Compositions containing predispersed polycaprolactone microspheres and injectable polycaprolactone gels prepared therefrom

Abstract

The present invention discloses a composition containing pre-dispersed polycaprolactone microspheres and a polycaprolactone injectable gel prepared therefrom. In the composition containing pre-dispersed polycaprolactone microspheres, the polycaprolactone microspheres maintain their perfect spherical shape with a smooth surface and good dispersion, and can continue to have a reduced degradation rate. Air bubbles can be reduced during the mixing process, thereby helping to ensure the stability of product quality and reducing the probability of nodules and granulomas caused by uneven dispersion after the microspheres are injected into the body. The application value of the polycaprolactone injectable gel prepared from the composition containing pre-dispersed polycaprolactone microspheres is higher.

Description

[Technical Field]

[0001] The present invention relates to the technical field of medical cosmetic or medical preparations, and in particular to a composition containing pre-dispersed polycaprolactone microspheres and a polycaprolactone injectable gel prepared therefrom. [Background technology]

[0002] Polycaprolactone (PCL) was first synthesized in the 1930s as a linear aliphatic polyester obtained by ring-opening polymerization of ε-caprolactone. It is a hydrophobic, semi-crystalline polymer that is rubbery at room temperature. It has excellent thermal stability, with a decomposition temperature much higher than that of other polyesters. The products of PCL decomposition are CO₂ and HO, which are non-toxic to humans. Due to its unique physicochemical and mechanical properties, viscoelasticity, and shapability, PCL-based products with various shapes and service lives have been manufactured, particularly depending on its biodegradation rate. PCL has been safely used in the biomedical field for over 70 years, and its most recent application is the formulation of PCL into microspheres for use as a medical cosmetic filler, an implantable material for stimulating collagen production. PCL-based collagen-simulating agents consist of PCL microspheres suspended in a carboxymethylcellulose gel carrier, which can provide a rapid and sustained filling-out effect. To achieve a sustained effect, the biocompatibility and morphology of PCL microspheres embedded in collagen fibers help create a unique three-dimensional support.

[0003] As demand in the medical aesthetic market steadily increases, the market prospects for PCL have expanded. This is primarily due to the use of PCL in microspheres. The application areas of PCL microspheres in gel form include the forehead, nasolabial folds, midface, nose, chin, and hands. PCL microspheres maintain their efficacy for up to 24 months, and their safety and efficacy have already been confirmed in numerous clinical trials. Generally, the diameter of PCL injectable microspheres can range from 25 to 50 μm. Microspheres of this size are suitable for avoiding phagocytosis by macrophages and maintaining their presence in body tissues. Both the size and shape of microspheres have been shown to have a significant impact on tissue reactions. The shape of the microspheres, i.e., whether they are round or irregular, determines the severity of the reaction. PCL microspheres have a regular spherical shape with a smooth surface, which is known to be optimal for minimizing inflammatory reactions. A smoother spherical shape is better for subcutaneous injection. Microspheres with a high level of smoothness can stimulate the coverage of fibro-forming cells beneath the wrinkles one by one, while also reducing the occurrence of granulomas and foreign body reactions. Generally, for injecting the microspheres, smooth-surfaced PCL microspheres (30% by volume) are prepared and uniformly suspended in 70% CMC gel.

[0004] Regarding the preparation of smooth-surfaced PCL microspheres, various methods for preparing smooth PCL microspheres have already been disclosed in the prior art. For example, CN104001209B discloses filtering, washing, and drying the resulting microspheres, and then dispersing the microspheres in a CMC gel. To avoid solidification of the PCL solution in a stirred aqueous medium, the conditions used in this preparation process include adding a PCL solution in DCM over a long period of time and allowing the DCM to evaporate for a long period of time so that the dispersed PCL particles harden. This document also investigates the Hunter method (Example 14 of U.S. Patent Application Publication No. 2003 / 0157187A) and the Erneta and Wu method (Examples of European Patent Application Publication No. 1872803), and summarizes the effects of surfactants in water and DCM, as well as surfactant viscosity and stirring speed, on particle shape and particle surface smoothness. CN109998997B discloses that microspheres prepared by membrane emulsification have an average microsphere diameter of 50 μm after filtration, washing, and drying, and that the microspheres have a smooth surface and good morphology in terms of appearance and morphology. However, if the prepared dried microspheres are to be dispersed in a gel and maintain their surface smoothness in the gel, further research is needed on the microsphere dispersion process and gel. Before PCL microspheres are mixed into the CMC gel, some air will likely be absorbed onto the surface, creating a problem in the homogeneous mixing process where liquid and gas begin to compete for the microsphere surface, making it difficult to remove air bubbles from the microsphere surface. Furthermore, because the CMC gel has a high viscosity, PCL microspheres are difficult to disperse during the homogeneous mixing process and easily form air bubbles. Therefore, a new method is needed to solve the above problems in the homogeneous mixing process. Furthermore, studies have found that the hydrolysis of PCL microspheres is related to the penetration of water into the microspheres. When water penetrates into the microspheres, a global degradation process occurs, resulting in the gradual hydrolysis of ester bonds throughout the polymer matrix from the inside.Therefore, further research into the microsphere dispersion process and gel fundamentals is needed to further reduce the hydrolysis of PCL and at the same time encourage the prepared PCL microspheres to have a smooth surface even in the gel. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the present invention provides a composition containing pre-dispersed polycaprolactone (PCL) microspheres and an injectable gel containing a high concentration of polycaprolactone, the gel being prepared from the composition. Through research, the inventors unexpectedly discovered that the homogenous mixing or redispersion step after drying the PCL microspheres was the main factor affecting the dispersion, bubble formation, and smoothness of injectable PCL microspheres. Furthermore, the inventors also unexpectedly discovered that, compared with commonly used PCL microsphere dispersion media in the prior art, i.e., purified water, distilled water, saline, etc., the dispersion media and gel matrix selected in the present invention can effectively reduce PCL degradation, and maintaining the smooth spherical shape of the microspheres helps to reduce the rate of microsphere degradation.

[0006] In a first aspect of the present invention, there is provided a composition of pre-dispersed polycaprolactone microspheres, the composition comprising polycaprolactone microspheres and a phosphate buffer.

[0007] Specifically, the phosphate buffer contains dibasic phosphate and / or monobasic phosphate, and more specifically, the phosphate buffer contains dibasic phosphate and monobasic phosphate.

[0008] Specifically, the dibasic phosphate is selected from one or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium hydrogen phosphate.

[0009] Specifically, the monobasic phosphate is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, or ammonium dihydrogen phosphate.

[0010] In some embodiments of the invention, the dibasic phosphate is disodium hydrogen phosphate and the monobasic phosphate is sodium dihydrogen phosphate.

[0011] In another embodiment of the present invention, the dibasic phosphate is disodium hydrogen phosphate and the monobasic phosphate is potassium dihydrogen phosphate.

[0012] In another embodiment of the present invention, the dibasic phosphate is dipotassium hydrogen phosphate and the monobasic phosphate is potassium dihydrogen phosphate.

[0013] In another embodiment of the present invention, the dibasic phosphate is dipotassium hydrogen phosphate and the monobasic phosphate is sodium dihydrogen phosphate.

[0014] Specifically, the phosphate buffer may further include one or more pH adjusters, such as hydrochloric acid, sodium hydroxide, and potassium hydroxide.

[0015] Specifically, the phosphate buffer has a pH of 6.0 to 8.0 (for example, 6.0, 6.2, 6.4, 6.5, 6.6, 6.8, 7.0, 7.2, 7.4, 7.5, 7.6, 7.8, 8.0), particularly 6.5 to 8.0, and preferably 7.0 to 7.5.

[0016] Specifically, the phosphate buffer may further include one or more of an osmolality adjusting agent, such as potassium chloride, sodium chloride, and glycerin.

[0017] Specifically, the phosphate buffer has an osmotic pressure of 300 to 700 mOsm / kg (for example, 300, 350, 400, 450, 500, 550, 60 mOsm / kg), particularly 500 to 600 mOsm / kg, and preferably 550 to 650 mOsm / kg.

[0018] In some preferred embodiments of the present invention, the phosphate buffer contains disodium hydrogen phosphate and sodium dihydrogen phosphate, and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, for example, 7.2) and an osmolality of 500 to 650 mOsm / kg, more specifically, the phosphate buffer consists of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, and water.

[0019] In some preferred embodiments of the present invention, the phosphate buffer comprises disodium hydrogen phosphate and potassium dihydrogen phosphate, and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, e.g., 7.2) and an osmolality of 300 to 700 mOsm / kg (particularly 600 mOsm / kg). More specifically, the phosphate buffer can be formed by combining disodium hydrogen phosphate (NaHPO), potassium dihydrogen phosphate (KHPO), and an aqueous solution of potassium chloride.

[0020] In some preferred embodiments of the present invention, the phosphate buffer contains dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, for example, 7.2) and an osmolality of 500 to 650 mOsm / kg, more specifically, the phosphate buffer consists of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, and water.

[0021] Specifically, the PCL microspheres have an average particle size range of 25 to 60 μm (e.g., 25, 30, 35, 40, 45, 50, 55, 60 μm).

[0022] Specifically, microspheres with particle sizes of 25-50 μm account for ≧65% of the PCL microspheres.

[0023] Specifically, the PCL microspheres have a weight average molecular weight of 8,000 to 80,000 Da (e.g., 10,000 Da, 20,000 Da, 30,000 Da, 40,000 Da, 45,000 Da, 60,000 Da, 80,000 Da), particularly 10,000 to 60,000 Da.

[0024] Specifically, in a composition in which polycaprolactone microspheres are pre-dispersed, the content of PCL microspheres can be 10 to 50 wt% (e.g., 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%).

[0025] Specifically, PCL microspheres were prepared by the following method: (1) Preparation of an aqueous phase: Mixing a solution containing one or more of a film-forming agent, a surfactant, and a thickener to function as an aqueous phase; (2) Preparation of oily phase: dissolving dry PCL in an organic solvent; (3) preparing microspheres; (4) volatilizing the organic solvent in the emulsion, hardening and filtering the microspheres, washing, collecting and drying; It can be prepared by

[0026] Specifically, film-forming agents include, but are not limited to, polyvinyl alcohol, poly(propylene glycol), gelatin, gum arabic, dextran sulfate, hyaluronic acid, pectin, carrageenan, and the like.

[0027] Specific surfactants include, but are not limited to, Tween, Span, sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, and the like.

[0028] Specifically, thickening agents include, but are not limited to, gelatin, starch, carrageenan, sodium alginate, chitosan, fructose, sodium carboxymethylcellulose, highly substituted carboxypropylcellulose, low substituted carboxypropylcellulose, microcrystalline cellulose, carboxypropylmethylcellulose, carboxyethylcellulose, and the like.

[0029] Specifically, the organic solvent is selected from benzyl alcohol, dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, ethyl acetate, ethyl formate, diethyl ether, cyclohexane, or a mixture thereof.

[0030] Specifically, the preparation of microspheres in step (3) can be performed using methods well known in the art, such as membrane emulsification and spray drying. For example, in the preparation of microspheres by membrane emulsification, an oily phase is extruded into a continuous aqueous phase at a flow rate of 50 to 10,000 ml / min through a membrane tube with membrane pores of 5 to 100 μm, using a pressure of 800 to 10,000 MPa, preferably 800 to 3,500 MPa, and more preferably 1,000 to 2,000 MPa. The microspheres thus prepared can have a D50 of 1 to 100 μm, a span of ≦2.0, uniform density, composition, and morphology, spherical appearance, and a smooth surface.

[0031] In some embodiments of the present invention, PCL microspheres are prepared by the following method: preparing an aqueous phase, preparing an oily phase from polycaprolactone using dichloromethane, emulsifying the aqueous phase and the oily continuous phase, and then vacuum drying to obtain polycaprolactone microspheres. The aqueous phase includes one or more of polyvinyl alcohol, carboxymethylcellulose, sodium carboxymethylcellulose, Tween 80, gelatin, carboxypropylcellulose starch, and sodium dodecyl sulfate.

[0032] In particular, the PCL microspheres can be sterile.

[0033] In a second aspect of the present invention, there is provided a method for preparing a composition containing pre-dispersed polycaprolactone microspheres, the method comprising the step of dispersing (uniformly) dry polycaprolactone microspheres in a dispersing liquid, the dispersing liquid being a phosphate buffer. Dispersing liquids for polycaprolactone microspheres are generally purified water, distilled water, or saline. Through research, the inventors have found that using a phosphate buffer as a dispersing liquid helps maintain optimal dispersion of the polycaprolactone microspheres and reduces the formation of air bubbles.

[0034] In particular, the polycaprolactone microspheres and the phosphate buffer have the definitions set out in the first aspect of the invention.

[0035] In a third aspect of the present invention, there is provided an injectable polycaprolactone gel prepared by a method comprising mixing the pre-dispersed composition described in the first aspect with a gel matrix, wherein the gel matrix comprises carboxymethylcellulose (sodium) (i.e., carboxymethylcellulose or carboxymethylcellulose sodium) and a dispersion liquid.

[0036] Specifically, the polycaprolactone injectable gel is prepared by a method comprising the steps of adding and mixing the pre-dispersed composition described in the first aspect to a gel matrix.

[0037] Specifically, the dispersion liquid for the gel matrix is ​​selected from water (for example, distilled water, purified water, water for injection), physiological saline, and phosphate buffer solution.

[0038] In a preferred embodiment of the invention, the dispersion of the gel matrix is ​​a phosphate buffer, in particular a phosphate buffer as described in the first aspect of the invention.

[0039] Specifically, a high content of polycaprolactone microspheres in the polycaprolactone injectable gel means that the content of polycaprolactone microspheres is higher than 20%, preferably higher than 25%, more preferably higher than 30%.

[0040] Specifically, the content of polycaprolactone microspheres in the polycaprolactone injectable gel is 28 to 38 wt% (e.g., 28%, 30%, 32%, 33%, 34%, 36%, 38%), particularly 30 to 36%.

[0041] Specifically, the content of carboxymethylcellulose (sodium) in the polycaprolactone injectable gel is 1 to 5 wt% (for example, 2 wt%, 2.3 wt%, 2.6 wt%, 2.9 wt%, 3 wt%, 4 wt%).

[0042] Specifically, the polycaprolactone injectable gel may further include a pH adjusting agent, such as one or more of hydrochloric acid, sodium hydroxide, and potassium hydroxide.

[0043] Specifically, the polycaprolactone injectable gel has a pH of 6.0 to 8.0 (for example, 6.0, 6.2, 6.4, 6.5, 6.6, 6.8, 7.0, 7.2, 7.4, 7.5, 7.6, 7.8, 8.0), particularly 6.5 to 8.0, and preferably 7.0 to 7.5.

[0044] Specifically, the polycaprolactone injectable gel may further comprise one or more of an osmotic agent, such as potassium chloride, sodium chloride, and glycerin.

[0045] The injectable polycaprolactone gel preferably has an osmotic pressure of 300 to 600 mOsm / kg (for example, 300, 350, 400, 450, 500, 550, 600 mOsm / kg), particularly 500 to 650 mOsm / kg, and preferably 550 to 650 mOsm / kg.

[0046] In particular, the polycaprolactone injectable gel may further comprise an anesthetic, such as lidocaine, tetracaine, and the like.

[0047] Specifically, polycaprolactone injectable gels may further contain lubricants such as glycerin.

[0048] Specifically, the polycaprolactone injectable gel may further contain an antibacterial agent to improve the antibacterial effect, so that the polycaprolactone injectable gel has better antibacterial effect during use, storage and transportation.

[0049] Specifically, the polycaprolactone injectable gel may further include an anti-inflammatory agent to reduce the inflammatory response of the organism.

[0050] Specifically, the polycaprolactone injectable gel may further include an antioxidant to improve resistance to oxidation.

[0051] In a fourth aspect of the present invention, there is provided a method for preparing a polycaprolactone injectable gel, comprising the steps of: (1) dispersing (uniformly) polycaprolactone microspheres in dispersion I to obtain a polycaprolactone pre-dispersed composition; (2) dispersing carboxymethylcellulose (sodium) in dispersion II to obtain a gel matrix; (3) adding the polycaprolactone pre-dispersed composition to the gel matrix and mixing (together); A method is provided which includes:

[0052] Specifically, Dispersion I is a phosphate buffer solution as described in the first aspect of the present invention.

[0053] Specifically, dispersion II is selected from water (e.g., distilled water, purified water, water for injection), saline and phosphate buffer, in particular the phosphate buffer described in the first aspect of the present invention.

[0054] Specifically, Dispersion I and Dispersion II may be the same phosphate buffer solution. For example, in some preferred embodiments of the present invention, the phosphate buffer solution contains disodium hydrogen phosphate and sodium dihydrogen phosphate and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, for example, 7.2) and an osmotic pressure of 500 to 650 mOsm / kg. More specifically, the phosphate buffer solution consists of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, and water. In other preferred embodiments of the present invention, the phosphate buffer solution contains disodium hydrogen phosphate and potassium dihydrogen phosphate and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, for example, 7.2). and has an osmolality of 300 to 700 mOsm / kg (particularly 600 mOsm / kg). Specifically, the phosphate buffer comprises disodium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, and water. In another preferred embodiment of the present invention, the phosphate buffer comprises dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and has a pH of 6.0 to 8.0 (particularly 6.5 to 7.5, for example, 7.2) and an osmolality of 500 to 650 mOsm / kg. More specifically, the phosphate buffer comprises dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, and water.

[0055] Specifically, step (1) may further include a step of adjusting the pH.

[0056] Specifically, step (1) may further include the step of adjusting the osmotic pressure.

[0057] Specifically, step (1) may further include a sterilization step.

[0058] Specifically, step (2) may further include a step of adjusting the pH.

[0059] Specifically, step (2) can further include the step of adjusting the osmotic pressure.

[0060] Specifically, step (2) may further include a sterilization step.

[0061] Specifically, the mixing in step (3) is carried out by stirring, and the stirring speed can be 800 to 1200 r / min (e.g., 1000 r / min), and the stirring time can be 1 to 10 minutes (e.g., 5 minutes).

[0062] Specifically, step (3) may further include a step of removing bubbles, for example, performing a stirring bubble removal treatment using a vacuum stirring bubble removal device.

[0063] In a fifth aspect of the present invention there is provided the use of the polycaprolactone pre-dispersed composition according to the first aspect for preparing a polycaprolactone injectable gel, implant or drug carrier.

[0064] In embodiments of the invention, the implant is a cosmetic implant, for example a subdermal implant (e.g., implanted in the forehead, nasolabial folds, mid-face, nose, chin, hands, etc., to reduce wrinkles, folds, scars, signs of aging, etc.), and in some embodiments of the invention the implant is a dermal filler.

[0065] In another embodiment of the invention, the implant is an implant for treating a disease, such as a stent.

[0066] The polycaprolactone microsphere pre-dispersed composition of the present invention has the following beneficial effects:

[0067] PCL microspheres maintain an intact spherical shape with a smooth surface, good dispersion, and a reduced degradation rate. Air bubbles can be reduced during mixing, helping to ensure stable product quality. After injection, the probability of nodule and granuloma formation due to uneven dispersion of the microspheres is reduced. Polycaprolactone injectable gels made from PCL microspheres have better application value. [Brief explanation of the drawings]

[0068] [Figure 1] FIG. 1 shows a micrograph of undispersed dry polycaprolactone microspheres. [Figure 2] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in distilled water. [Figure 3] FIG. 1 shows an electron microscope photograph of polycaprolactone microspheres after dispersion in distilled water. [Figure 4] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in 0.9% saline. [Figure 5] FIG. 1 shows an electron microscope photograph of polycaprolactone microspheres after dispersion in 0.9% saline. [Figure 6] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in sodium-based 3-2 isotonic phosphate buffer. [Figure 7] FIG. 1 shows an electron microscope photograph of polycaprolactone microspheres after dispersion in sodium-based 3-2 isotonic phosphate buffer. [Figure 8] FIG. 1 shows micrographs of polycaprolactone microspheres after dispersion in potassium-based 1, 3-5 isotonic phosphate buffers. [Figure 9] FIG. 1 shows electron micrographs of polycaprolactone microspheres after dispersion in potassium-based 1, 3-5 isotonic phosphate buffers. [Figure 10]FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in potassium-based 2, 3-8 isotonic phosphate buffer. [Figure 11] FIG. 1 shows electron micrographs of polycaprolactone microspheres after dispersion in potassium-based 2, 3-8 isotonic phosphate buffer. [Figure 12] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in a sodium-based buffer solution (4-1-6) with an osmolality of 600 mOsm / kg. [Figure 13] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in potassium-based 1 buffer (4-2-6) with an osmolality of 600 mOsm / kg. [Figure 14] FIG. 1 shows a micrograph of polycaprolactone microspheres after dispersion in potassium-based 2 buffer (4-3-6) with an osmolality of 600 mOsm / kg. [Figure 15] FIG. 1 shows an electron microscope photograph of polycaprolactone microspheres after dispersion in potassium-based 1 buffer (4-2-6) with an osmolality of 600 mOsm / kg. [Figure 16] FIG. 1 shows a photograph of the appearance of an injectable gel containing polycaprolactone microspheres of Example 11. [Figure 17] FIG. 1 shows a micrograph of an injectable gel containing polycaprolactone microspheres of Example 11. [Figure 18] FIG. 1 shows a photograph of the appearance of the injectable gel containing polycaprolactone microspheres of Example 12 after stirring at 1000 r / min. [Figure 19] FIG. 1 shows a photograph of the appearance of the injectable gel containing polycaprolactone microspheres of Example 12 after stirring at 2200 r / min. [Figure 20] FIG. 1 shows a micrograph of an injectable gel containing polycaprolactone microspheres of Example 12 after stirring at 2200 r / min. [Figure 21]FIG. 1 shows a photograph of the appearance of the injectable gel containing polycaprolactone microspheres of Example 13 after stirring at 1000 r / min. [Figure 22] FIG. 1 shows a photograph of the appearance of the injectable gel containing polycaprolactone microspheres of Example 13 after stirring at 2200 r / min. Specific Embodiments

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0070] The disclosures of various publications, patents and disclosed patent specifications cited herein are hereby incorporated by reference in their entireties.

[0071] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and obviously, the described embodiments are only a part of the embodiments of the present invention, but are not all of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without inventive efforts fall within the protection scope of the present invention.

[0072] The measurement method used in the following embodiments has the following specific operations.

[0073] Morphology and particle size determination of dry microspheres Take an appropriate amount of dried microspheres, cut approximately 0.5 cm of conductive adhesive tape and stick it on a sample tray, scrape a small amount of powder and stick it on the conductive adhesive tape, use a bulb syringe to blow off excess floating powder from the conductive adhesive tape, sputter coat with gold, put the sample stage into an apparatus for observation, and take electron micrographs using a thermal field emission scanning electron microscope (e.g., JEOL-JSM-7001F).

[0074] A small amount of dry microspheres is taken and dispersed in the dispersion liquid, and stirred at high speed or ultrasonicated for 10 minutes. When the microspheres are completely dispersed, they are dropped into a quartz dish and the particle size distribution of the microspheres is measured using a Zeta particle size analyzer.

[0075] Determination of morphology and particle size of dispersed microspheres A small amount of dry microspheres is taken and dispersed in the dispersion liquid, and the mixture is stirred at high speed or sonicated for 10 minutes, and the dispersion of the microspheres and the formation of bubbles are observed using a microscope (XP-550C polarizing microscope).

[0076] A small amount of dry microspheres is taken and dispersed in the dispersion liquid, and stirred at high speed or ultrasonicated for 10 minutes. When the microspheres are completely dispersed, they are dropped into a quartz dish and the particle size distribution of the microspheres is measured using a Zeta particle size analyzer.

[0077] Measurement of microsphere degradation in dispersions Six aliquots of PCL microspheres of the same mass were weighed out separately (W0), then immersed separately in a distilled water dispersion and placed on a vibration table at 37°C with a vibration speed of 60 r / min. The dispersion was changed every week, and measurements were carried out for 48 weeks, with each 8-week degradation period being one. At the end of each degradation period, the samples were removed, thoroughly washed with distilled water, and weighed until a constant weight (W t ) and freeze-dry under vacuum until the decomposition rate = (W0 - W t ) / W0×100%.

[0078] Measurement of microsphere degradation in gels Six aliquots of PCL microspheres with the same mass were weighed out (W0) and then mixed with distilled water as a dispersion to prepare the corresponding carboxymethylcellulose (or sodium carboxymethylcellulose) gels. These were then placed on a vibration table at 37°C with a vibration speed of 60 r / min. Measurements were conducted for 48 weeks, with each 8-week period representing a degradation period. At the end of each degradation period, one sample was taken, and the microspheres were collected by centrifugation, thoroughly washed with distilled water, and freeze-dried under vacuum until the weight reached a constant value (Wt). The degradation rate of the PCL microspheres in the gel prepared from the dispersion was calculated as (W0-Wt) / W0×100%.

[0079] For the measurement of the degradation rate in carboxymethylcellulose (or sodium carboxymethylcellulose) gels prepared using 0.9% saline and PBS as the dispersing liquid, the preparation and measurement process was the same as that described above in which distilled water served as the dispersing liquid.

[0080] 1. Preparation of Dry Polycaprolactone Microspheres Example 1 10-20 grams of PCL with a molecular weight of 8 kDa was dissolved in dichloromethane (DCM, 10-20 w / w%), and the solution was dispersed in 1000 ml of water containing 0.1%-5% MC. The solution was extracted with a solvent at 1000 rpm, and the resulting microspheres were filtered, washed, and dried. Particles with an average diameter of 40 μm were obtained with a span of 1.18 and a yield of approximately 67%. Microspheres with a particle size of 25-50 μm accounted for 68.6% of the PCL microspheres.

[0081] Example 2 53.9 g of PCL with a molecular weight of 10,000 Da was weighed and dissolved in dichloromethane (DCM, viscosity 700 cp). The oil phase solution was dispersed in an aqueous solution containing polyvinyl alcohol (1%), Tween 80 (0.1%), and sodium carboxymethylcellulose (2.2%) using a membrane emulsification method at a high shear pressure of 800 MPa. The resulting microspheres were filtered, washed, and dried. The microspheres had an average diameter of approximately 50 μm, a span of 1.19, and a yield of approximately 70%. Microspheres with particle sizes between 25 and 50 μm accounted for 70.4% of the PCL microspheres.

[0082] Example 3 54.9 g of PCL with a molecular weight of 40,000 Da was weighed and dissolved in dichloromethane (DCM, viscosity 800 cp). Using a high-speed homogenization emulsification method, the oil phase solution was dispersed in an aqueous solution containing polyvinyl alcohol (1%), aqueous gelatin (0.5%), and sodium carboxymethylcellulose (3.7%) under high-speed shear. The resulting microspheres were filtered, washed, and dried. The microspheres had an average diameter of approximately 55 μm, with a span of 1.19 and a yield of approximately 65%. Microspheres with a particle size of 25-50 μm accounted for 65.6% of the PCL microspheres.

[0083] Example 4 54.9 g of PCL with a molecular weight of 60,000 Da was weighed and dissolved in dichloromethane (DCM, viscosity 800 cp). The oil phase solution was dispersed in an aqueous solution containing polyvinyl alcohol (1%) and carboxypropyl cellulose (2.2%) using a membrane emulsification method at a high shear pressure of 800 MPa. The resulting microspheres were filtered, washed, and dried. The microspheres had an average diameter of approximately 60 μm, a span of 1.19, and a yield of approximately 55%. Microspheres with particle sizes between 25 and 50 μm accounted for 66.2% of the PCL microspheres.

[0084] Example 5 53.9 g of PCL with a molecular weight of 80,000 Da was weighed and dissolved in dichloromethane (DCM, viscosity 700 cp). The oil phase solution was dispersed in an aqueous solution containing polyvinyl alcohol (1%), sodium dodecyl sulfate (0.1%), and carboxymethylcellulose (2.2%) using a membrane emulsification method at a high shear pressure of 800 MPa. The resulting microspheres were filtered, washed, and dried. The microspheres had an average diameter of approximately 50 μm, a span of 1.19, and a yield of approximately 70%. Microspheres with particle sizes between 25 and 50 μm accounted for 73.3% of the PCL microspheres.

[0085] 2. Dispersion of Dried Polycaprolactone Microspheres In the following examples, the effects of different dispersing liquids on the degree of dispersion, air bubble content, and smoothness of the resulting PCL microspheres are investigated using the PCL microspheres prepared by the method of Example 2. Figure 1 shows a photomicrograph (XP-550C polarizing microscope, 10x) of undispersed microspheres, which exhibit agglomerations.

[0086] Example 6: Dispersion 1 (distilled water) The resulting microspheres were dispersed in distilled water and observed for surface smoothness, spherical integrity, and dispersion using a microscope and an electron microscope. Figures 2 and 3 show a photomicrograph (XP-550C polarizing microscope, 10x) and an electron microscope photograph of the PCL microspheres, respectively.

[0087] As shown in Figure 2, the microspheres do not disperse well in distilled water.

[0088] As shown in Figure 3, the surface smoothness of the microspheres is reduced and the spherical integrity of the microspheres is compromised.

[0089] Example 7: Dispersion 2 (0.9% saline) The resulting microspheres were dispersed in 0.9% saline and observed for surface smoothness, spherical integrity, and dispersion using a microscope and an electron microscope. Figures 4 and 5 show a photomicrograph (XP-550C polarizing microscope, 20x) and an electron microscope photograph of the PCL microspheres, respectively.

[0090] As shown in Figure 4, the dispersion degree of the microspheres in saline is improved compared to distilled water, and as can be seen from the electron micrograph in Figure 5, the surface smoothness of the microspheres is impaired to a relatively small extent, while the spherical integrity is improved.

[0091] Example 8: Dispersion 3: (isotonic phosphate buffers with different pH values) 1. Preparation of Sodium-Based Isotonic Phosphate Buffer Disodium hydrogen phosphate: 0.1M disodium hydrogen phosphate (Na2HPO4), store at 4°C. Sodium dihydrogen phosphate: 0.1 M sodium dihydrogen phosphate (NaH2PO4·H2O).

[0092] Prepare a solution of the required pH according to the table below.

[0093] [Table 1]

[0094] The resulting microspheres were dispersed in the above-mentioned dispersions 3-1 to 3-3, and observed using a microscope and an electron microscope for the following: surface smoothness (smooth +++++, almost smooth ++++, slightly uneven +++, quite uneven ++, quite uneven +), sphericity (spherical +++++, almost spherical ++++, one to two ellipsoidal vertices +++, two to four ellipsoidal vertices ++, five or more ellipsoidal vertices +), and dispersity (no clustering +++++, almost no clustering ++++, slight clustering +++, three or more clusters of quite a few microspheres ++, three or more clusters of many microspheres +). The observation results are shown in the table below. Figures 6 and 7 show a photomicrograph (XP-550C polarizing microscope, 10x magnification) and an electron microscope photograph of the PCL microspheres in dispersion 3-2, respectively.

[0095] [Table 2]

[0096] From Figures 6 and 7 (corresponding to Dispersion 3-2) and the above table, it can be seen that the dispersion degree of the microspheres in the sodium-based isotonic phosphate buffer solution is further improved, and from the electron micrographs, it can be seen that the surface smoothness of the microspheres is impaired to a relatively small extent, and the spherical integrity is improved.

[0097] 2. Preparation of isotonic phosphate buffer solution of potassium system 1: Disodium hydrogen phosphate: 0.1M disodium hydrogen phosphate (Na2HPO4), store at 4°C. Potassium dihydrogen phosphate: 0.1M potassium dihydrogen phosphate (KH2PO4), store at 4°C.

[0098] Prepare a solution of the required pH according to the table below.

[0099] [Table 3] The resulting microspheres were dispersed in the above dispersions 3-4 to 3-6, and the surface smoothness, spherical integrity, and degree of dispersion of the PCL were observed using a microscope and an electron microscope. The observation results are shown in the table below. Figures 8 and 9 show a photomicrograph (XP-550C polarizing microscope, 10x) and an electron microscope photograph of the PCL microspheres in dispersion 3-5, respectively.

[0100] [Table 4]

[0101] From Figures 8-9 (corresponding to Dispersions 3-5) and the above table, it can be seen that the dispersion degree of the microspheres in potassium-based 1 isotonic phosphate buffer is further improved, and from the electron microscope photographs, it can be seen that the surface smoothness of the microspheres is only slightly impaired, and the spherical integrity is high.

[0102] 3. Preparation of potassium-based isotonic phosphate buffer solution: Dipotassium hydrogen phosphate (divalent): 0.1 M dipotassium hydrogen phosphate (K2HPO4), store at 4°C. Potassium dihydrogen phosphate: 0.1M potassium dihydrogen phosphate (KH2PO4), store at 4°C.

[0103] Prepare a solution of the required pH according to the table below.

[0104] [Table 5] The resulting microspheres were dispersed in the above dispersions 3-7 to 3-9, and the surface smoothness, spherical integrity, and degree of dispersion of the PCL were observed using a microscope and an electron microscope. The observation results are shown in the table below. Figures 10 and 11 show a photomicrograph (XP-550C polarizing microscope, 10x) and an electron microscope photograph of the PCL microspheres in dispersion 3-8, respectively.

[0105] [Table 6]

[0106] From Figures 10-11 (corresponding to Dispersions 3-8) and the above table, it can be seen that the microspheres in potassium-based 2 isotonic phosphate buffer and sodium-based dispersions are similar, with good dispersion in both cases, and the electron micrographs show that the surface smoothness of the microspheres is only slightly impaired and the spherical integrity is high. Example 9: Dispersion 4: (Phosphate buffers with different osmotic properties)

[0107] 1. Preparation of buffer solutions with different osmotic properties based on sodium-based isotonic phosphate buffer (pH 7.2, 100 ml) With reference to Dispersion 3-2 in Table 2 of Example 8, the osmotic pressure is adjusted by adjusting the amount of NaCl added to obtain Dispersions 4-1-1 to 4-1-8.

[0108] The obtained microspheres were dispersed in the above dispersions 4-1-1 to 4-1-8, and the smoothness of the PCL surface, the completeness of the sphericity, and the degree of dispersion were observed using a microscope and an electron microscope. The observation results are shown in the table below.

[0109] [Table 7]

[0110] 2. Preparation of buffer solutions of different osmotic properties based on potassium system 1. Isotonic phosphate buffer solution (pH 7.2, 100 ml)

[0111] With reference to Dispersion 3-5 in Table 3 of Example 8, the osmotic pressure is adjusted by adjusting the amount of KCl added to obtain Dispersions 4-2-1 to 4-2-8.

[0112] The obtained microspheres were dispersed in the above dispersions 4-2-1 to 4-2-8, and the smoothness of the PCL surface, the completeness of the sphericity, and the degree of dispersion were observed using a microscope and an electron microscope. The observation results are shown in the table below.

[0113] [Table 8]

[0114] 3. Preparation of buffer solutions of different osmotic properties based on potassium-based 2 isotonic phosphate buffer (pH 7.2, 100 ml) With reference to Dispersion 3-8 in Table 5 of Example 8, the osmotic pressure is adjusted by adjusting the amount of KCl added to obtain Dispersions 4-3-1 to 4-3-8.

[0115] The resulting microspheres were dispersed in the above dispersions 4-3-1 to 4-3-8, and the surface smoothness, spherical integrity, and degree of dispersion of the PCL were observed using a microscope (XP-550C polarizing microscope, 10x) and an electron microscope. The observation results are shown in the table below.

[0116] [Table 9]

[0117] From Figures 12 to 14 (corresponding to dispersions 4-1-6, 4-2-6 and 4-3-6, respectively) and the above table, it can be seen that when microspheres are dispersed in a buffer solution with an osmotic pressure of 600 in potassium system 1, compared with dispersions with other osmotic pressures in sodium system, potassium system 2 and potassium system 1, the microspheres have a good dispersion degree, the surface smoothness of the microspheres is impaired to a very small extent, and no significant change in the spherical integrity is observed.

[0118] Example 10: Effect of Dispersion Fluid on Microsphere Degradation 750 mg (W0) of PCL microspheres (weight average molecular weight of PCL = 40,000) were weighed out into 18 aliquots, and then 6 aliquots were separately immersed in 10 mL of PBS solution (dispersion 4-2-6 in Example 9), 10 mL of 0.9% saline, and 10 mL of distilled water, and placed on a vibration table at 37 °C and a vibration speed of 60 r / min. The solution was changed weekly, and measurements were conducted for 48 weeks, with each 8-week degradation period representing one degradation period. At the end of each degradation period, the samples were removed, thoroughly washed with distilled water, and freeze-dried under vacuum until a constant weight (Wt) was reached. The degradation rate = (W0 - Wt) / W0 x 100%.

[0119] [Table 10]

[0120] From the table above, it can be seen that the degradation rate of PCL pre-dispersed in PBS (Dispersion 4-2-6 in Example 9) is lower than that in saline and significantly lower than that in distilled water. Therefore, it can be seen that PBS as a dispersion can effectively reduce PCL degradation, and maintaining the smooth spherical shape of the microspheres helps to reduce the rate of microsphere degradation.

[0121] 1. Preparation of polycaprolactone microsphere gels: Example 11: The injectable gel of polycaprolactone microspheres was prepared by the following steps: (1) Stirring and uniformly mixing CMC with deionized water to obtain a CMC suspension, adding sodium hydroxide solution to the CMC suspension and uniformly mixing, then adding hydrochloric acid to adjust the pH value to neutral to obtain a CMC-Na gel, and weighing out 33 g of the CMC-Na gel; (2) preparing dispersion 4-2-6 of Example 9 using a phosphate buffer; (3) dispersing 33 g of the sterilized PCL microspheres in 33 g of a dispersion liquid, the dispersion liquid being a phosphate buffer solution with a pH value of about 7, at a stirring rotation speed of 500 r / min to form a uniformly pre-dispersed composition; (4) adding the pre-dispersed composition to CMC-Na gel (the CMC-Na content in the final product is 2.6 wt%), adding glycerin in an amount corresponding to 1 wt% of the product, and pre-stirring for 5 minutes using a glass rod or a thin scraper; (5) Preparing a premixed sample and subjecting it to a defoaming treatment using a vacuum defoaming device at a rotation speed of 1000 r / min for 6 minutes. The amount of PCL used in the final product is 33 wt%.

[0122] Example 12: (Comparative 1): Adding PCL microspheres directly to CMC-Na gel without preparing a pre-dispersed composition The injectable gel of polycaprolactone microspheres was prepared by the following steps: (1) dissolving 2.6 g of CMC-Na powder in 63.4 g of the phosphate buffer solution prepared in Example 11 to form a gel; (2) adding 33 g of sterilized PCL microspheres to the CMC-Na gel (the CMC-Na content in the final product is 2.6 wt%), adding glycerin in an amount corresponding to 1 wt% of the product, and pre-stirring for 5 minutes using a glass rod or a thin scraper; (3) Prepare a premixed sample and perform defoaming treatment using a vacuum defoamer at a rotation speed of 1000 r / min for 6 minutes. The amount of PCL used in the final product is 33 wt%. Then, increase the rotation speed to 2200 r / min and process for 10 minutes.

[0123] Example 13 (Comparative Example 2): PCL microspheres, CMC-Na powder, phosphate buffer solution, and glycerin are directly mixed without preparing a pre-dispersed composition. The injectable gel of polycaprolactone microspheres was prepared by the following steps: (1) Stirring 33 g of PCL microspheres, 63.4 g of the phosphate buffer solution prepared by the method of Example 11, and 1 g of glycerin at a rotation speed of 500 r / min to form a uniform suspension; (2) Put 2.6 g of CMC-Na powder into a container, add a suspension formed by PCL microspheres, phosphate buffer solution and 1 g of glycerin into the container, and pre-stir using a glass rod or a thin scraper for 5 minutes, so that the CMC-Na content in the product is 2.6 wt%; (3) Preparing a premixed sample and subjecting it to a defoaming treatment using a vacuum defoaming device at a rotation speed of 1000 r / min for 5 minutes, with the amount of PCL used in the final product being 33 wt%, and then increasing the rotation speed to 2200 r / min for 10 minutes.

[0124] Example 14: Comparison of a gel product containing no microspheres with a product in which PCL microspheres were added directly to a CMC-Na gel 2.6 g of CMC-Na powder was dissolved in 96.4 g of the phosphate buffer solution prepared in Example 11, and 1 wt % of glycerin was added to form a gel (the CMC-Na content in the gel was 2.6 wt %).

[0125] The physicochemical properties of the gel containing no microspheres and the CMC-Na gel containing microspheres prepared in Example 12 were compared, and the results are shown in the table below.

[0126] [Table 11]

[0127] From the table above, it can be seen that after adding PCL microspheres to the CMC-Na gel, the shear viscosity of the resulting polycaprolactone injectable gel increases significantly, making the gel more viscous and more difficult to mix uniformly. In the prior art, mixing methods for high-viscosity fluids generally involve mixing with a high-shear mixer or high-viscosity homogenizer, as described above, or other mixing methods. However, in this process, the CMC gel traps air bubbles, introducing additional heat into the system and causing contraction and deformation of the microspheres in the injectable gel, which ultimately affects the injection results. For this reason, in Example 11, a method was used in which a composition containing pre-dispersed PCL microspheres was added to the CMC gel to reduce the viscosity when the microspheres were mixed with the CMC-Na gel, thereby reducing air bubbles and improving mixing efficiency.

[0128] Example 15: Comparison of the degree of dispersion of air bubbles and microspheres in the gel products of Examples 11 to 13 The product prepared in Example 11 and the comparative products 1 and 2 prepared in Examples 12 and 13 were compared for the degree of air bubbles (no air bubbles -, a few air bubbles +, a few air bubbles ++, quite a lot of air bubbles +++, many air bubbles ++++, full of air bubbles +++++) and the degree of dispersion of microspheres, and the results are shown in the table below.

[0129] [Table 12]

[0130] The micrograph in Figure 16 (BM2000 microscope, 10x) shows that the number of bubbles in the gel product is significantly reduced when using the pre-dispersed composition compared to the comparative product, and the micrograph in Figure 17 (XP-550C polarizing microscope, 10x) shows that a gel product with uniformly dispersed PCL microspheres can be obtained by using a mixing rotation speed of 1000 r / min for 5 minutes, while the comparative product requires an increase in rotation speed and rotation time to continue mixing.

[0131] Without the pre-dispersion step, many obvious air bubbles were formed in both Comparative Product 1 and Comparative Product 2 during mixing (in Figures 18 and 21, the large dark spheres with whitish centers are air bubbles), and the number of air bubbles was particularly large in Comparative Product 2 when PCL microspheres, CMC-Na powder, phosphate buffer solution, and glycerin were directly mixed. Furthermore, due to insufficient mixing, CMC-Na formed many small white pieces, and stirring for 5 minutes at a rotation speed of 1000 r / min was insufficient, making it relatively difficult to further mix the agglomerated CMC pieces to obtain a uniform gel-like injection solution.

[0132] Figure 20 (XP-550C polarized microscope, 10x) of Comparative Product 1 shows that the gel contains many air bubbles and some microspheres are agglomerated, and the dispersion effect is similar to that when deionized water is used as the dispersion liquid; in both cases, there is some degree of cluster formation with incomplete dispersion.

[0133] To continue processing the gel, tests were conducted using a longer stirring time and a higher rotation speed. For Comparative Example 1, the rotation speed was increased to 2200 r / min and processing for 10 minutes. As shown in Figure 19, after processing for the same time, the gel uniformity improved somewhat with increased transparency, and large air bubbles were dispersed into smaller ones, but the number of bubbles was still large. For Comparative Example 2, after increasing the rotation speed for the same processing, there was a slight reduction in clumps and agglomerations, but many air bubbles still existed, and the gel dispersion was still uneven overall, inferior to the dispersion of the reprocessed sample in Example 12.

[0134] Example 16: Effect of gel matrix on microsphere degradation Six aliquots of 750 mg (W0) of PCL microspheres (PCL with a weight-average molecular weight of 40,000 Da) were weighed out and then mixed separately with distilled water, then mixed with sodium carboxymethylcellulose gel, and then placed on a vibration table at 37°C with a vibration speed of 60 r / min. Measurements were carried out for 48 weeks, with each 8-week period being one degradation period. At the end of each degradation period, one sample was taken, and the microspheres were collected by centrifugation, washed thoroughly with distilled water, and freeze-dried under vacuum until the weight was constant (Wt), resulting in the degradation rate of the PCL microspheres in the gel prepared using distilled water as the dispersion liquid.

[0135] For the degradation rate in sodium carboxymethylcellulose gel prepared using 0.9% saline and potassium system 1 PBS (dispersion 4-2-6 in Example 9) as the dispersing liquid (its osmotic pressure was adjusted with KCl), the preparation and measurement process was the same as the above process in which distilled water served as the dispersing liquid.

[0136] [Table 13]

[0137] From the table above, it can be seen that the degradation rate of PCL in the gel prepared using PBS (Dispersion 4-2-6 in Example 9) as the dispersion liquid is lower than that in saline and significantly lower than that in distilled water. Therefore, it can be seen that PBS as a dispersion liquid can effectively reduce PCL degradation, and maintaining the smooth spherical shape of the microspheres helps to reduce the rate of microsphere degradation.

[0138] The above studies have shown that the use of phosphate buffer as a dispersing liquid, particularly a buffer prepared from disodium hydrogen phosphate and potassium dihydrogen phosphate at a pH of 6.0-8.0 and an osmolality of 300-650 mOsm / kg, can effectively maintain the smooth surface and spherical shape of PCL microspheres and reduce or prevent the formation of bubbles. Furthermore, the use of CMC-Na as a gel matrix together with KCl as an osmolality adjuster and at an osmolality of 300-650 mOsm / kg can effectively maintain the smooth surface and spherical shape of PCL microspheres and effectively reduce the degradation of PCL microspheres.

[0139] It should be pointed out that the above are only preferred embodiments of the present patent, and those skilled in the art can make improvements and substitutions without departing from the technical principles of the present patent, and these improvements and substitutions should also be considered to fall within the protection scope of the present patent.

Claims

1. A composition of pre-dispersed polycaprolactone microspheres, comprising polycaprolactone microspheres and Dispersion I, said Dispersion I comprising a phosphate buffer, said phosphate buffer comprising a dibasic phosphate salt and / or a monobasic phosphate salt, said Dispersion I having a pH of 7.0 to 7.5 and an osmolality of 550 to 650 mOsm / kg; A polycaprolactone microsphere predispersed composition, wherein said polycaprolactone microsphere predispersed composition is prepared from dry polycaprolactone microspheres uniformly dispersed in Dispersion I.

2. 2. The polycaprolactone microsphere predispersed composition of claim 1, wherein the dibasic phosphate is selected from one or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate, or diammonium hydrogen phosphate, and the monobasic phosphate is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, or ammonium dihydrogen phosphate.

3. 3. The polycaprolactone microsphere predispersed composition of claim 2, wherein said dispersion I further comprises a pH adjuster.

4. 4. The polycaprolactone microsphere pre-dispersed composition of claim 3, wherein the pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, and potassium hydroxide.

5. 5. The polycaprolactone microsphere predispersed composition of claim 4, wherein said dispersion I further comprises an osmolality adjusting agent.

6. 6. The polycaprolactone microsphere pre-dispersed composition of claim 5, wherein the osmolality adjusting agent is selected from one or more of potassium chloride, sodium chloride, and glycerin.

7. 7. The polycaprolactone microsphere predispersed composition of claim 6, wherein the dibasic phosphate is disodium hydrogen phosphate, the monobasic phosphate is potassium dihydrogen phosphate, the osmolality is modified to 300-650 mOsm / kg, and the osmolality adjuster is potassium chloride.

8. 8. The polycaprolactone microsphere pre-dispersed composition of claim 1, wherein the polycaprolactone microspheres have an average particle size range of 25 to 60 μm, microspheres having a particle size of 25 to 50 μm account for 65% or more of the polycaprolactone microspheres, and the polycaprolactone microspheres have a weight average molecular weight of 8,000 to 80,000 Da.

9. 9. A polycaprolactone injectable gel comprising the polycaprolactone microsphere pre-dispersed composition of any one of claims 1 to 8 and a gel matrix, wherein the gel matrix comprises Dispersion II, and carboxymethylcellulose or sodium carboxymethylcellulose; the dispersion II of the gel matrix is ​​selected from water, saline, or phosphate buffer; The injectable polycaprolactone gel has a pH of 7.0 to 7.5 and an osmotic pressure of 550 to 650 mOsm / kg.

10. 10. The polycaprolactone injectable gel according to claim 9, wherein the content of polycaprolactone microspheres in the polycaprolactone injectable gel is 28-38 wt %, and the content of carboxymethylcellulose or sodium carboxymethylcellulose in the polycaprolactone injectable gel is 1-5 wt %.

11. 11. A method for preparing the polycaprolactone injectable gel according to claim 9 or 10, comprising the steps of: (1) dispersing polycaprolactone microspheres in Dispersion I to obtain a polycaprolactone pre-dispersed composition; (2) dispersing carboxymethylcellulose or carboxymethylcellulose sodium in dispersion II to obtain a gel matrix; (3) adding the polycaprolactone pre-dispersed composition of step (1) to the gel matrix of step (2) and mixing; A method comprising:

12. Use of the polycaprolactone microsphere pre-dispersed composition according to any one of claims 1 to 8 for preparing a polycaprolactone injectable gel, implant or drug carrier.

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