A soft tissue filler composition for injection and a method of preparing the same

Abstract

The application discloses a soft tissue filler composition for injection and a preparation method thereof, and belongs to the technical field of biomedical materials.The soft tissue filler composition comprises, in percentage by mass, 1-40% of hydroxyapatite microspheres, 1-10% of a suspending agent, 0.1-10% of a slip agent, and the rest is a solvent;the particle size of the hydroxyapatite microspheres is 25-45 mu m, and the tap density is 0.6 g / cm 3 -2.1 g / cm 3 The preparation method does not need to add any chemical cross-linking agent in the whole process.The soft tissue filler composition is applied to facial filling, has good biocompatibility, and can effectively and stably stimulate the regeneration of facial subcutaneous collagen.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and relates to medical aesthetics and plastic surgery technology, specifically to an injectable soft tissue filler composition and its preparation method. Background Technology

[0002] With the rapid development of the medical aesthetics industry, injectable soft tissue fillers have gradually become an important means of correcting tissue defects, repairing facial deformities, and achieving facial rejuvenation. According to their functional characteristics, injectable fillers are mainly divided into two categories: (1) space-occupying fillers, represented by collagen and hyaluronic acid, which correct tissue depressions immediately through physical filling, but the filling effect lasts for a relatively short time and requires regular repeated injections; (2) regeneration-stimulating fillers, represented by synthetic polymers such as polylactic acid (PLA), polycaprolactone (PCL), and hydroxyapatite (HAP), which stimulate fibroblasts to secrete collagen, thereby achieving the natural continuation and long-term maintenance of the filling effect.

[0003] Regenerative injectable fillers are popular due to their ability to stimulate collagen production, resulting in more natural and longer-lasting filling effects. In the field of injectable cosmetic procedures, the mainstream hydroxyapatite fillers currently include the following representative products: One of them is Radiesse ® Radiesse (a subsidiary of Merz, Germany): ® This is an injectable soft tissue filler with hydroxyapatite microspheres as the main active ingredient, providing immediate filling and support via a carboxymethyl cellulose gel carrier. However, the carboxymethyl cellulose carrier is rapidly absorbed within approximately 1-3 months after injection. If newly formed collagen has not fully compensated, the filled area will experience volume loss. Although hydroxyapatite microspheres can continuously induce collagen regeneration to achieve long-term effects, the initial volume loss issue remains to be addressed. Furthermore, the microspheres in this product lack a topological structure conducive to cell adhesion, limiting support for fibroblast adhesion and orderly collagen regeneration. This may result in insufficient regularity in the arrangement of regenerated collagen fibers, thus affecting the uniformity and naturalness of the filling effect.

[0004] The second is HarmonyCa TM (Allergan): HarmonyCa TMThis product enhances immediate filling effects by introducing a cross-linked hyaluronic acid system, which reduces the significant decrease in filler volume within 1-2 months after injection. However, the use of BDDE (1,4-butanediol diglycidyl ether) for chemical cross-linking of hyaluronic acid increases the risk of cross-linking agent residue, potentially causing delayed adverse reactions. Furthermore, the surface properties of the microspheres in this product also limit their ability to support cell adhesion and collagen regeneration, which is detrimental to the uniform deposition of newly formed collagen fibers and the stable maintenance of tissue support.

[0005] The third is Aphranel ® Aphranel (Shanghai Moyang R&D): ® As a domestically developed hydroxyapatite injectable filler, it adopts a "raspberry-like porous structure" microsphere design. This structure can provide more adhesion sites for fibroblasts, thus improving its ability to stimulate collagen regeneration. However, this type of hydroxyapatite filler based on carboxymethyl cellulose generally suffers from a large density difference between the microspheres and the matrix. Because the density of hydroxyapatite microspheres is significantly higher than that of carboxymethyl cellulose gel, the microspheres are prone to gravitational sedimentation in the gel system. Furthermore, after injection, as the gel carrier is gradually replaced or absorbed by the interstitial fluid, the remaining microspheres may migrate and focally aggregate under the contraction of facial muscles and tissue compression, thereby inducing the formation of nodules on the skin surface and affecting the smoothness and aesthetic effect of the filled area. Summary of the Invention

[0006] The invention aims to overcome the problems of poor filling effect stability and residual risk of chemical crosslinking agents in the prior art of hydroxyapatite soft tissue fillers after injection, and provides an injectable soft tissue filler composition and its preparation method.

[0007] The technical solution adopted by this invention to achieve its purpose is as follows: An injectable soft tissue filler composition, by weight percentage, comprises 1%-40% hydroxyapatite microspheres, 1%-10% suspending agent, 0.1%-10% lubricant, and the remainder being solvent; Furthermore, the hydroxyapatite microspheres have a particle size of 25-45 μm and a tap density of 0.6 g / cm³. 3 -2.1g / cm 3 .

[0008] Preferably, the tap density of the hydroxyapatite microspheres is 0.8 g / cm³. 3 -1.8 g / cm 3 .

[0009] Further, the suspending agent is agarose, or a combination of agarose and at least one selected from the group consisting of: sodium hyaluronate, chondroitin sulfate, gelatin, collagen, silk fibroin, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, dextran, chitin, chitosan, alginate, xanthan gum, and gum arabic.

[0010] Furthermore, the mass ratio of agarose to other components in the suspending agent is 1:0 to 1:0.2.

[0011] Preferably, the suspending agent content is 1%-5% by mass percentage.

[0012] Furthermore, the lubricant is one or more of sodium hyaluronate, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, glycerin, and mannitol.

[0013] Furthermore, the content of the lubricant is 0.1%-10% by mass percentage.

[0014] Preferably, the content of the lubricant is 0.25%-2.5% by mass percentage.

[0015] Further, the solvent is one or more of physiological saline, phosphate buffer with pH 6.8-7.4, and Tris buffer with pH 6.8-7.4.

[0016] Furthermore, the osmotic pressure of the injectable soft tissue filler composition is 260-340 mOsmol / kg.

[0017] A method for preparing an injectable soft tissue filler composition includes the following steps: (1) Add hydroxyapatite microspheres, suspending agent and lubricant to solvent according to the formula ratio, stir at 50-1000 rpm for 3-60 min at 15-65 ℃ to obtain premixed solution. There are no special requirements for the order of adding hydroxyapatite microspheres, suspending agent and lubricant. (2) Place the premixed liquid obtained in step (1) in a constant temperature water bath at 65-98 ℃ and stir continuously at 50-800 rpm for 10-60 min to allow each component to fully swell, dissolve and disperse evenly. (3) Cool the mixture obtained in step (2) to 30-50 ℃ at a cooling rate of 0.5-2 ℃ / min and a stirring speed of 50-800 rpm to form a uniform three-dimensional network structure of gel. (4) The gel obtained in step (3) is allowed to stand and cool until it is completely solidified. After granulation and filling, an injectable soft tissue filler containing hydroxyapatite microspheres and agarose gel is obtained.

[0018] Furthermore, the stirring rate in step (1) is preferably 300-600 rpm, and the stirring time is 10-30 min.

[0019] Furthermore, the stirring rate in step (2) is preferably 200-500 rpm, and the stirring time is 20-40 min.

[0020] Furthermore, the stirring rate in step (3) is preferably 200-500 rpm, and the final temperature is 35-45 ℃.

[0021] Further, the granulation method in step (4) is extrusion sieving granulation, in which the gel is passed through a sieve and the undersize material is collected to obtain a composition of hydroxyapatite microspheres and gel particles.

[0022] Application of the injectable soft tissue filler composition in the preparation of medical aesthetic injectable products.

[0023] The beneficial effects of this invention are: (1) The hydroxyapatite microsphere material used in this invention has good biocompatibility and chemical stability, which can provide a good adhesion environment for fibroblasts, thus promoting cell attachment and proliferation. At the same time, hydroxyapatite has a chemical composition similar to that of natural human bone tissue, which can effectively support the integration of surrounding tissues and enhance the mechanical bonding force between the microspheres and the tissue, thereby reducing the displacement of fillers in the tissue to a certain extent and maintaining the spatial morphological stability of the filled area. In addition, the surface of hydroxyapatite can bind and enrich bioactive factors (such as amino acids, growth factors, etc.) in the human body and create a suitable cell growth microenvironment, thereby promoting the generation of collagen fibers and tissue regeneration.

[0024] (2) The agarose material used in this invention is non-ionic and has low water absorption and swelling properties. It does not swell significantly in aqueous media, so the filling volume remains basically unchanged after injection, enabling immediate and precise shaping and achieving a "what you see is what you get" effect. The volume of the agarose-based filler remains stable after injection, avoiding mid-term and long-term volume fluctuations. In addition, the agarose used in this invention is a non-chemically cross-linked natural polysaccharide, requiring no cross-linking agents such as BDDE, and eliminating the risk of delayed inflammatory reactions caused by cross-linking agent residues. Its chemical inertness and good biocompatibility allow it to function physically in vivo, without relying on inflammatory responses to stimulate collagen regeneration, which helps ensure the durability of the filling effect and a natural appearance. Taking the commercially available product Algeness as an example, this product is based on agarose material. Due to its good biocompatibility and low hydrophilicity, it solves the common water absorption and swelling problem in traditional products, ensuring immediate filling effect and long-term morphological stability, providing the market with a safe and efficient filling solution. Attached Figure Description

[0025] Figure 1 This is a picture of the product prepared in Example 2 of the present invention and a photograph of it passing through a needle.

[0026] Figure 2 From left to right are the filler product images of Embodiment 1, Embodiment 2, and Embodiment 3 of the present invention.

[0027] Figure 3 This is a microscope image of the filler prepared according to the present invention.

[0028] Figure 4 This is a diagram showing the extrusion force of the filler prepared according to the present invention.

[0029] Figure 5 These are the viscoelastic data of the filler prepared in this invention at 1 Hz.

[0030] Figure 6 These are the osmotic pressure data of the filler prepared in this invention. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0032] Example 1

[0033] An injectable soft tissue filler composition comprises hydroxyapatite microspheres, agarose, sodium hyaluronate, and physiological saline. The hydroxyapatite microspheres have a spherical structure, a particle size of 25-45 μm, and a tap density of 0.9 g / cm³. 3 .

[0034] Its preparation process is as follows: (1) Weigh 0.3 g hydroxyapatite microspheres, 0.35 g agarose, 0.2 g sodium hyaluronate and 9.15 g physiological saline and stir them in a 45 ℃ constant temperature water bath for 10 min at a speed of 400 rpm; (2) After mixing, stir and dissolve in a 90 ℃ constant temperature water bath for 30 min at a speed of 500 rpm; (3) After dissolution, continue stirring at 300 rpm and a cooling rate of 1 ℃ / min to cool down to 40℃; (4) Stop stirring and heating, and after the gel cools and solidifies, squeeze it through a sieve to granulate and fill it to obtain an injectable soft tissue filler.

[0035] Example 2

[0036] Unlike Example 1, in this example, the content of hydroxyapatite microspheres in the injectable soft tissue filler is increased to 18%; the content of agarose is reduced to 2.5%; the lubricant is replaced with sodium carboxymethyl cellulose at a content of 1.5%; and the solvent is replaced with phosphate buffer solution with a pH of 7.2-7.4. The specific ratios are shown in Table 1, and the preparation method is the same as in Example 1.

[0037] Example 3

[0038] Unlike Example 1, in this example, the hydroxyapatite microsphere content in the injectable soft tissue filler is increased to 38%; the agarose content is reduced to 1.5%; the lubricant is replaced with glycerol at a content of 1%; and the solvent is replaced with Tris buffer solution at pH 7.4. The specific proportions are shown in Table 1, and the preparation method is the same as in Example 1.

[0039] Figure 2 From left to right, the images show the products of Examples 1, 2, and 3. A clear gradient in the appearance of the filler can be observed: the leftmost side is a cool white with a bright, slightly transparent texture; towards the right, the microsphere content increases, the white gradually becomes denser and less transparent, and the hue changes from cool white to warm yellowish-white.

[0040] Example 4

[0041] Unlike Example 2, in this example, the content of hydroxyapatite microspheres in the injectable soft tissue filler remains unchanged, but it is replaced with a material with a tap density of 1.4 g / cm³. 3 The hydroxyapatite microspheres are prepared according to the same method as in Example 1, with specific proportions shown in Table 1.

[0042] Example 5

[0043] Unlike Example 2, in this example, the content of hydroxyapatite microspheres in the injectable soft tissue filler remains unchanged, but it is replaced with a material with a tap density of 1.8 g / cm³. 3 Hydroxyapatite microspheres were prepared using a Tris buffer solution at pH 7.4 as the solvent, with specific ratios as shown in Table 1. The preparation method was the same as in Example 1.

[0044] Example 6

[0045] Unlike Example 1, in this example, the content of hydroxyapatite microspheres in the injectable soft tissue filler is reduced to 15%; the suspending agent is agarose and hydroxypropyl methylcellulose; the lubricant is changed to sodium carboxymethyl cellulose with a content of 0.5%, and the specific ratio is shown in Table 1. The preparation method is the same as in Example 1.

[0046] Comparative Example 1 Unlike Example 2, the content of hydroxyapatite microspheres in the injectable soft tissue filler in this example is reduced to 15%; no lubricant is added, and the specific ratio is shown in Table 1. The preparation method is the same as in Example 1.

[0047] Comparative Example 2 Unlike Example 2, the injectable soft tissue filler composition in this example does not contain agarose, and uses sodium carboxymethyl cellulose as a suspending agent and lubricant. The specific proportions are shown in Table 1, and the preparation method is the same as in Example 1.

[0048] The pushing force, viscoelasticity, and osmotic pressure data for Comparative Example 2 were obtained immediately after preparation. After only 24 hours of standing, the microspheres settled and separated from the gel system, indicating that without highly viscoelastic agarose, the CMC system alone cannot effectively suspend the hydroxyapatite microspheres. In all examples and Comparative Example 1, agarose was added as a suspending agent. After prolonged standing, none of these systems showed stratification, and the microspheres were uniformly dispersed in the gel matrix, indicating that agarose can effectively suspend the hydroxyapatite microspheres and maintain the storage stability of the composition.

[0049] In addition, Comparative Example 2 has a similar CMC mass percentage to Radiesse® and Aphranel®, but without the addition of glycerol, indicating that the CMC system at this concentration alone cannot effectively suspend hydroxyapatite microspheres.

[0050] The specific raw material compositions of Examples 1-6 and Comparative Examples 1-2 are shown in Table 1: Table 1 Raw Material Composition Table

[0051] Performance Testing and Result Analysis The injectable soft tissue filler compositions prepared according to the methods in Examples 1-6 and Comparative Examples 1-2 were subjected to microscopic observation, extrusion force, rheological properties testing and osmotic pressure testing.

[0052] The microscopic observation and testing methods are as follows: Squeeze a small amount of gel into a petri dish, then drop a small amount of staining solution onto the gel. Gently stir with a glass rod, add a small amount of water to disperse the gel, and use a dropper to transfer a small amount of gel onto a glass slide. Cover with a coverslip and observe.

[0053] The method for testing the pushing force is as follows: Place a 1 mL syringe containing the injectable soft tissue filler composition on the pushing force measuring instrument, push the plunger at a speed of 30 mm / min, and record the pushing force value within a pushing displacement of 12 mm.

[0054] The rheological performance testing methods are as follows: At 25 °C, a rheometer was used to test the elastic modulus (G´) and viscous modulus (G´´) against the logarithm of the frequency, and the ratio of viscosity to elasticity (Tanδ=G´´ / G´) was plotted.

[0055] The osmotic pressure test method is as follows: At 25 °C, the test was conducted using a freezing point osmometer. Three parallel samples were tested for each sample, and the average value of the results was taken.

[0056] The injectable soft tissue filler compositions prepared in the above embodiments and comparative examples were analyzed as follows: (1) Morphological analysis Figure 3 The image shown is a microscope image of Example 2. As can be seen from the image, the particle size of the hydroxyapatite microspheres is 25-45 μm. Some of the hydroxyapatite microspheres are located in the gel, while others are dispersed between the gel particles.

[0057] (2) Pushing force analysis Figure 4 The figures show the pushing force data for Examples 1-6 and Comparative Examples 1 and 2. As can be seen from the images, an increase in hydroxyapatite microsphere content leads to an increase in pushing force, and an increase in microsphere tap density also results in a rise in pushing force. Compared to Comparative Example 1 without added lubricant, the lubricant significantly improved the lubricity of the composition, resulting in a marked decrease in pushing force and a significantly reduced fluctuation in the pushing force curve, making the injection process smoother. While the pushing force curve of Comparative Example 2 showed less drastic fluctuation than that of Comparative Example 1, the overall fluctuation was still higher than in the other examples. This is because Comparative Example 2 did not add agarose as a suspending agent, preventing the microspheres from being stably suspended in the matrix and resulting in poor dispersion uniformity.

[0058] (3) Viscoelasticity analysis Figure 5 The images show the viscoelastic data for Examples 1-6 and Comparative Examples 1 and 2. As can be seen from the images, at a frequency f = 1 Hz, the elastic modulus G´ of each example is higher than the viscous modulus G´´, and G´ increases with increasing microsphere content and tap density. This indicates that the gel system in the examples can form a three-dimensional network structure dominated by elasticity, which is beneficial for maintaining the spatial morphological stability of the filled area. In contrast, the viscous modulus G´´ of Comparative Example 2 is higher than the elastic modulus G´, indicating that the composition exhibits a dominant viscous response at 1 Hz, and the gel elastic network structure is relatively weak.

[0059] Finally, it should be noted that the above-described embodiments are merely specific implementations of the present invention, used to illustrate the technical solutions of the present invention, and not to limit them. The scope of protection of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any person skilled in the art can still modify or easily conceive of changes to the technical solutions described in the foregoing embodiments within the scope of the technology disclosed in the present invention, or make equivalent substitutions for some of the technical features; and these modifications, changes, or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered within the scope of protection of the present invention.

Claims

1. An injectable soft tissue filler composition, characterized in that, The composition, by mass percentage, includes 1%-40% hydroxyapatite microspheres, 1%-10% suspending agent, 0.1%-10% lubricant, and the remainder is solvent; the hydroxyapatite microspheres have a particle size of 25-45 μm and a tap density of 0.6 g / cm³. 3 -2.1 g / cm 3 .

2. The injectable soft tissue filler composition according to claim 1, characterized in that, The suspending agent is agarose, or a combination of agarose and at least one selected from the group consisting of: sodium hyaluronate, chondroitin sulfate, gelatin, collagen, silk fibroin, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, dextran, chitin, chitosan, alginate, xanthan gum, and gum arabic.

3. The injectable soft tissue filler composition according to claim 1, characterized in that, The lubricant is one or more of sodium hyaluronate, methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, glycerin, and mannitol.

4. The injectable soft tissue filler composition according to claim 1, characterized in that, The solvent is one or more of physiological saline, phosphate buffer, and Tris buffer; the pH of the phosphate buffer is 6.8-7.4, and the pH of the Tris buffer is 6.8-7.

4.

5. The injectable soft tissue filler composition according to claim 1, characterized in that, The osmotic pressure of the injectable soft tissue filler composition is 260-340 mOsmol / kg.

6. The method for preparing an injectable soft tissue filler composition as described in claim 1, characterized in that, Includes the following steps: (1) Add hydroxyapatite microspheres, suspending agent and lubricant to solvent according to the formula ratio, and stir at 50-1000 rpm for 3-60 min at 15-65℃ to obtain premixed solution; (2) Place the premixed solution obtained in step (1) in a constant temperature water bath at 65-98℃ and stir continuously at 50-800 rpm for 10-60 min to allow each component to fully swell, dissolve and disperse evenly. (3) Cool the mixture obtained in step (2) to 30-50℃ with a cooling rate of 0.5-2℃ / min and a stirring speed of 50-800 rpm to form a uniform three-dimensional network structure of gel. (4) The gel obtained in step (3) is allowed to stand and cool until it is completely solidified. After granulation and filling, an injectable soft tissue filler containing hydroxyapatite microspheres and agarose gel is obtained.

7. The method for preparing an injectable soft tissue filler composition according to claim 6, characterized in that, The granulation method is extrusion sieving granulation, in which the gel is passed through a sieve and the sieve-underfill material is collected to obtain a composition of hydroxyapatite microspheres and gel particles.

8. The use of the injectable soft tissue filler composition according to claims 1-5 in the preparation of medical aesthetic injectable products.

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