Composite microsphere, filler and preparation method thereof

Abstract

The invention discloses a composite microsphere, a filling agent and a preparation method of the filling agent, and the composite microsphere comprises an active component and a polycaprolactone layer or a polylactic acid layer wrapping the active component. According to the composite microsphere, the active component is introduced into the composite microsphere to adjust the degradation performance of the microsphere and the compatibility with gel, so that the composite microsphere is easy to disperse and degrade, meanwhile, the use of an organic solvent is avoided, the safety of the product is greatly improved, the production process is simple, and the production cost is saved.

Description

Technical Field

[0001] The present application relates to the field of medical cosmetology technology, and in particular to a composite microsphere, a filler and a preparation method thereof. Background Art

[0002] Facial injection of skin soft tissue fillers is currently the main way to rejuvenate the face, and fillers with hyaluronic acid as the main ingredient are the mainstream products on the market. Hyaluronic acid is an endogenous component in the human body and has excellent safety. It also has good viscoelasticity and is effective for facial injection filling. However, it is easily affected by hyaluronidase in the body and degrades, which in turn affects its sustained filling and shaping effect. In order to extend the residence time, cross-linked hyaluronic acid has become a new filler product, which has an immediate shaping effect and a greatly extended maintenance time, but it will still lose its effect within 1 year due to rapid degradation.

[0003] As the market demand for long-acting fillers continues to increase, synthetic polymers such as polycaprolactone and polylactic acid have become new choices for filler raw materials due to their clear safety and slow degradation rate. Studies have shown that polycaprolactone and polylactic acid can stimulate tissue regeneration to form new collagen, thereby achieving self-produced collagen to improve facial aging. However, this process usually takes 6 months to 1 year, and it is impossible to achieve instant shaping. In addition, polycaprolactone or polylactic acid alone is difficult to inject, and is currently mainly dispersed into macromolecules in the form of microspheres for use. However, there are two problems that need to be solved urgently. First, the current preparation method of polycaprolactone or polylactic acid microspheres mainly relies on the solvent volatilization method, and it is difficult to introduce hydrophilic substances to adjust the physical and chemical properties of the microspheres; in addition, the solvent volatilization method inevitably involves the problem of solvent residues, which cannot be ignored for the adverse effects of implantation in the body, and it also imposes a huge burden on the environment and increases the post-processing costs of enterprises. Therefore, it is of great significance to improve the preparation process of polycaprolactone microspheres. Secondly, polycaprolactone and polylactic acid have poor hydrophilicity and are easy to agglomerate in the aqueous phase, which greatly limits their addition amount in the filler. At the same time, adverse reactions such as granulomas and nodules formed due to excessive immune response caused by microspheres have also put forward new requirements for microsphere fillers. Therefore, improving the dispersion effect and biocompatibility of microspheres in the dispersed phase is of great significance to solve the adverse reactions caused. Summary of the invention

[0004] In order to solve the above problems, the present application provides a composite microsphere, which introduces active components into the composite microsphere to adjust the degradation performance of the microsphere and the compatibility with the gel, so that the composite microsphere is easy to disperse and degrade. At the same time, the use of organic solvents is avoided, which greatly improves the safety of the product. In addition, the production process is simple and the production cost is saved.

[0005] The present application provides a composite microsphere, comprising an active component and a polycaprolactone layer or a polylactic acid layer encapsulating the active component.

[0006] Furthermore, the particle size distribution of the composite microspheres is 20-50 μm.

[0007] Further, the mass ratio of the active component to the polycaprolactone layer is (0.01-30):100, preferably (0.01-20):100; or

[0008] The mass ratio of the active component to the polylactic acid layer is (0.01-30):100, preferably (0.01-20):100.

[0009] Furthermore, the active component is selected from one or more of hyaluronic acid, collagen, and PDRN, preferably hyaluronic acid or collagen.

[0010] The present application also provides a method for preparing composite microspheres, comprising the following steps:

[0011] Adding the active component into molten polycaprolactone or polylactic acid and mixing them uniformly to obtain a mixture 1;

[0012] Adding the mixture 1 to the dispersed phase, and rapidly stirring until the mixture 1 is evenly dispersed, to obtain a mixture 2;

[0013] Post-treating the mixture to remove the dispersed phase, thereby obtaining composite microspheres;

[0014] The composite microsphere has a shell formed by a polycaprolactone layer or a polylactic acid layer, and active components are encapsulated in the shell.

[0015] Furthermore, in the process of preparing the mixture 1, the melting temperature of the polycaprolactone or polylactic acid is 50-70°C or 125-180°C.

[0016] Furthermore, the dispersed phase includes a surfactant and a dispersant, and the mass ratio of the surfactant to the dispersant is (0.1-10): (0.01-35).

[0017] Furthermore, the surfactant is selected from one or two or more of Span, fatty alcohol polyoxyethylene ether, sodium dodecylbenzene sulfonate, and polyvinyl alcohol; or

[0018] The dispersant is selected from one or more of polyvinyl alcohol, carbomer, cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and carrageenan.

[0019] Furthermore, the prepared composite microspheres are the composite microspheres described above.

[0020] The present application provides a filler, comprising the aforementioned composite microspheres.

[0021] Furthermore, the filler also includes a gel phase, and the gel phase covers the composite microspheres;

[0022] The mass ratio of the composite microspheres to the gel phase is (5-30):(100).

[0023] Furthermore, the gel phase includes one or more of cross-linked collagen gel, hyaluronic acid gel, and carboxymethyl cellulose.

[0024] Furthermore, the gel phase also includes an anesthetic and a saline solution.

[0025] Furthermore, the anesthetic is one or more of lidocaine, bupivacaine, procaine, chloroprocaine, and tetracaine, and the saline solution is physiological saline or phosphate buffer.

[0026] The present application also provides a method for preparing a filler.

[0027] Composite microspheres were prepared according to the aforementioned method;

[0028] preparing a gel phase;

[0029] The composite microspheres and the gel phase are mixed in a certain ratio, stirred and evenly mixed, and sterilized to obtain the filler.

[0030] The composite microspheres described in the present application are easy to disperse and degrade by introducing active components into the composite microspheres to adjust the degradation performance of the microspheres and the compatibility with the gel. At the same time, the use of organic solvents is avoided, which greatly improves the safety of the product. The production process is simple and the production cost is saved.

[0031] The filler described in the present application comprises composite microspheres and a gel phase, so that the filler can simultaneously achieve instant shaping and long-term formation of collagen.

[0032] The preparation method of the composite microspheres of the present application can not only conveniently introduce active components to adjust the degradation performance of the microspheres and the compatibility with the gel, but also avoid the use of organic solvents, greatly improving the safety of the product, and the production process is simple, saving production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The accompanying drawings are used to better understand the present application and do not constitute an improper limitation on the present application.

[0034] Figure 1 is a flow chart of the preparation of the filler according to Example 1. DETAILED DESCRIPTION

[0035] The following is a description of the exemplary embodiments of the present application, including various details of the embodiments of the present application to facilitate understanding, which should be considered as merely exemplary. Therefore, it should be recognized by those of ordinary skill in the art that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present application. Similarly, for the sake of clarity and conciseness, the description of well-known functions and structures is omitted in the following description.

[0036] The present application provides a composite microsphere, comprising an active component and a polycaprolactone layer or a polylactic acid layer encapsulating the active component.

[0037] The particle size distribution of the composite microspheres is 20-50 μm.

[0038] In this paper, the composite microspheres were passed through a sieve to determine their particle size distribution.

[0039] The weight average molecular weight of polycaprolactone is 3kDa-150kDa. In some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-120kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-100kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-80kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-60kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-40kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 3kDa-20kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 10kDa-150kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 30kDa-150kDa, in some embodiments, the weight average molecular weight of polycaprolactone is 50kDa-120kDa.

[0040] The weight average molecular weight of the polylactic acid is 5kDa-100kDa. In some embodiments, the weight average molecular weight of the polylactic acid is 5kDa-80kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 5kDa-60kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 5kDa-40kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 5kDa-20kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 10kDa-80kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 20kDa-80kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 30kDa-80kDa, in some embodiments, the weight average molecular weight of the polylactic acid is 40kDa-80kDa.

[0041] In the present application, the mass ratio of the active component to the polycaprolactone layer is (0.01-30):100, preferably (0.01-20):100.

[0042] In some embodiments, the mass ratio of the active component to the polycaprolactone layer is (0.01-25):100.

[0043] In some embodiments, the mass ratio of the active component to the polycaprolactone layer is (0.01-20):100.

[0044] In some embodiments, the mass ratio of the active component to the polycaprolactone layer is (0.01-15):100.

[0045] In some embodiments, the mass ratio of the active component to the polycaprolactone layer is (0.01-10):100.

[0046] Specifically, the mass ratio of the active component to the polycaprolactone layer is 0.01:100, 0.05:100, 0.1:100, 0.5:100, 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100、9:100、10:100、11:100、12:100、13:100、14:100、15:100、 16:100、17:100、18:100、19:100、20:100、21:100、22:100、23:100、

[0049] 24:100, 25:100, 26:100, 27:100, 28:100, 29:100, 30:100, etc.

[0050] In the present application, the mass ratio of the active component to the polylactic acid layer is (0.01-30):100, preferably (0.01-20):100.

[0051] In some embodiments, the mass ratio of the active component to the polylactic acid layer is (0.01-25):100.

[0052] In some embodiments, the mass ratio of the active component to the polylactic acid layer is (0.01-20):100.

[0053] In some embodiments, the mass ratio of the active component to the polylactic acid layer is (0.01-15):100.

[0054] In some embodiments, the mass ratio of the active component to the polylactic acid layer is (0.01-10):100.

[0055] Specifically, the mass ratio of the active component to the polylactic acid layer is 0.01:100, 0.05:100, 0.1:100, 0.5:100, 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100、9:100、10:100、11:100、12:100、13:100、14:100、15:100、 16:100、17:100、18:100、19:100、20:100、21:100、22:100、23:100、

[0058] 24:100, 25:100, 26:100, 27:100, 28:100, 29:100, 30:100, etc.

[0059] Too much of the active component will lead to a fast degradation rate of the composite microspheres, thereby causing a poor effect of stimulating tissue regeneration, while too little will fail to achieve the effect of improving the properties of the composite microspheres and alleviating adverse reactions.

[0060] In the present application, the active component is selected from one or more of hyaluronic acid, collagen, and PDRN, preferably hyaluronic acid or collagen.

[0061] In some embodiments, the active component is hyaluronic acid, and the mass ratio of the hyaluronic acid to the polycaprolactone layer is (0.01-30):100.

[0062] The molecular weight of the hyaluronic acid is 30kDa-150kDa. In some embodiments, the molecular weight of the hyaluronic acid is 30kDa-120kDa, in some embodiments, the molecular weight of the hyaluronic acid is 30kDa-100kDa, in some embodiments, the molecular weight of the hyaluronic acid is 30kDa-80kDa, in some embodiments, the molecular weight of the hyaluronic acid is 30kDa-50kDa, in some embodiments, the molecular weight of the hyaluronic acid is 40kDa-150kDa, in some embodiments, the molecular weight of the hyaluronic acid is 50kDa-150kDa, in some embodiments, the molecular weight of the hyaluronic acid is 60kDa-150kDa, in some embodiments, the molecular weight of the hyaluronic acid is 70kDa-150kDa, in some embodiments, the molecular weight of the hyaluronic acid is 80kDa-150kDa, etc.

[0063] Furthermore, the active component may be composed of hyaluronic acid of different molecular weights, for example, the active component is composed of high molecular weight hyaluronic acid and low molecular weight hyaluronic acid, the molecular weight of the high molecular weight hyaluronic acid may be 90kDa-150kDa, and the molecular weight of the low molecular weight hyaluronic acid may be 30kDa-60kDa.

[0064] In some embodiments, the active component is collagen, and the mass ratio of the collagen to the polycaprolactone layer is (0.01-30):100.

[0065] The collagen is extracted from pig skin collagen, extracted from bovine Achilles tendon collagen or recombinant human collagen.

[0066] Collagen has good water solubility, which can improve the hydrophobic properties of polycaprolactone and reduce the immune response of polycaprolactone microspheres. In addition, collagen can directly supplement collagen, improve skin quality, and enhance skin elasticity.

[0067] The present application provides a method for preparing composite microspheres, comprising the following steps:

[0068] Step 1: adding the active component into molten polycaprolactone or polylactic acid, and mixing evenly to obtain a mixture 1;

[0069] Step 2: adding the mixture 1 to the dispersed phase, and rapidly stirring until the mixture 1 is evenly dispersed to obtain a mixture 2;

[0070] Step 3: Post-treating the mixture 2 to remove the dispersed phase, thereby obtaining composite microspheres;

[0071] The composite microsphere has a shell formed by a polycaprolactone layer or a polylactic acid layer, and active components are encapsulated in the shell.

[0072] In step 1, the melting temperature of the polycaprolactone is 50-70°C, for example, 50°C, 52°C, 54°C, 56°C, 58°C, 60°C, 62°C, 64°C, 66°C, 68°C, 70°C, etc. The melting temperature of the polylactic acid is 125-180°C, for example, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, etc. When the melting temperature is too low, the viscosity of the polycaprolactone or polylactic acid is large, so that the particle size of the prepared composite microsphere is large. When the melting temperature is too high, the viscosity of the polycaprolactone or polylactic acid is small, so that the particle size of the prepared composite microsphere is small.

[0073] In the mixture one in step one, the active component is coated by the polycaprolactone or polylactic acid.

[0074] In step 2, the dispersed phase includes a surfactant and a dispersant, and the mass ratio of the surfactant to the dispersant is (0.1-10):(0.01-35).

[0075] In some embodiments, the mass ratio of the surfactant to the dispersant is 0.1:(0.01-35).

[0076] In some embodiments, the mass ratio of the surfactant to the dispersant is 0.1:(1-35).

[0077] In some embodiments, the mass ratio of the surfactant to the dispersant is 0.1:(10-35).

[0078] In some embodiments, the mass ratio of the surfactant to the dispersant is 1:(0.01-35).

[0079] In some embodiments, the mass ratio of the surfactant to the dispersant is 1:(1-35).

[0080] In some embodiments, the mass ratio of the surfactant to the dispersant is 1:(10-35).

[0081] In some embodiments, the mass ratio of the surfactant to the dispersant is 5:(0.01-35).

[0082] In some embodiments, the mass ratio of the surfactant to the dispersant is 5:(1-35).

[0083] In some embodiments, the mass ratio of the surfactant to the dispersant is 5:(10-35).

[0084] In some embodiments, the mass ratio of the surfactant to the dispersant is 10:(0.01-35).

[0085] In some embodiments, the mass ratio of the surfactant to the dispersant is 10:(1-35).

[0086] In some embodiments, the mass ratio of the surfactant to the dispersant is 10:(10-35).

[0087] Specifically, the mass ratio of the surfactant to the dispersant can be 0.1:0.01, 0.1:1, 0.1:5, 0.1:15, 0.1:20, 0.1:25, 0.1:30, 0.1:35, 1:0.01, 1:1, 1:5, 1:15,

[0088] 1:20, 1:25, 1:30, 1:35, 3:0.01, 3:1, 3:5, 3:15, 3:20, 3:25, 3:30, 3:35, 5:0.01, 5:1, 5:5, 5:15, 5:20, 5:25, 5:30, 5:35, 8:0.01, 8:1, 8:5, 8:15, 8:20, 8:25, 8:30, 8:35, 10:0.01, 10:1, 10:5, 10:15, 10:20, 10:25, 10:30, 10:35, etc.

[0089] Furthermore, in the dispersed phase, the mass fraction of the surfactant is 0.1%-10%, and the content of the dispersant is 0.01%-35%.

[0090] In the dispersed phase, the mass fraction of the surfactant can be 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, etc.

[0091] In the dispersed phase, the mass fraction of the dispersant can be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 3%, 5%, 7%, 9%, 10%, 13%, 15%, 17%, 19%, 20%, 23%, 25%, 27%, 29%, 30%, 33%, 35%, etc.

[0092] In step 2, the dispersed phase can prevent the composite microspheres from agglomerating during the forming process, thereby making the size of the formed composite microspheres more uniform.

[0093] The surfactant is selected from one or two or more of Span, fatty alcohol polyoxyethylene ether, sodium dodecylbenzene sulfonate, and polyvinyl alcohol, preferably polyvinyl alcohol.

[0094] The dispersant is selected from one or more of polyvinyl alcohol, carbomer, cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and carrageenan, preferably carboxymethyl cellulose or hydroxyethyl cellulose.

[0095] In step three, the mixture 2 is filtered to remove the dispersed phase, and the specific operation is as follows: the obtained mixture 2 is filtered through a 50-micron sieve, the filtrate is retained, and the filtrate is filtered again using a 20-micron sieve, and at the same time, it is rinsed with a large amount of pure water to completely remove the dispersed phase to obtain composite microspheres with a size of 20-50 microns.

[0096] The composite microspheres prepared by the preparation method described in the present application are the aforementioned composite microspheres.

[0097] The present application provides a filler, comprising the aforementioned composite microspheres and a gel phase, wherein the gel phase covers the composite microspheres.

[0098] The mass ratio of the composite microspheres to the gel phase is (5-30): 100. If the mass ratio is too large, the composite gel will lose its extrudability.

[0099] In some embodiments, the mass ratio of the composite microspheres to the gel phase is (10-30):100.

[0100] In some embodiments, the mass ratio of the composite microspheres to the gel phase is (20-30):100.

[0101] Specifically, the mass ratio of the composite microspheres to the gel phase can be 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 11:100, 12:100, 13:100, 14:100, 15:100, 16:100, 17:100, 18:100, 19:100, 20:100, 21:100, 22:100, 23:100, 24:100, 25:100, 26:100, 27:100, 28:100, 29:100, 30:100, etc.

[0102] Furthermore, the gel phase includes one or more of cross-linked collagen gel, hyaluronic acid gel, and carboxymethyl cellulose.

[0103] In this context, the water content in the gel phase is 5% to 80%, for example, 5%, 10%,

[0104] 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, etc.

[0105] The gel phase also includes an anesthetic and a saline solution.

[0106] The anesthetic is one or more of lidocaine, bupivacaine, procaine, chloroprocaine and tetracaine.

[0107] In the gel phase, the mass concentration of the anesthetic is 0.05 mg / ml-1 mg / ml, preferably 0.3 mg / ml. For example, it can be 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.15 mg / ml, 0.2 mg / ml, 0.25 mg / ml, 0.3 mg / ml,

[0108] 0.35mg / ml, 0.4mg / ml, 0.45mg / ml, 0.5mg / ml, 0.55mg / ml, 0.6mg / ml,

[0109] 0.65mg / ml, 0.7mg / ml, 0.75mg / ml, 0.8mg / ml, 0.85mg / ml, 0.9mg / ml,

[0110] 0.95mg / ml, 1mg / ml, etc.

[0111] The salt solution is physiological saline or phosphate buffer.

[0112] In some embodiments, the filler consists of composite microspheres and a gel phase, the gel phase is a cross-linked collagen gel, and the composite microspheres are dispersed in the cross-linked collagen gel.

[0113] In some embodiments, the filler consists of composite microspheres and a gel phase, the gel phase is hyaluronic acid gel, and the composite microspheres are dispersed in the hyaluronic acid gel.

[0114] In some embodiments, the filler consists of a composite microsphere gel phase, the gel phase consists of a cross-linked collagen gel, an anesthetic and a saline solution, and the composite microspheres are dispersed in the gel phase.

[0115] The mass of the salt solution is 2-20 times, preferably 4-6 times, of the mass of the cross-linked collagen gel, for example, 2 times, 4 times, 6 times, 8 times, 10 times, 12 times, 14 times, 16 times, 18 times, 20 times, etc.

[0116] In some embodiments, the filler consists of a composite microsphere gel phase, the gel phase consists of hyaluronic acid gel, anesthetic and saline solution, and the composite microspheres are dispersed in the gel phase.

[0117] The mass of the saline solution is 2-20 times, preferably 4-6 times, of the mass of the hyaluronic acid gel, for example, 2 times, 4 times, 6 times, 8 times, 10 times, 12 times, 14 times, 16 times, 18 times, 20 times, etc.

[0118] The present application also discloses a method for preparing a filler, comprising the steps of:

[0119] Step 1: preparing composite microspheres according to the above method;

[0120] Step 2: preparing a gel phase;

[0121] Step 3: Mix the composite microspheres with the gel phase in a certain proportion, stir and mix them evenly, and sterilize them to obtain the filler.

[0122] In some embodiments, in step 2, the recombinant collagen is dissolved in water, a cross-linking agent is added, and after a period of reaction, a recombinant collagen gel is obtained by post-treatment, crushing and granulation, and then the pH is adjusted to neutral, and then a salt solution and an anesthetic are added to disperse the gel evenly, thereby obtaining a gel phase.

[0123] In some embodiments, in step 2, hyaluronic acid is dissolved in water, a cross-linking agent is added, and after a period of reaction, hyaluronic acid gel is obtained by post-treatment, crushing and granulation, and then the pH is adjusted to neutral, and then a salt solution and an anesthetic are added to disperse the gel evenly, thereby obtaining a gel phase.

[0124] Specifically, the cross-linking agent is one of BDDE, glutaraldehyde, and transglutaminase.

[0125] Preferably, the cross-linking agent is BDDE or transglutaminase.

[0126] In some embodiments, the mass ratio of recombinant collagen gel to cross-linking agent is 1:(0.01-0.2), for example, it can be 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.2, etc.

[0127] In some embodiments, the molar ratio of hyaluronic acid gel to cross-linking agent is 1:(0.01-0.1), for example, it can be 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, etc.

[0128] The cross-linking reaction time is 6-12h.

[0129] In some embodiments, dilute hydrochloric acid is used to adjust the pH of the gel.

[0130] The mass of the salt solution is 2-20 times, preferably 4-6 times, the mass of the gel.

[0131] In the gel phase, the mass concentration of the anesthetic is 0.05 mg / ml-1 mg / ml.

[0132] The filler described in this application, because the preparation process of the composite microspheres adopts the melting method, avoids the use of organic solvents, and effectively improves the safety of the product. At the same time, the introduction of active components such as hyaluronic acid into the composite microspheres can enrich the functions of the microspheres and synergistically promote facial rejuvenation. Moreover, because the composite microspheres have the properties of being easy to disperse and degrade, the interaction between the composite microspheres and the external gel phase is improved, and the composite microspheres are better mixed and dispersed with the gel phase, reducing the risk of agglomeration; solving the problem of long degradation cycle of microspheres and excessive tissue immune formation adverse reactions.

[0133] Example

[0134] The experimental methods used in the following examples are all conventional methods unless otherwise specified.

[0135] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0136] Example 1

[0137] The preparation process of this embodiment is as follows Figure 1 In this example, 10 g of carboxymethyl cellulose and 0.5 g of polyvinyl alcohol were dissolved in 500 mL of pure water as the dispersed phase.

[0138] Step 1: Heat 50g of polycaprolactone at 60°C until completely melted, add 0.5g of hyaluronic acid powder, stir evenly to obtain a mixture of polycaprolactone-coated hyaluronic acid, and then transfer the mixture to the preheated dispersed phase, start stirring, and the stirring speed is 400-600 revolutions per minute. After the polycaprolactone is evenly dispersed, a mixture 2 is obtained, and the mixture 2 is quickly cooled to room temperature using an ice water bath. Then the obtained mixture 2 is filtered through a 50-micron mesh to remove the dispersed phase, retain the filtrate, and the filtrate is filtered again using a 20-micron mesh, and a large amount of pure water is used to rinse to completely remove the dispersed phase to obtain a composite microsphere with a size of 20-50 microns.

[0139] Step 2: Prepare a recombinant collagen gel solution with a mass concentration of 10%, use 1 mol / L sodium hydroxide to adjust the pH to 9-10, add 5% BDDE by mass, cross-link for 6-8 hours, cut the gel into pieces, granulate through a 60-mesh sieve to obtain a gel, then use dilute hydrochloric acid to adjust the pH to neutral, and then add saline solution and anesthetics to disperse the gel evenly, thereby obtaining a recombinant collagen gel solution, wherein the mass of physiological saline is 4 times that of the gel, and the concentration of lidocaine hydrochloride in the recombinant collagen gel solution is 0.3 mg / ml.

[0140] Step 3: Mix the above recombinant collagen gel solution with the composite microspheres, stir and mix evenly to obtain an injectable soft tissue filler containing polycaprolactone composite microspheres. In the filler, the mass of the composite microspheres is 15 mg, and the mass of the gel phase is 100 mg.

[0141] The parameters of the filler in this example are shown in Table 1.

[0142] The difference between Example 2 to Example 4 and Example 1 is that the types of active components are different. The parameters of this example are shown in Table 1.

[0143] The difference between Example 5 to Example 9 and Example 1 is that the mass ratio of polycaprolactone to the active component is different. The parameters of this example are shown in Table 1.

[0144] The difference between Example 10 to Example 12 and Example 1 is that the types of dispersants are different. The parameters of this example are shown in Table 1.

[0145] The difference between Example 13 to Example 15 and Example 1 is that the types of surfactants are different. The parameters of this example are shown in Table 1.

[0146] The difference between Example 16 to Example 19 and Example 1 is that the mass ratio of the composite microspheres to the gel phase is different. The parameters of this example are shown in Table 1.

[0147] The difference between Example 20 and Example 1 is that the polycaprolactone layer is replaced by a polylactic acid layer. The parameters of this example are shown in Table 1.

[0148] The difference between Comparative Example 1 and Example 1 is that the comparative example does not have step 2 and step 3, and in the process of preparing the composite microspheres, the dispersed phase and the hyaluronic acid are first mixed evenly, and then mixed with the molten polycaprolactone to form a structure in which the hyaluronic acid encapsulates the polycaprolactone. The parameters of this example are shown in Table 1.

[0149] Table 1 shows the parameters of each embodiment and comparative example.

[0150]

[0151]

[0152] Note: The particle size distribution in the table refers to the particle size distribution of the composite microspheres in mixture 2.

[0153] Summary: Most microsphere fillers in the prior art are prepared by the organic solvent volatilization method, which easily leads to organic solvent residues and can cause adverse reactions when injected into the skin. In addition, it is difficult to modify the components of PCL microspheres in the prior art, which causes excessive immune response and causes adverse reactions such as granulomas. The composite microspheres prepared in this application, on the one hand, avoid the use of organic solvents, and at the same time, greatly improve the characteristics of the composite microspheres by adding active substances such as hyaluronic acid, which can not only provide active ingredient supplements for the skin and improve skin condition, but also effectively reduce the risk of causing adverse reactions. Not only that, but also the composite microspheres prepared in the present application, most of the particle size is 20-60 μm before sieving, the raw material utilization rate is high, less than 20 μm is easily phagocytosed by macrophages, and more than 60 μm will increase the immune response, causing adverse reactions such as nodules or granulomas, and the composite microspheres of the present application and the cross-linked collagen gel compounding to form the filler, can simultaneously achieve instant shaping and long-term formation of collagen, the pushing force of the filler is 17.5-22N, similar to the existing products without microspheres, indicating that the active ingredients in the composite microspheres effectively improve the properties of the microspheres, and the interaction with the gel phase makes the microspheres more evenly dispersed, so the pushing force is close to the existing products, which facilitates the operation of the doctor during the operation. In addition, the product prepared by the method in Comparative Example 1 is first mixed evenly with the dispersed phase and hyaluronic acid, and then mixed with polycaprolactone in a molten state, so that the product formed is a microsphere of hyaluronic acid wrapped with polycaprolactone, and hyaluronic acid is located on the outside of polycaprolactone.

[0154] Although the embodiments of the present application are described above, the present application is not limited to the above specific embodiments and application fields, and the above specific embodiments are merely illustrative and instructive, rather than restrictive. A person of ordinary skill in the art can make many forms under the guidance of this specification and without departing from the scope of protection of the claims of the present application, all of which belong to the protection of the present application.

Claims

1. A composite microsphere, wherein: The invention comprises an active component and a polycaprolactone layer or a polylactic acid layer which wraps the active component.

2. The composite microsphere according to claim 1, wherein The particle size distribution of the composite microspheres is 20-50 μm.

3. The composite microsphere according to claim 1, wherein The mass ratio of the active component to the polycaprolactone layer is (0.01-30):100, preferably (0.01-20):100; or The mass ratio of the active component to the polylactic acid layer is (0.01-30):100, preferably (0.01-20):

100.

4. The composite microsphere according to claim 1, wherein The active component is selected from one or more of hyaluronic acid, collagen, and PDRN, preferably hyaluronic acid or collagen.

5. A method for preparing composite microspheres, wherein: The steps include: Adding the active component into molten polycaprolactone or polylactic acid and mixing them uniformly to obtain a mixture 1; Adding the mixture 1 to the dispersed phase, and rapidly stirring until the mixture 1 is evenly dispersed, to obtain a mixture 2; Post-treating the mixture to remove the dispersed phase, thereby obtaining composite microspheres; The composite microsphere has a shell formed by a polycaprolactone layer or a polylactic acid layer, and active components are encapsulated in the shell.

6. The preparation method according to claim 5, wherein: In the process of preparing mixture one, the melting temperature of the polycaprolactone or polylactic acid is 50-70°C or 125-180°C.

7. The preparation method according to claim 5, wherein: The dispersed phase includes a surfactant and a dispersant, and the mass ratio of the surfactant to the dispersant is (0.1-10): (0.01-35).

8. The preparation method according to claim 7, wherein: The surfactant is selected from one or two or more of Span, fatty alcohol polyoxyethylene ether, sodium dodecylbenzene sulfonate, and polyvinyl alcohol; or The dispersant is selected from one or more of polyvinyl alcohol, carbomer, cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and carrageenan.

9. A filler, wherein: The composite microsphere comprises the composite microsphere according to any one of claims 1 to 4.

10. A method for preparing a filler, wherein: Prepare composite microspheres according to any one of claims 5 to 8; preparing a gel phase; The composite microspheres and the gel phase are mixed in a certain ratio, stirred and evenly mixed, and sterilized to obtain the filler.

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