Carboxymethyl cellulose-carboxymethyl chitosan composite gel as well as preparation method and application thereof in injection type soft tissue filling agent

Abstract

The invention belongs to the field of biomedical materials, also belongs to the field of medical cosmetology, and particularly relates to a composite gel carrier material for loading an injection type soft tissue filler as well as preparation and application of the composite gel carrier material. The composite gel is prepared from carboxymethyl cellulose and carboxymethyl chitosan under the physical crosslinking action of citric acid, the carboxymethyl cellulose accounts for 2-4% of the total mass, the carboxymethyl chitosan accounts for 0-4% of the total mass and is not equal to 0, the citric acid accounts for 0.1-0.3% of the total mass, and the balance is water. Compared with a carboxymethyl cellulose gel carrier traditionally used in an injection type soft tissue filling material, the composite gel can support and uniformly load the polycaprolactone microspheres, on the premise that the needle passing performance is not affected, the mechanical supporting force of the gel is improved, the degradation speed is slowed down, the filling time of a polycaprolactone microsphere filling agent is prolonged, and the filling efficiency of the polycaprolactone microsphere filling agent is improved. And the high inflammatory reaction and the falling period of the filling effect caused by poor supporting force and rapid degradation of the carrier are effectively avoided.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and also to the field of medical aesthetics, and specifically relates to a carboxymethyl cellulose-carboxymethyl chitosan composite gel, its preparation method, and its application in injectable soft tissue fillers. Background Technology

[0002] The primary culprit behind facial tissue aging is collagen loss, manifesting as sagging skin, wrinkles, and sunken contours. Regenerative facial fillers are formed by loading filler materials (such as polycaprolactone microspheres, poly-L-lactic acid microspheres, hydroxyapatite, etc.) into carboxymethyl cellulose (CMC) gel. The gel acts not only as a carrier for the filler material but also provides immediate filling upon application. Within the body, the filler material triggers a foreign-mediated inflammatory response, activating fibroblasts and subsequently leading to the synthesis of large amounts of autologous collagen, thus achieving long-lasting support and contour reshaping. Therefore, regenerative facial fillers outperform widely used clinical hyaluronic acid and collagen in terms of both duration of effect and overall efficacy.

[0003] However, regenerative facial fillers currently have several problems. First, there are numerous reports of adverse reactions such as inflammation, redness, swelling, granulomas, and nodules. Second, due to insufficient mechanical support and rapid degradation of CMC gel, the filler volume rapidly diminishes before the peak of collagen regeneration, resulting in a noticeable "dropout period" in the filling effect. Simply increasing the mechanical strength of the gel, such as cross-linking the CMC, is a straightforward solution. However, increased mechanical strength is accompanied by increased viscosity, leading to increased injection pressure and even preventing the filler from passing through the needle, thus negating the gel's fundamental function as a carrier for injectable fillers. Summary of the Invention

[0004] To address the problems of high adverse reaction rates and insufficient mechanical support in existing regenerative facial fillers, this invention provides a carboxymethyl cellulose-carboxymethyl chitosan composite gel, its preparation method, and its application in injectable soft tissue fillers.

[0005] This invention is achieved through the following technical solution: In a first aspect, there is a carboxymethyl cellulose-carboxymethyl chitosan composite gel, wherein the composite gel is prepared by the physical cross-linking of carboxymethyl cellulose and carboxymethyl chitosan under the action of citric acid, wherein carboxymethyl cellulose accounts for 2-4% of the total mass, carboxymethyl chitosan accounts for 0-4% of the total mass (not 0), citric acid accounts for 0.1-0.3% of the total mass, and the remainder is water.

[0006] Secondly, a method for preparing a carboxymethyl cellulose-carboxymethyl chitosan composite gel includes the following steps: (1) Add carboxymethyl cellulose and carboxymethyl chitosan to water and stir until completely dissolved to form a homogeneous solution.

[0007] (2) Add citric acid to the solution in step (1), stir evenly, and let stand at room temperature for more than 5 hours to allow them to fully crosslink, thus obtaining a carboxymethyl cellulose-carboxymethyl chitosan composite gel.

[0008] Thirdly, the application of the carboxymethyl cellulose-carboxymethyl chitosan composite gel in the carrier of injectable soft tissue fillers.

[0009] Specifically, the carrier is a face-filled polycaprolactone microsphere carrier.

[0010] The present invention provides a carboxymethyl cellulose-carboxymethyl chitosan composite gel, its preparation method, and its application in injectable soft tissue fillers, which have the following advantages compared with the prior art: 1) Carboxymethyl cellulose (CMC) has good biocompatibility and strong thickening properties. It relies on enzymatic hydrolysis and biodegradation to ultimately convert into CO2 and water, making its gel suitable as a carrier for injectable soft tissue fillers. However, CMC lacks sufficient physical support and dissolves and degrades rapidly. Before regenerated filler materials stimulate sufficient collagen formation, the filling effect experiences a "decline period." Increasing the mechanical strength of CMC gel often leads to decreased fluidity and increased viscosity, resulting in increased extrusion force of the filler, making it difficult to pass through the needle and increasing the difficulty and risk of surgery.

[0011] This invention selects carboxymethyl chitosan (CMCS), which degrades slowly and produces endogenous, non-toxic, and non-accumulating degradation products, and combines it with CMC to prepare a composite gel. While reducing the degradation rate, the anti-inflammatory and antibacterial activities of CMCS itself can reduce adverse reactions during and after surgery. However, the composite gel formed by combining the two polymers has lower mechanical strength, increased fluidity, decreased viscosity, and a slightly alkaline pH, resulting in insufficient support for the microspheres, making it difficult to disperse evenly, and even causing phase separation between the carrier and the microspheres.

[0012] 2) Citric acid (CA) is one of the most effective antibacterial compounds among monoterpenes. It can be degraded into CO2 and water in vivo and is known as a green cross-linking agent. The carboxyl and hydroxyl groups in the CA molecule can undergo esterification reactions with biopolymers (such as cellulose and chitosan) above 80°C, forming a stable ester cross-linking network, which greatly improves the mechanical strength of the gel. However, the result of chemical cross-linking is that the gel loses its fluidity and its basic function as an injectable carrier.

[0013] like Figure 1 As shown, under environmental conditions, the carboxyl groups at both ends of CA can crosslink the polymer molecules by forming hydrogen bonds with the hydroxyl groups in CMC and CMCS molecules, thereby improving the mechanical strength of the composite gel and lowering its pH, making it suitable for soft tissue injection.

[0014] 3) This invention, through formulation screening, enables appropriate physical cross-linking between CMC and CMCS, improving the mechanical strength of the gel (e.g., suitable viscosity and flowability, without increasing the extrusion force of the filler) while meeting the basic performance requirements of the gel carrier. Figure 2 As shown in Table 1), the etching time was extended, which allowed for uniform dispersion of polycaprolactone microspheres (as shown in Table 1). Figure 3 As shown), the resulting filler has better filling and regeneration properties (e.g. Figure 4 (As shown). The raw materials used in this invention are widely available and inexpensive, and the preparation process is very simple. It can be industrially applied as a carrier for injectable soft tissue fillers. Attached Figure Description

[0015] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a schematic diagram showing the structure and intermolecular interactions of carboxymethyl cellulose (CMC), carboxymethyl chitosan (CMCS), and citric acid (CA).

[0018] Figure 2 SEM images and physical images of Examples 1, 7, and 8 are shown (where the tilt angle of the liquid surface is used to measure the fluidity of the gel). As can be seen from the figures, while Examples 7 and 1 have similar fluidity, the spatial network structure of Example 7 is denser than that of Example 1, exhibiting better mechanical strength and making it more suitable as a carrier for injectable fillers. Example 8 has a denser spatial network structure than Example 7 and has lost its fluidity, indicating that when the CA dosage is too high, excessive cross-linking of the polymers CMC and CMCS occurs, resulting in excessive infusion resistance and loss of the basic function of an injectable filler carrier.

[0019] Figure 3 This is a SEM image of PCL microspheres loaded in Example 7. The image shows that the PCL microspheres are uniformly dispersed within the composite gel framework.

[0020] Figure 4The figures show a comparison of the filling and regeneration effects and inflammatory response of mice implanted with polycaprolactone microspheres loaded in Example 7 and Example 1 for 16 weeks. As can be seen from the figures, the filling time, regenerated collagen, and number of new blood vessels were all higher with the polycaprolactone filler used in Example 7 than with the filler used in Example 1 (conventional carboxymethyl cellulose gel), while the inflammatory response was lower in Example 1. Detailed Implementation

[0021] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0022] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0023] The specific embodiments of the present invention will be described in detail below.

[0024] Examples 1-8: 100g of each example was prepared. Carboxymethyl cellulose, carboxymethyl chitosan, citric acid, and water were accurately weighed according to the formula shown in Table 1. Carboxymethyl cellulose and carboxymethyl chitosan were added to water and stirred until completely dissolved to form a homogeneous solution. Then, citric acid was added, stirred evenly, and allowed to stand at room temperature for 6 hours to allow for full cross-linking, thus obtaining the carboxymethyl cellulose-carboxymethyl chitosan composite gel.

[0025] Table 1. Formulations and performance of the embodiments evaluate: Evaluation 1: Carrier Performance Evaluation As shown in Table 1, the polycaprolactone microspheres loaded with 30% (by mass) of the microspheres in Example 1 exhibited good needle-passing properties, but were rapidly dissolved in vitro.

[0026] After physically crosslinking Example 1 with 0.2% CA, Example 2, although the in vitro etching time was prolonged, had increased viscosity, poor fluidity, and a more acidic pH. After loading microspheres, it had poor needle passage and caused 27G needle blockage.

[0027] Example 3, a 4% CMCS gel, had too low viscosity. Example 4, obtained after CA crosslinking, still had very low viscosity, insufficient to support and uniformly disperse the polycaprolactone microspheres; phase separation occurred between the gel and the polycaprolactone microspheres during needle insertion.

[0028] Example 5, prepared by combining 2% CMC and 2% CMCS, still had low gel viscosity, and phase separation occurred when passing through a needle.

[0029] Physical crosslinking of Example 5 with CA resulted in progressively higher viscosities in Examples 6-8 as the CA dosage increased from 0.1% to 0.3%. However, the viscosity of the composite gel in Example 6 was still significantly lower than that in Example 1, exhibiting poor needle penetration and making it unsuitable as a carrier. The composite gel in Example 8, on the other hand, had excessively high crosslinking, despite a longer dissolution time and a denser three-dimensional network structure (e.g., ...). Figure 2 As shown), the mechanical strength is significantly improved, but the viscosity is high and the flowability is poor (as shown). Figure 2 As shown in the image, this causes needle blockage.

[0030] Compared to Example 1, the composite gel of Example 7 exhibits a denser three-dimensional network structure, improved mechanical strength, prolonged dissolution time, and a pH close to 7, making it suitable for subcutaneous injection. Crucially, it achieves uniform dispersion of 30% polycaprolactone microspheres even with reduced viscosity and decreased extrusion force through a 27G needle (e.g., ...). Figure 3 As shown in the figure, it demonstrates superior carrier performance. Evaluation 2: Evaluation of Filling and Regeneration Effects

[0031] The polycaprolactone microspheres (30%) loaded in Examples 1 and 7 were implanted subcutaneously into mice. Figure 4 The results showed that at 16 weeks after implantation, Example 7 had a higher filling volume (marked within the yellow dashed circle), regenerated collagen (blue-stained area), and neovascularization (marked with dark blue arrows) than Example 1, while having fewer inflammatory cells. This was because the reduced dissolution and degradation rates of Example 7 slowed the release and degradation of the polycaprolactone microspheres, reduced foreign body stress, and improved the filling and regeneration effects of the product.

[0032] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the present invention. Although detailed descriptions have been provided with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments, and they should all be covered within the protection scope of the claims.

Claims

1. A carboxymethyl cellulose-carboxymethyl chitosan composite gel, characterized in that, The composite gel is prepared by the physical cross-linking of carboxymethyl cellulose and carboxymethyl chitosan under the action of citric acid. Carboxymethyl cellulose accounts for 2-4% of the total mass, carboxymethyl chitosan accounts for 0-4% of the total mass (not 0), citric acid accounts for 0.1-0.3% of the total mass, and the remainder is water.

2. The method for preparing a carboxymethyl cellulose-carboxymethyl chitosan composite gel according to claim 1, characterized in that... Includes the following steps: (1) Add carboxymethyl cellulose and carboxymethyl chitosan to water and stir until completely dissolved to form a homogeneous solution; (2) Add citric acid to the solution in step (1), stir evenly, and let stand at room temperature for more than 5 hours to allow them to fully crosslink, thus obtaining carboxymethyl cellulose-carboxymethyl chitosan composite gel.

3. The application of the carboxymethyl cellulose-carboxymethyl chitosan composite gel according to claim 1 in the carrier of injectable soft tissue fillers.

4. The application as described in claim 3, characterized in that, The carrier is a facial-filled polycaprolactone microsphere carrier.

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