A biodegradable polymer solution composition and a method for preparing and using the same

Abstract

The present application relates to the technical field of medical biological materials, and particularly relates to a biodegradable polymer solution composition, a preparation method and application thereof. The composition comprises a degradable polyester component and a solvent component; the degradable polyester component is composed of a high molecular weight fraction and a low molecular weight fraction; the weight average molecular weight of the high molecular weight fraction is 50KDa-200KDa; the weight average molecular weight of the low molecular weight fraction is 5KDa-30KDa; and the mass ratio of the high molecular weight fraction to the low molecular weight fraction is 1:1-10:1. The composition is injected into the body to form an in-situ gel through solvent exchange, and the degradation period in the body is 6-24 months. The composition provided by the present application forms an injectable precursor solution through a simple dissolving process and a biologically safe and friendly solvent, and after being injected into the body, the degradable polyester is precipitated to form a semi-solid gel due to solvent exchange, so as to stimulate the production of collagen.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical biomaterials technology, specifically to a biodegradable polymer solution composition, its preparation method, and its application. Background Technology

[0002] With the rapid development of the medical aesthetics industry, injectable fillers have become an important means of soft tissue filling, wrinkle correction, and facial contouring due to their advantages such as minimal trauma, rapid recovery, and significant effects. Currently, medical aesthetic fillers used in clinical practice are mainly divided into two categories: non-degradable materials and biodegradable materials.

[0003] Non-degradable materials mainly include polyacrylamide hydrogel and silicone. These materials can maintain a volume-filling effect in the body for a long time, but this also brings significant clinical risks. Because the materials cannot be metabolized and absorbed by the body, their long-term presence in tissues may induce persistent foreign body reactions, manifesting as chronic inflammation, fibrous capsule formation, tissue deformation, and even granulomas. More seriously, once these complications occur, material removal is extremely difficult, often leading to irreversible consequences such as tissue defects and morphological deformities, placing a great psychological and physical burden on patients. Based on safety considerations, the application of non-degradable materials in the field of cosmetic fillers has been strictly limited.

[0004] In contrast, biodegradable materials, due to their ability to gradually degrade and be metabolized and excreted in the body, exhibit good biocompatibility and predictability, making them the mainstream research direction for current cosmetic filler materials. Existing biodegradable materials mainly include hyaluronic acid, poly-L-lactic acid, and polycaprolactone. However, these materials have also revealed their respective limitations in clinical applications.

[0005] Hyaluronic acid is currently the most widely used filler material, but its main problem lies in its short degradation cycle in the body, typically 6-12 months, which makes it difficult to meet the demand for long-term filling effects. At the same time, hyaluronic acid has strong water absorption; if the injection depth is improper or the dosage is not precisely controlled, it can easily lead to "bloating," i.e., excessive swelling of the local tissue, resulting in an unnatural shape and severely affecting the aesthetic effect.

[0006] Synthetic polymers such as poly-L-lactic acid and polycaprolactone have gradually attracted attention due to their adjustable degradation cycles and good mechanical properties. However, in the current technology, the product forms of these materials in the field of medical aesthetic fillers are mainly divided into two types: one is irregular sheet or block materials, and the other is microsphere formulations.

[0007] Irregularly shaped sheet-like materials are typically prepared using freeze-drying processes, resulting in extremely uneven distribution of shape and size. After injection into tissues, these materials, due to their uncontrollable physical morphology, are prone to causing unpredictable inflammatory reactions, potentially leading to fibrosis or granuloma formation in severe cases, affecting both the filling effect and safety. Furthermore, sheet-like materials are prone to clogging needles during injection, making the procedure difficult and hindering the achievement of uniform distribution.

[0008] Microsphere-based materials involve more complex preparation processes. To achieve ideal injection performance and tissue compatibility, the particle size of microspheres typically needs to be strictly controlled within a certain range (e.g., 20-50 μm) to avoid them being phagocytosed and cleared by macrophages if too small, or causing embolism or granulomas if too large. However, existing microsphere preparation technologies, such as solvent evaporation and membrane emulsification, suffer from cumbersome process steps, large batch-to-batch variations, and difficulty in precisely controlling the morphology and particle size distribution of microspheres. Furthermore, post-processing steps such as freeze-drying and sterilization can lead to microsphere aggregation and morphological damage, further affecting product quality stability. More critically, regardless of whether the microspheres are irregular flakes or microspheres, the degradation cycles of existing polylactic acid and polycaprolactone materials exhibit significant individual differences, making it difficult to achieve predictable degradation behavior that matches tissue regeneration or filling requirements. Excessive degradation leads to insufficient effect duration, while excessively slow degradation may cause delayed inflammation or foreign body reactions due to material residue.

[0009] Therefore, there is a need for a material that can be designed with molecular structure to form in-situ gels through solvent exchange and has a programmable degradation cycle. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides a biodegradable polymer solution composition, its preparation method, and its applications. The biodegradable polymer is synthesized by fractionating two molecules within a specific molecular weight range. When injected into the body, the composition forms an in-situ gel through solvent exchange, with a degradation cycle linearly adjustable between 6 and 24 months. Simultaneously, this invention uses a simple dissolution process and a biosafe and friendly solvent to form an injectable precursor solution. After injection into the body, due to solvent exchange, the biodegradable polyester precipitates to form a semi-solid gel, thereby stimulating collagen production.

[0011] The first aspect of the present invention relates to a biodegradable polymer solution composition comprising a biodegradable polyester component and a solvent component; The biodegradable polyester component is composed of high molecular weight fractions and low molecular weight fractions; The weight-average molecular weight of the high molecular weight fraction is 50 kDa-200 kDa; The weight-average molecular weight of the low molecular weight fraction is 5 kDa-30 kDa; The mass ratio of the high molecular weight fraction to the low molecular weight fraction is 1:1-10:1; The biodegradable polyester component accounts for 5%-60% of the composition by mass.

[0012] Preferably, the biodegradable polyester component is selected from one or more of polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and polylactic-glycolic acid copolymer (PLGA).

[0013] More preferably, the molar ratio of lactic acid (LA) to glycolic acid (GA) in the polylactic acid-glycolic acid copolymer (PLGA) is 50:50-85:15.

[0014] Preferably, the weight-average molecular weight difference between the high molecular weight fraction and the low molecular weight fraction is not less than 30 kDa.

[0015] Preferably, the solvent component is selected from one or more of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and other acceptable subcutaneous injectable organic solvents.

[0016] More preferably, the solvent component is N-methylpyrrolidone and dimethyl sulfoxide, and the mass ratio of N-methylpyrrolidone to dimethyl sulfoxide is 1:1-3:1.

[0017] Preferably, the composition further includes a subcutaneous injection dispersion medium selected from one or more of deionized water, phosphate buffer, physiological saline, polyethylene glycol 400, and glycerol.

[0018] More preferably, the subcutaneous injection dispersion medium accounts for 0%-3% of the mass of the composition.

[0019] More preferably, the subcutaneous injection dispersion medium is polyethylene glycol 400 and glycerin, and the mass ratio of polyethylene glycol 400 to glycerin is 2:8-6:4.

[0020] Preferably, the biodegradable polymer is injected into the body to form an in-situ gel through solvent exchange, and the biodegradation cycle in the body is linearly adjustable between 6 and 24 months.

[0021] A second aspect of the present invention relates to a method for using the above-described biodegradable polymer solution composition, comprising the following steps: S1, Weigh the high molecular weight fraction and the low molecular weight fraction according to the preset mass ratio; S2, After mixing the two evenly, add them to the solvent component; S3 is prepared by stirring under aseptic conditions until completely dissolved and then allowing to stand to defoam.

[0022] A third aspect of the present invention relates to the use of the above-described biodegradable polymer solution composition or the biodegradable polymer solution composition prepared by the above method in the preparation of medical aesthetic fillers.

[0023] Preferably, the medical aesthetic filler is used for facial soft tissue filling, wrinkle correction, or contouring.

[0024] The beneficial effects of the present invention are: (1) Programmable degradation: no need to change the type of material, different clinical needs can be covered by simply adjusting the molecular weight ratio; (2) High safety: the degradation products are carbon dioxide and water, with no organic solvent residue. Detailed Implementation

[0025] To clarify the purpose, technical solution, and advantages of this invention, the following detailed description is provided in conjunction with specific embodiments. To facilitate understanding of the technical means, creative features, and achieved objectives and effects of this invention, the following detailed description further clarifies the invention in conjunction with specific embodiments. However, these embodiments are merely preferred embodiments and not exhaustive. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. In the following embodiments, unless otherwise specified, the operating methods used are conventional operating methods, the equipment used is conventional equipment, and the equipment materials used in each embodiment are the same. This invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in this invention are all commercially available products in this technical field, with a purity of 98% or higher.

[0026] Example 1: Short-term filling type Raw material: PLGA (LA:GA=75:25, molar ratio) High molecular weight fraction (Mw=80,000Da): 24wt% Low molecular weight fraction (Mw=15,000Da): 16wt% Solvent: 40wt% N-methylpyrrolidone and 20wt% dimethyl sulfoxide.

[0027] Preparation method: Weigh the high molecular weight fraction and the low molecular weight fraction according to the preset mass ratio; mix them evenly and add them to the solvent component; stir under sterile conditions until completely dissolved, let stand to defoam, and the product is obtained.

[0028] Example 2: Medium- to long-term filling type Raw material: PLGA (LA:GA=75:25, molar ratio) High molecular weight fraction (Mw=120,000Da): 30wt% Low molecular weight fraction (Mw=12,000Da): 10wt% Solvent: 40wt% N-methylpyrrolidone and 20wt% dimethyl sulfoxide.

[0029] Preparation method: Weigh the high molecular weight fraction and the low molecular weight fraction according to the preset mass ratio; mix them evenly and add them to the solvent component; stir under sterile conditions until completely dissolved, let stand to defoam, and the product is obtained.

[0030] Example 3: Long-lasting filling type Raw material: PLGA (LA:GA = 70:30, molar ratio) High molecular weight fraction (Mw=180,000Da): 32wt% Low molecular weight fraction (Mw=10,000Da): 8wt% Solvent: 40wt% N-methylpyrrolidone and 20wt% dimethyl sulfoxide.

[0031] Preparation method: Weigh the high molecular weight fraction and the low molecular weight fraction according to the preset mass ratio; mix them evenly and add them to the solvent component; stir under sterile conditions until completely dissolved, let stand to defoam, and the product is obtained.

[0032] Example 4: Long-lasting filling type Raw material: PLGA (LA:GA = 70:30, molar ratio) High molecular weight fraction (Mw=150,000Da): 40wt% Low molecular weight fraction (Mw=15,000Da): 4wt% Solvent: 42wt% N-methylpyrrolidone and 14wt% dimethyl sulfoxide.

[0033] Preparation method: Weigh the high molecular weight fraction and the low molecular weight fraction according to the preset mass ratio; mix them evenly and add them to the solvent component; stir under sterile conditions until completely dissolved, let stand to defoam, and the product is obtained.

[0034] Comparative Example 1: The difference from Example 1 is that the molar ratio of lactic acid to glycolic acid in the polylactic-co-glycolic acid copolymer (PLGA) is 30:70. The rest is the same as in Example 1.

[0035] Comparative Example 2 The difference from Example 1 is as follows: High molecular weight fraction (Mw=80,000Da): 37wt% Low molecular weight fraction (Mw=15,000Da): 3wt% The rest is the same as in Example 1.

[0036] Comparative Example 3 The difference from Example 1 is that the solvent is 60 wt% N-methylpyrrolidone, and it does not contain dimethyl sulfoxide. Otherwise, it is the same as Example 1.

[0037] Comparative Example 4 The difference from Example 1 is that the solvent is 60 wt% dimethyl sulfoxide and does not contain N-methylpyrrolidone. Otherwise, it is the same as Example 1.

[0038] Comparative Example 5 The difference from Example 1 is that the concentration of the biodegradable polyester component in the composition is 3 wt%. The rest is the same as in Example 1.

[0039] Comparative Example 6 The difference from Example 1 is that the concentration of the biodegradable polyester component in the composition is 65 wt%. The rest is the same as in Example 1.

[0040] Comparative Example 7 The difference from Example 1 is that the weight-average molecular weight difference between the high molecular weight fraction and the low molecular weight fraction in this comparative example is 20 kDa. Specifically: Raw material: PLGA (LA:GA=75:25, molar ratio) High molecular weight fraction (Mw=50,000Da): 24wt% Low molecular weight fraction (Mw=30,000Da): 16wt% Solvent: 40wt% N-methylpyrrolidone and 20wt% dimethyl sulfoxide.

[0041] The preparation method is the same as in Example 1.

[0042] Test Example 1: In-situ gelation verification and gel homogeneity (1) In-situ gelation verification (simulating in vivo environment) Draw each composition into a 1 mL syringe equipped with a 24G needle; preheat the syringe in a 37°C constant temperature incubator for 10 minutes (simulating body temperature); inject the composition into 37°C preheated PBS buffer (pH 7.4); observe whether an insoluble, non-dispersible semi-solid gel block is formed within 5 minutes after injection.

[0043] Simultaneously, the microstructure of the gel was observed using a scanning electron microscope (SEM) to identify whether there were uneven regions such as bubbles or aggregates in the gel.

[0044] The experimental results are shown in Table 1.

[0045] Table 1: In-situ gelation verification and gel homogeneity results

[0046] Note: "-" indicates that the product cannot be gelled.

[0047] The compositions of Examples 1-4 and Comparative Examples 5-6 all successfully gelled, and the gels were uniform, meeting the design expectations. Comparative Example 1 could gel, but the gel was not uniform, and polymer aggregation was observed; Comparative Example 2 could not gel; Comparative Example 3 gelled at room temperature, but the gelation temperature was too low, which easily clogged the needle during injection; Comparative Example 4 could gel, but microscopic bubbles were present, resulting in poor uniformity; Comparative Example 7 could gel at normal body temperature, but microscopic phase separation was observed, resulting in poor uniformity.

[0048] Test Example 2: Degradation Cycle Determination Since Comparative Examples 1-4 and Comparative Examples 7 did not meet the technical effect requirements of the present invention in Test Example 1, Test Example 2 only measured the degradation period of the compositions of Examples 1-4, Comparative Examples 5 and 6. The specific process is as follows: Take the test solutions from each group and place them in 37℃ to form in-situ gels. Freeze-dry under vacuum until constant weight and record the initial dry weight. Completely immerse the gels in PBS solution (pH=7.4 phosphate buffer) preheated to 37℃, seal, and incubate in a 37℃ constant temperature water bath. Replace with fresh PBS every 15 days to maintain system stability. Samples are collected at 1, 3, 6, 9, 12, 15, 18, 22, and 24 months. Wash away any residual medium, centrifuge to remove impurities, freeze-dry under vacuum until constant weight, and weigh. The formula for calculating the percentage of remaining mass is: Residual mass percentage (%) = Sample dry weight ÷ Initial dry weight × 100%; A curve was plotted based on the percentage of remaining mass of each sample at different time points, and the degradation cycle was predicted based on the curve.

[0049] Judgment criteria: When the percentage of remaining gel mass is ≤5%, it is judged as completely degraded, and the corresponding time is the degradation cycle.

[0050] The results are shown in Table 2.

[0051] Table 2: Degradation period determination results for each group of samples

[0052] Based on the above results, it can be seen that the present invention achieves the requirement of a degradation cycle of 6-24 months by adjusting the mass ratio of the high molecular weight fraction to the low molecular weight fraction and the molar ratio of the components in the polymer; while in Comparative Example 5, the degradation rate is significantly accelerated due to the low concentration of the degradable polyester component in the composition; while in Comparative Example 6, the degradation rate is significantly slowed down due to the high concentration of the degradable polyester component in the composition, and degradation cannot be completed within 24 months.

[0053] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A biodegradable polymer solution composition, characterized in that, The composition comprises a biodegradable polyester component and a solvent component; The biodegradable polyester component is composed of high molecular weight fractions and low molecular weight fractions; The weight-average molecular weight of the high molecular weight fraction is 50 kDa-200 kDa; The weight-average molecular weight of the low molecular weight fraction is 5 kDa-30 kDa; The mass ratio of the high molecular weight fraction to the low molecular weight fraction is 1:1-10:1; The biodegradable polyester component accounts for 5%-60% of the composition by mass.

2. The biodegradable polymer solution composition according to claim 1, characterized in that, The biodegradable polyester component is selected from one or more of polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polyhydroxyalkanoate, and polycarbonate.

3. The biodegradable polymer solution composition according to claim 2, characterized in that, The molar ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer is 50:50-85:

15.

4. The biodegradable polymer solution composition according to claim 1, characterized in that, The weight-average molecular weight difference between the high molecular weight fraction and the low molecular weight fraction is not less than 30 kDa.

5. The biodegradable polymer solution composition according to claim 1, characterized in that, The solvent component is selected from one or more of N-methylpyrrolidone, dimethyl sulfoxide, and other acceptable subcutaneous injectable organic solvents.

6. The biodegradable polymer solution composition according to claim 5, characterized in that, The solvent components are N-methylpyrrolidone and dimethyl sulfoxide, and the mass ratio of N-methylpyrrolidone to dimethyl sulfoxide is 1:1 to 3:

1.

7. The biodegradable polymer solution composition according to claim 1, characterized in that, The composition further includes a subcutaneous injection dispersion medium selected from one or more of deionized water, phosphate buffer, physiological saline, polyethylene glycol 400, and glycerin; the subcutaneous injection dispersion medium accounts for 0%-3% of the composition by mass.

8. The biodegradable polymer solution composition according to claim 7, characterized in that, The subcutaneous injection dispersion medium is polyethylene glycol 400 and glycerin, and the mass ratio of polyethylene glycol 400 to glycerin is 2:8-6:

4.

9. A method for preparing the biodegradable polymer solution composition according to any one of claims 1-6, characterized in that, Includes the following steps: S1, Weigh the high molecular weight fraction and the low molecular weight fraction; S2, after mixing the two thoroughly, add them to the solvent component; S3 is prepared by stirring under aseptic conditions until completely dissolved and then allowing to stand to defoam.

10. The use of the biodegradable polymer solution composition according to any one of claims 1-8 in the preparation of a cosmetic filler, said cosmetic filler being used for facial soft tissue filling, wrinkle correction, or contouring.

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