPEG5k, add 10 mL of phosphate buffer, and stir thoroughly until completely dispersed; heat the dispersion to 60°C and stir at 900 rpm for 45 minutes; fill the resulting micelle solution into a prefilled syringe, place it in a high-temperature and high-pressure sterilizer, sterilize it at 121°C, 0.1 MPa for 15 minutes, and then cool and reduce the pressure to room temperature and pressure. Figure 3 The macroscopic properties and microscopic morphology of Comparative Example 4 are shown.

[0125] In summary, the sterilization process of the polycaprolactone copolymer solution is based on the temperature-sensitive properties of the polycaprolactone copolymer and its phase change mechanism. By precisely controlling the copolymer segment ratio, polymer solution concentration and moist heat sterilization parameters, the hydrophilic-hydrophobic interaction is balanced and crystal aggregation is inhibited, thereby achieving the technical goal of uniform dispersion, no sedimentation and long-term stable preservation of the solution after sterilization. The process avoids the disintegration or aggregation of micelles and ensures that the solution after sterilization is uniformly dispersed and stable for a long time. There is no need to add stabilizers. Moreover, mild pressure is used to adapt conventional equipment while taking into account large-particle micelles, making it suitable for large-scale production.

[0126] With the above-described preferred embodiments of the present invention as a guide, and with reference to the above description, relevant personnel are fully capable of making various changes and modifications without departing from the technical scope of this invention. The technical scope of this invention is not limited to the contents of the specification and must be determined according to the scope of the claims.

Claims

1. A sterilization process for a polycaprolactone copolymer solution, characterized in that: The steps include: S1, dispersing the polycaprolactone copolymer in a buffer salt system, heating and stirring to obtain a homogeneous solution; S2, adding the homogeneous solution to a filling container, placing it in a sterilization chamber, raising the temperature to 111-114° C., raising the pressure to 0.1-0.15 MPa, ensuring that F0>12, continuing the reaction, and then lowering the temperature and pressure to room temperature and pressure to obtain a polycaprolactone copolymer solution; Furthermore, the polycaprolactone copolymer is a block copolymer, including a polycaprolactone-methoxypolyethylene glycol diblock copolymer or a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, wherein the weight average molecular weight ratio of the polycaprolactone to polyethylene glycol segments is 1:4 to 5:1; The mass percentage of the polycaprolactone copolymer is 5 to 50% of the polycaprolactone copolymer solution.

2. The sterilization process according to claim 1, wherein The weight average molecular weight of the polycaprolactone copolymer is 10 to 40 kDa; The weight average molecular weight of the polycaprolactone chain segment is 2 to 30 kDa, and the weight average molecular weight of the polyethylene glycol chain segment is 5 to 10 kDa.

3. The sterilization process according to claim 1, wherein The heating temperature of the heating and stirring in step S1 is 60-105° C., the stirring speed is 500-1000 rpm, and the reaction time is 30-120 min.

4. The sterilization process according to claim 1, wherein The buffer salt system includes any one of water for injection, phosphate buffer, citrate buffer, sodium chloride solution or a combination thereof.

5. The sterilization process according to claim 1, wherein: The filling containers in step S2 include prefilled syringes and vials.

6. A polycaprolactone copolymer solution, characterized in that The product is prepared by the sterilization process according to any one of claims 1 to 5.

7. The polycaprolactone copolymer solution according to claim 6, wherein The polycaprolactone copolymer in the solution includes large-particle micelles with a particle size D90 of ≥220 nm.

8. The polycaprolactone copolymer solution according to claim 6, wherein The pH value of the solution ranges from 7.0 to 7.

5.

9. The polycaprolactone copolymer solution according to claim 6, wherein The osmotic pressure of the solution is in the range of 300 mOsmol / kg to 350 mOsmol / kg.

10. Use of the polycaprolactone copolymer solution prepared by the process according to any one of claims 1 to 5 or the polycaprolactone copolymer solution according to any one of claims 6 to 9 in the fields of drug carriers, soft tissue fillers, etc.

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