Core-shell structured micellar microspheres and their preparation method and use

Abstract

The present invention belongs to the technical field of medicine, and particularly relates to a core-shell structured micelle microsphere and its preparation method and use. The core-shell structured micelle microsphere of the present invention has an outer shell composed of amphiphilic lipid, an inner shell composed of hydrophilic chain polymer, and a core of drug molecules wrapped in a network structured copolymer. The double-layer shell structure can realize effective drug delivery, reduce drug loss during delivery, and improve drug utilization rate, and the wrapped drug molecules can be used as the core to realize sustained drug release. The present invention also optimizes the core-shell material, and selects amphiphilic phospholipid as the outer shell, thereby improving biocompatibility and drug delivery efficiency, and selects hydrophilic chain polymer as the inner shell, thereby effectively preventing drug burst release, and selects mPEG-PLGA block copolymer as the one for wrapping drug molecules, thereby further preventing drug burst release and realizing control over drug release rate, which can meet the complex needs of practical use.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical technology, in particular to the field of composite materials for coated catheters under IPC classification number A61L29 / 12, specifically to core-shell structured micellar microspheres and their preparation method and use. [Background technology]

[0002] Microspheres are a recently developed novel dosage form in which drugs are dispersed in a matrix material to form spherical particles, which can be administered by injection or interventional surgery. After administration, the microsphere framework degrades and erodes, allowing the encapsulated drug molecules to diffuse, thereby achieving sustained or delayed release. Currently, microspheres have various structures, including porous, core-shell, and solid structures.

[0003] In particular, expandable balloon-based interventional therapy is widely used clinically. To achieve targeted chemotherapy, the expandable balloon is typically coated with a drug. However, both injectables and drug-coated expandable balloons suffer from the problem of drug loss in the blood before reaching the target site, significantly reducing drug bioavailability. Furthermore, most microsphere formulations rely on intermolecular forces, such as electrostatic interactions, to carry the drug, resulting in insufficient tight binding and the presence of some drug moieties on the microsphere surface. This can lead to burst release, potentially causing adverse reactions, and the drug release cycle is too short to achieve long-term therapeutic efficacy. Therefore, the development of microspheres with stable structures and excellent sustained-release effects is urgently needed in the pharmaceutical field.

[0004] Prior art CN105106174B discloses core-shell double-layer microspheres prepared with a copolymer of polyketal and poly(lactic acid-co-glycolic acid), which can solve the phenomenon of burst release; however, the microspheres are large, have high requirements for injection conditions, are not suitable for drug coating on expandable balloons, and have a low drug release rate, resulting in low drug bioavailability. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the object of the present invention is to provide a core-shell structured micellar microsphere that has high drug availability, is easy to prepare, has a small particle size, is applicable in a wide range of applications, and can realize long-term sustained drug release.

[0006] Meanwhile, an object of the present invention is to further provide a method for preparing micellar microspheres with a core-shell structure, which requires mild conditions and is a simple process.

[0007] Meanwhile, an object of the present invention is to further provide uses of the above-mentioned core-shell structured micellar microspheres.

[0008] To achieve the above object of the invention, the present invention uses the following technical solutions:

[0009] A micellar microsphere with a core-shell structure, wherein the core of the micellar microsphere with the core-shell structure is a plurality of drug molecules wrapped in a copolymer, and the shell of the micellar microsphere with the core-shell structure is, from the inside to the outside, a chain polymer layer and a lipid layer, the copolymer has a network structure, and the chain polymer layer is a network structure formed by intermolecular forces of the chain polymer.

[0010] Preferably, the particle size of the core-shell micellar microspheres is 1 to 10 μm.

[0011] Preferably, the lipid layer is composed of amphipathic lipids, the hydrophilic ends of the amphipathic lipids facing into the shell and the lipophilic ends facing out of the shell.

[0012] More preferably, the amphiphilic lipid is soy lecithin.

[0013] The core-shell micellar microspheres of the present invention have an outer layer composed of amphiphilic lipids, with the hydrophilic end facing inward and the lipophilic end facing outward. The lipids have an affinity with the hydrophilic inner layer, forming a dense bilayer structure and preventing the diffusion of drug molecules in the core. During preparation, the similar polarity allows the formation of a bilayer spherical shell in a solvent, simplifying the preparation process. The lipophilic end facing outward provides a significant difference in polarity with blood when delivered via the bloodstream, forming a hydrophobic surface on the outer shell, preventing the drug molecules from diffusing into the bloodstream, reducing drug loss during delivery and improving drug bioavailability. When the microspheres come into contact with blood vessel walls, the lipophilic end has excellent affinity with cell membranes, particularly due to the similar structure of phospholipids and cell membranes. This affinity between the lipid layer and cell membrane opens a drug delivery pathway, enabling drug release and further improving drug availability. In particular, when the core-shell structured micelle microspheres of the present invention are used as a drug coating for an expandable drug balloon, the expansion of the balloon brings the microspheres into contact with the blood vessel wall at the target site, and the affinity of the lipid layer with the cell membrane allows the drug to remain at the target site, improving targeting and reducing damage to healthy tissue and adverse reactions.

[0014] Preferably, the chain polymer is a hydrophilic chain polymer and includes one or more of PEG (polyethylene glycol), hyaluronic acid, chitosan, iopromide, shellac, tannic acid, polylactide, and PLGA (poly(lactic-co-glycolic acid)).

[0015] Preferably, the mass fraction of the drug molecules in the core-shell micellar microspheres is 30% to 50%.

[0016] Preferably, the mass ratio of the lipid layer to the chain polymer layer is 1 to 5:1.

[0017] In the present invention, a network structure formed by a hydrophilic chain polymer is selected as the inner shell of the core-shell micellar microspheres, which has an affinity with the hydrophilic end of the amphiphilic lipid layer, forming a bilayer spherical shell. Furthermore, when the microspheres have an affinity with the vascular wall, the chain polymer decomposes and releases the drug, preventing burst release and achieving sustained or delayed release. The inventors have invented the idea that the particle size and shape of the microspheres can be controlled by adjusting the weight ratio of lipid to hydrophilic chain polymer. Specifically, the present invention selects a weight ratio of lipid to hydrophilic chain polymer of 1 to 5:1 to obtain core-shell micellar microspheres with a regular shape, a particle size of 10 + 0.5 μm or less, and appropriate dimensions. Therefore, the microspheres can be used as a drug coating for expandable drug balloons, expanding the scope of application. At the same time, when the microspheres of the present invention can be used as a drug coating for an expandable drug balloon, the drawback of low drug utilization rate due to the hydrophilic chain polymer absorbing water and the drug coating easily peeling off from the surface of the balloon, leaving excess coating on the balloon, is overcome.

[0018] Preferably, the copolymer is selected from one or more of mPEG-PLGA block copolymer, PEG-PLGA block copolymer, and PEG-hyaluronic acid copolymer.

[0019] Preferably, the mass fraction of mPEG (methoxypolyethylene glycol) in the mPEG-PLGA block copolymer is 0.1 to 5.0%, more preferably 1%.

[0020] Preferably, the mass fraction of mPEG in the mPEG-PLGA block copolymer is 550 to 2,000, and the number average molecular weight of PLGA is 5,000 to 60,000.

[0021] Specifically, the present invention uses a network structure formed by a block copolymer of mPEG with a number-average molecular weight of 550-2000 and PLGA with a number-average molecular weight of 5000-60000 to encapsulate drug molecules and release the drug as it degrades at the target site, thereby enabling the drug release rate to be tailored. The inventors unexpectedly discovered that the higher the mPEG content, the faster the drug release rate. At mPEG content greater than 5 wt%, the drug release rate is relatively fast, with the possibility of burst release. At mPEG content of 1 wt%, the drug release rate is rapid in the early stage, resulting in a rise in blood drug concentration, followed by a slower release rate in the later stage, resulting in nearly continuous release for 90 days. At mPEG content of 0.1 wt%, the drug release rate from the microspheres slows and becomes nearly linear, achieving a nearly uniform and stable release. Based on this inventive idea, the core-shell structured micellar microspheres of the present invention can be endowed with different drug release rate characteristics by adjusting the mPEG ratio in the mPEG-PLGA block copolymer, thereby meeting various complex requirements in clinical practice.

[0022] Meanwhile, the present invention provides a method for preparing the above-mentioned core-shell structured micellar microspheres, the method comprising: Step S1: dissolving the drug and copolymer in organic solvent A, mixing them uniformly, dissolving them sufficiently, and leaving them to stand for 2 to 8 hours to obtain a mixed solution a; Step S2: dissolving lipids and linear polymers in solvent B and mixing them uniformly to obtain a mixed solution b; Step S3: Add the mixed solution a to the mixed solution b and mix uniformly to obtain a core-shell structured micellar microsphere solution; Step S4: drying and precipitating the core-shell structured micelle microsphere solution to obtain core-shell structured micelle microspheres; Includes.

[0023] Preferably, the drug is selected from one or more of rapamycin, rapamycin derivatives, taxol, heparin and hirudin.

[0024] Preferably, the weight ratio is 20 to 80 parts by weight of the drug, 10 to 70 parts by weight of the lipid, 5 to 60 parts by weight of the chain polymer, and 5 to 60 parts by weight of the copolymer.

[0025] Preferably, the organic solvent A comprises one or more of ethanol, isopropanol, acetone, methylene chloride, chloroform, ethyl acetate, acetonitrile, butyl acetate, ether, and carbon tetrachloride.

[0026] Preferably, the solvent B comprises one or more of methyl alcohol, ethanol, isopropanol, methylene chloride, chloroform, ethyl acetate, acetonitrile, butyl acetate, ether, and carbon tetrachloride.

[0027] Preferably, the organic solvent A and solvent B are each 10,000 to 25,000 parts by weight.

[0028] Meanwhile, the present invention provides the use of the core-shell structured micellar microspheres, which can be used as drug coatings for expandable drug balloons or as injections.

[0029] Preferably, the method for preparing the drug coating includes the steps of: ultrasonically atomizing the core-shell micelle microsphere solution to form mist droplets; and spraying the mist droplets onto the surface of the balloon of the expandable drug balloon catheter with nitrogen; during the spraying process, the solvent evaporates, and the core-shell micelle microspheres adhere to the surface of the balloon to form a drug coating.

[0030] Preferably, the drug coating has a thickness of 1 to 10 microns.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The shell-structured micellar microspheres of the present invention have an outer layer composed of amphiphilic lipids, which can prevent the diffusion of drug molecules in the core, and form a hydrophobic surface on the outside of the shell, which can reduce the loss of drug during delivery and improve the bioavailability of the drug.

[0033] 2. The present invention selects amphiphilic lipids, especially phospholipids, as the outer shell structure, which has excellent affinity with cell membranes, and can realize drug release through affinity with cell membranes, improve drug availability, realize drug retention at target locations, improve targeting, and reduce adverse reactions.

[0034] 3. The present invention uses a network structure formed by a hydrophilic chain polymer as the inner shell of the core-shell micellar microsphere, which prevents burst release of the drug and achieves the effect of sustained or delayed release.

[0035] 4. The inventors have found that the particle size and shape of the microspheres can be controlled by adjusting the weight ratio of lipid to hydrophilic chain polymer. In particular, when a specific weight ratio of lipid to hydrophilic chain polymer is selected between 1 and 5:1, micellar microspheres with a regular shape and a particle size of 10 + 0.5 μm or less can be obtained, thereby expanding the application range of core-shell structured micellar microspheres.

[0036] 5. The present invention specifically selects a network structure formed by mPEG-PLGA block copolymers with a specific molecular weight to encapsulate drug molecules and further achieve sustained drug release.

[0037] 6. This invention creatively explores the relationship between the mPEG content of mPEG-PLGA block copolymers and the drug release rate of the resulting core-shell micellar microspheres. By adjusting the mPEG content of mPEG-PLGA block copolymers, different drug release rate characteristics can be achieved, thereby meeting the complex requirements of clinical practice. [Brief explanation of the drawings]

[0038] [Figure 1] 1 is a scanning electron microscope photograph of a core-shell structured micellar microsphere in Example 2. [Figure 2] 1 is a topography photograph of a core-shell structured micellar microsphere in Example 2 taken by an optical microscope. [Figure 3] 1 is a topography photograph of a core-shell structured micellar microsphere in Comparative Example 1 taken by an optical microscope. [Figure 4] Schematic of a drug molecule (green) encapsulated in an mPEG-PLGA block copolymer (black). [Figure 5] 1 is a schematic diagram of the cross-sectional structure of a core-shell structured micellar microsphere of the present invention. [Figure 6] FIG. 1 shows the time course of drug release rate curves for core-shell micellar microspheres prepared with mPEG-PLGA block copolymers having mPEG mass fractions of 0.1% (Example 1), 1% (Example 2), and 5% (Example 3). [Figure 7] FIG. 1 is a graph showing the change curve of drug release rate over time for core-shell micellar microspheres prepared with an mPEG-PLGA block copolymer having an mPEG mass fraction of 9% (Comparative Example 2). DETAILED DESCRIPTION OF THE INVENTION

[0039] The parts in the examples refer to parts by weight. Example 1

[0040] This embodiment provides a core-shell micellar microsphere, the core of which is a plurality of drug molecules encapsulated in a network copolymer, and the shell of which is a network structure formed by a chain polymer layer and a lipid layer, in order from the inside to the outside.

[0041] The lipid layer is composed of soybean lecithin, the hydrophilic end of the soybean lecithin facing into the shell and the lipophilic end facing out of the shell;

[0042] the chain polymer is PEG,

[0043] the mass ratio of the lipid layer to the network structure formed by the chain polymer is 3:2;

[0044] the drug molecule is a rapamycin molecule;

[0045] the mass fraction of the drug molecules in the core-shell micellar microspheres is 40%;

[0046] The copolymer is an mPEG-PLGA block copolymer, where the molecular weight of mPEG is 550, the molecular weight of PLGA is 60,000, and the mass fraction of mPEG is 0.1%. The mPEG-PLGA block copolymer is purchased from Eichuan Special Chemical (Shanghai) Co., Ltd.

[0047] An embodiment of the present invention further provides a method for preparing the above-mentioned core-shell structured micellar microspheres, the method comprising: Step S1: dissolving 40 parts of rapamycin and 60 parts of mPEG-PLGA block copolymer in 20,000 parts of acetone, mixing uniformly, dissolving sufficiently, and leaving to stand for 6 hours to obtain a mixed solution a; Step S2: dissolving 60 parts of soybean lecithin and 40 parts of PEG in 20,000 parts of ethyl acetate and mixing uniformly to obtain a mixed solution b; Step S3: Add the mixed solution a to the mixed solution b and mix uniformly to obtain a core-shell structured micellar microsphere solution; Step S4: spraying the solution of core-shell structured micellar microspheres, drying and precipitating the solution to obtain core-shell structured micellar microspheres; Includes.

[0048] This embodiment further provides a use of the core-shell structured micellar microspheres, which can be used as a drug coating for an expandable drug balloon or as an injection;

[0049] The method for preparing the drug coating includes the steps of ultrasonically atomizing the core-shell micelle microsphere solution to form mist droplets, and then spraying the mist droplets onto the surface of the balloon of the expandable drug balloon catheter with nitrogen, during which the solvent evaporates and the core-shell micelle microspheres adhere to the surface of the balloon to form a drug coating.

[0050] The drug coating is 10 microns thick. Example 2

[0051] This example further provides core-shell micellar microspheres and their preparation and use, which are the same as those in Example 1, with the following differences: the mass fraction of mPEG in the mPEG-PLGA block copolymer is 1%, and the mPEG-PLGA block copolymer is purchased from Eichuang Special Chemical (Shanghai) Co., Ltd.

[0052] The particle size of the core-shell structured micellar microspheres of this example was 2.5 to 10.5 μm, and a scanning electron micrograph thereof is shown in FIG. 1, and a topography photograph thereof taken by an optical microscope is shown in FIG. Example 3

[0053] This example further provides core-shell micellar microspheres and their preparation and use, which are the same as those in Example 1, with the following differences: the mass fraction of mPEG in the mPEG-PLGA block copolymer is 5%, and the mPEG-PLGA block copolymer is purchased from Eichuan Special Chemical (Shanghai) Co., Ltd. (Comparative Example 1)

[0054] This example further provides core-shell structured micellar microspheres and their preparation and use, and its embodiment is the same as that of Example 2, with the following differences: the mass ratio of the lipid layer to the network structure formed by the chain polymer is 1:3, and its optical microscope topography photograph is shown in Figure 3. (Comparative Example 2)

[0055] This comparative example further provides core-shell micellar microspheres and their preparation and use, which are the same as those in Example 2, with the following differences: the mass fraction of mPEG in the mPEG-PLGA block copolymer is 9%, and the mPEG-PLGA block copolymer is purchased from Jinan Jufukai Biotechnology Co., Ltd.

[0056] Performance Test

[0057] In the drug release study, animal experiments were performed to verify the sustained release effect of core-shell micellar microspheres prepared with mPEG-PLGA block copolymers at different mass fractions. A miniature pig model was used in this experiment, and the drug-coating formulations used in Examples 1-3 and Comparative Example 2 were used within the miniature pigs. The drug release was measured at 0 (immediate), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days. The pig vascular model was then removed and the drug was tested on the blood vessels.

[0058] The experimental subjects were miniature pig models weighing approximately 25 to 45 kg.

[0059] The experimental product contained 1 to 10 μg / mm 2 1 shows drug coatings in Examples 1 to 3 and Comparative Example 2.

[0060] The experimental method is as follows.

[0061] (1) Seven pig animal models were selected for each group, corresponding to the timings of 0 (immediately), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days. The balloons of the expandable balloon catheters sprayed with drug coatings in Examples 1 to 3 and Comparative Example 2 were implanted into the cardiovascular RCA, LCX, and LAD of the pig animal models in each group.

[0062] (2) At the timing of 0 (immediately), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days, the pigs are killed, and the blood vessels are removed to measure the drug content.

[0063] The experimental results are as follows: Based on the obtained drug content, a drug release curve (see Figures 6 and 7) was drawn, and the drug release rate on the vertical axis is the ratio of the drug content in the vascular wall to the drug content on the surface of the balloon before implantation. [Explanation of symbols]

[0064] 1. Lipid layer, 2. Chain polymer layer, 3. Drug molecules, 4. Network structure copolymer.

Claims

1. A micellar microsphere having a core-shell structure, wherein the core of the micellar microsphere is a plurality of drug molecules wrapped in a copolymer, and the shell of the micellar microsphere is a chain polymer layer and a lipid layer, in this order from the inside to the outside, the copolymer is a network structure formed of a block copolymer composed of mPEG having a number average molecular weight of 550 to 2000 and PLGA having a number average molecular weight of 5000 to 60000, and the chain polymer layer is a network structure formed by intermolecular forces of the chain polymer, The particle size of the core-shell micellar microspheres is 1 to 10 μm; The lipid layer is composed of amphipathic lipids, and the hydrophilic ends of the amphipathic lipids are oriented toward the inside of the shell. The lipophilic end faces outward from the shell. the mass fraction of mPEG in the mPEG-PLGA block copolymer is 0.1 to 5.0%; The mass ratio of the lipid layer to the chain polymer layer is 1 to 5:

1. A micellar microsphere having a core-shell structure, characterized in that:

2. The core-shell structured micellar microsphere of claim 1, wherein the chain polymer is a hydrophilic chain polymer and includes one or more of PEG, hyaluronic acid, chitosan, iopromide, shellac, tannic acid, polylactide, and PLGA.

3. The core-shell micellar microsphere according to claim 1, wherein the copolymer is selected from one or more of mPEG-PLGA block copolymer, PEG-PLGA block copolymer, and PEG-hyaluronic acid copolymer.

4. Step S1: dissolving the drug and copolymer in organic solvent A, mixing them uniformly, dissolving them sufficiently, and leaving them to stand for 2 to 8 hours to obtain a mixed solution a; Step S2: dissolving the lipid and the chain polymer in the solvent B and mixing them uniformly to obtain a mixed solution b; Step S3: Add the mixed solution a to the mixed solution b and mix them uniformly to obtain a solution of micellar microspheres with a core-shell structure; Step S4: drying and precipitating the core-shell structured micelle microsphere solution to obtain core-shell structured micelle microspheres; 2. The method for producing the core-shell structured micellar microspheres of claim 1, comprising:

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