CN117357498A - Polycaprolactone microsphere and preparation method and application thereof - Google Patents

Polycaprolactone microsphere and preparation method and application thereof Download PDF

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Publication number
CN117357498A
CN117357498A CN202311591823.1A CN202311591823A CN117357498A CN 117357498 A CN117357498 A CN 117357498A CN 202311591823 A CN202311591823 A CN 202311591823A CN 117357498 A CN117357498 A CN 117357498A
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polycaprolactone
chitosan
microsphere
solution
pcl
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吴首标
刘树涛
喻倩
崔俊生
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Beijing Baihualixi Biotechnology Co ltd
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Beijing Baihualixi Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a polycaprolactone microsphere and a preparation method and application thereof, and relates to the technical field of microsphere preparation. In particular to a method for preparing microspheres by using polycaprolactone as a skeleton structure and chitosan molecules as emulsifying agents through an emulsification technology. The preparation method of the polycaprolactone microsphere comprises the following steps: and (3) contacting the chitosan aqueous solution with the dichloromethane solution of polycaprolactone, stirring at the same time, stirring at normal temperature after emulsification is completed to remove dichloromethane, and centrifugally washing to obtain the microsphere with the diameter of 20-100 mu m.

Description

Polycaprolactone microsphere and preparation method and application thereof
Technical Field
The invention relates to a degradable material, in particular to a polycaprolactone microsphere, a preparation method and application thereof.
Background
Degradable polymer microspheres have proven to be a high-efficiency and low-toxic and low-side effect stent material and drug release control system, and have recently received extensive attention from researchers and consumers. Polymer materials are numerous, such as Polycaprolactone (PCL), polyvinyl alcohol (PVA), poly L-lactide-caprolactone (PLCL), polydioxanone (PDO), polylactic glycolic acid (PLGA) or polylactic acid (PLA), etc., which are degradable materials in the human body and are also widely used in the medical and cosmetic fields. Polycaprolactone is an artificially synthesized high molecular polymer, has biocompatibility and biodegradability, has slow degradation speed, and can be metabolized by a body or discharged from the body, thus being widely applied to a bracket material and a slow release microsphere system. In addition, polycaprolactone has good mechanical properties, flexibility and good permeability to small molecule compounds. Today, polycaprolactone is a biological material approved by the FDA in the united states and applicable to human body, has stronger hydrophobicity, and is one of the alternative materials of bone tissue engineering scaffolds. The chitosan is obtained by removing partial acetyl groups from chitin, and contains a large number of amino groups and hydroxyl groups in the structure, so that the chitosan is the only alkaline chitosan in natural chitosan. Chitosan has no toxicity, biodegradability, good water solubility and certain hemostatic and antibacterial properties, so that the chitosan has wide application fields such as medicine slow release, beauty, spinning, food addition and antibacterial products.
Emulsion solvent evaporation refers to a process in which the drug is mixed with a solution of carrier material, dispersed in an immiscible medium to form a water-in-oil (W/O) like or oil-in-water (O/W) emulsion, and then the internal phase is solidified and separated to produce microspheres by solvent evaporation of the internal phase. The emulsifying solvent diffuses typically dissolving the carrier in the dispersed phase, in which the drug is in a dissolved or state. The solvent of the inner dispersed phase must have a certain solubility in the outer continuous phase. The solvent of the internal disperse phase continuously diffuses to the external phase under stirring. And after the internal disperse phase solvent is completely diffused, the carrier in the disperse phase is separated out to form a capsule film, and the material is wrapped in the capsule film until the microsphere is completely solidified.
Disclosure of Invention
The invention adopts PCL as a carrier material, and prepares the bracket microsphere material of polycaprolactone by an O/W emulsion solvent volatilization method, and the method is simple and easy to operate. The method mainly comprises the step of fumbling PCL microsphere operation parameters to obtain the optimal preparation flow and formula.
Specifically, the invention comprises the following technical scheme:
dissolving polycaprolactone in an oil solvent to form an oil phase;
dissolving chitosan in water to form aqueous phase solution, and regulating pH to 4-6 with inorganic acid;
mixing the oil phase and the water phase according to the volume ratio of (1-10), and mechanically obtaining uniformly dispersed emulsion after mixing;
after the emulsification is finished, the oil solvent is removed by stirring at normal temperature or vibration heating, and the polycaprolactone microsphere with the diameter of 20-100 mu m is obtained by further centrifugation, washing and drying.
In the preparation method of the polycaprolactone microsphere according to the invention, the types of chitosan include, but are not limited to, chitosan and derivatives thereof.
In the preparation method of the polycaprolactone microsphere, inorganic acids such as acetic acid and hydrochloric acid are used for adjusting the pH of the chitosan aqueous phase solution.
In the preparation method of the polycaprolactone microsphere, the content of chitosan in the chitosan aqueous solution is 0.1-10wt% based on the mass of water.
In the preparation method of the polycaprolactone microsphere, the oil phase solvent of the polycaprolactone comprises but is not limited to dichloromethane, chloroform and N, N-dimethylformamide.
In the preparation method of the polycaprolactone microsphere, the mass concentration of the polycaprolactone is 0.01-0.2 g/mL.
In the preparation method of the polycaprolactone microsphere, the mechanical method comprises but is not limited to ultrasonic, vortex mixing and stirring.
Advantageous technical effects
The microsphere prepared by the preparation method of the polycaprolactone microsphere provided by the invention has the following characteristics:
(1) The microsphere has smooth surface and complete sphere, and the diameter range is 20-100 μm;
(2) The size distribution is uniform, and the grain diameter is mainly about 40 mu m;
(3) The cost is low, the biological safety is high, and the smooth and round polycaprolactone microsphere can be prepared by using the biocompatible chitosan.
Drawings
FIG. 1 is an SEM image of microspheres prepared according to example 1.
FIG. 2 is an SEM image of microspheres prepared in example 2.
FIG. 3 is an SEM image of microspheres prepared in example 3.
FIG. 4 is an SEM image of microspheres prepared in example 4.
FIG. 5 is an SEM image of microspheres prepared according to example 5.
FIG. 6 is an SEM image of microspheres prepared according to example 6.
FIG. 7 is a graph of the CLSM for microspheres prepared in example 2.
FIG. 8 shows the particle size distribution of the microspheres prepared in example 2.
Detailed Description
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The following examples are designed to prepare microsphere materials with different particle diameters according to different stirring speeds and concentration ratios of oil phase to inorganic phase, and the optimal proportion is obtained by Scanning Electron Microscope (SEM) and laser confocal microscope (CLSM) and observing microsphere morphology and particle size distribution.
The present invention will be described in detail with reference to examples. Examples detailed embodiments and procedures are set forth to fully disclose and illustrate the invention as being practical, and are not to be construed as limiting the invention, which is not to be limited in scope by the following examples. All other embodiments obtained by those skilled in the art without creative efforts are within the protection scope of the present invention based on the specific embodiments of the present invention.
Example 1
800mg of PCL having Mw of 14000 was dissolved in 40mL of methylene chloride (DCM) to prepare a PCL/DCM solution having a mass concentration of 0.02 g/mL.
1g of Chitosan (CHI) was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare CHI/H with a mass concentration of 0.5% 2 O solution.
PCL/DCM solution and CHI/H 2 The O solution was mixed at a volume ratio of 1:10 and stirred at a stirring speed of 300rpm to obtain an emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in fig. 1, and PCL microspheres can be formed under the condition, however, the particle size is not uniform.
Example 2
800mg of Polycaprolactone (PCL) having Mw of 14000 was dissolved in 40mL of Dichloromethane (DCM) to prepare a PCL/DCM solution having a mass concentration of 0.02 g/mL.
1g of low molecular weight Chitosan (CHI) was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare CHI/H with a mass concentration of 0.5% 2 O solution.
PCL/DCM solution and CHI/H 2 The O solution was mixed at a volume ratio of 1:5 and stirred at a stirring speed of 300rpm to obtain an emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in figure 2, the PCL particles formed under the condition are spherical, the surface is smoother, the particle size is more uniform, and the size is about 40 mu m.
Example 3
800mg of Polycaprolactone (PCL) having Mw of 14000 was dissolved in 40mL of Dichloromethane (DCM) to prepare a PCL/DCM solution having a mass concentration of 2%.
1g of low molecular weight Chitosan (CHI) was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare CHI/H with a mass concentration of 0.5% 2 O solution.
PCL/DCM solution and CHI/H 2 O solution toMixing the materials according to the volume ratio of 3:10, and stirring the materials at the stirring speed of 300rpm to obtain emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in fig. 3, and the PCL particle part is spherical and irregular in shape.
Example 4
800mg of Polycaprolactone (PCL) having Mw of 14000 was dissolved in 40mL of Dichloromethane (DCM) to prepare a PCL/DCM solution having a mass concentration of 2%.
1g of low molecular weight Chitosan (CHI) was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare CHI/H with a mass concentration of 0.5% 2 O solution.
PCL/DCM solution and CHI/H 2 The O solution was mixed at a volume ratio of 1:10 and stirred at a stirring speed of 450rpm to obtain an emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in FIG. 4, the PCL particles are obviously broken, and the unbroken parts are spherical particles.
Example 5
800mg of Polycaprolactone (PCL) having Mw of 14000 was dissolved in 40mL of Dichloromethane (DCM) to prepare a PCL/DCM solution having a mass concentration of 2%.
1g of low molecular weight Chitosan (CHI) was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare CHI/H with a mass concentration of 0.5% 2 O solution.
PCL/DCM solution and CHI/H 2 The O solution was mixed at a volume ratio of 1:5 and stirred at a stirring speed of 450rpm to obtain an emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in FIG. 5, and the PCL particles are basically spherical, but have relatively small size, and the particle size of most PCL microspheres is between 20 and 30 mu m.
Example 6
800mg of Polycaprolactone (PCL) having Mw of 14000 was dissolved in 40mL of Dichloromethane (DCM) to prepare a PCL/DCM solution having a mass concentration of 2%.
1g of Chitosan (CHI) with low molecular weight was dissolved in 200mL of water and pH was adjusted to 4.5 with glacial acetic acid to prepare a solution with a mass concentration of 0.5%CHI/H 2 O solution.
PCL/DCM solution and CHI/H 2 The O solution was mixed at a volume ratio of 3:10 and stirred at a stirring speed of 450rpm to obtain an emulsion. Stirring at normal temperature to remove dichloromethane, and finally centrifugally washing and drying to obtain the PCL microspheres. The morphology is shown in FIG. 6, and the PCL/DCM and CHI/H are continuously improved 2 The volume ratio of the O solution, the PCL particles are basically spherical, but the size is still relatively small, and the size of most PCL microspheres is between 20 and 30 mu m.
By combining a plurality of factors such as the shape, integrity, surface smoothness, microsphere size and uniformity of the control particles, it can be found that the particle size of the PCL microspheres is reduced with the increase of the PCL proportion and stirring speed, and the PCL microspheres obtained under the conditions of example 2 in examples 1 to 6 are optimal.
Example 7
In view of the above experimental results, the PCL microspheres prepared in example 2 were further observed by an optical microscope, and as shown in fig. 7, the microspheres were regular in shape and substantially spherical. Statistical analysis by Nano Measure software found that the particle size of the microsphere was mainly concentrated to 40 μm (FIG. 8), so the condition of example 2 was the optimal formulation of the present invention.
The protection of the present invention is not limited to the above embodiments. Variations and substitutions that would occur to one skilled in the art without departing from the spirit and scope of the inventive concept are intended to be included in the invention, and the scope of protection is defined by the claims that follow.

Claims (10)

1. A preparation method of polycaprolactone microsphere is characterized in that aqueous phase solution containing chitosan is respectively mixed with oil phase solution of Polycaprolactone (PCL), mixed and emulsified, then oil phase is removed, and finally the mixture is centrifuged, washed and dried to obtain the polycaprolactone microsphere with the diameter of 20-100 μm.
2. The method of producing polycaprolactone microspheres according to claim 1, wherein the chitosan species include, but are not limited to, chitosan and derivatives thereof.
3. The method for preparing polycaprolactone microsphere according to claim 1, wherein the pH of the aqueous chitosan solution is between 4 and 6.
4. The method for preparing polycaprolactone microsphere according to claim 1, wherein the pH of the aqueous chitosan solution is adjusted by using inorganic acids, the inorganic acids including acetic acid and hydrochloric acid;
the oil phase solution solvents of polycaprolactone include, but are not limited to, methylene chloride, chloroform, N-dimethylformamide.
5. The method for preparing polycaprolactone microsphere according to claim 1, wherein the content of chitosan in the aqueous chitosan solution is 1-10wt% based on the mass of water.
6. The method for preparing the polycaprolactone microsphere according to claim 1, wherein the mass concentration of the polycaprolactone in the oil phase solution of the Polycaprolactone (PCL) is 0.01-0.2 g/mL.
7. The method for preparing polycaprolactone microsphere according to claim 1, wherein the volume ratio of the oil phase solution of polycaprolactone to the aqueous solution of chitosan is 1 (1-10).
8. The method of preparing polycaprolactone microspheres according to claim 1, wherein the method of mixing emulsification includes, but is not limited to, sonication, vortex mixing, stirring;
methods of removing the oil phase include, but are not limited to, stirring at ambient temperature, and shaking heating.
9. Polycaprolactone microsphere characterized in that it is obtained by the process for the preparation of polycaprolactone microspheres according to any one of claims 1 to 8.
10. Use of the polycaprolactone according to claim 9 for the preparation of a drug-eluting carrier, dermal filler or tissue engineering scaffold.
CN202311591823.1A 2023-11-27 2023-11-27 Polycaprolactone microsphere and preparation method and application thereof Pending CN117357498A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118480193A (en) * 2024-03-21 2024-08-13 深圳聚生生物科技有限公司 Controllable and rapid degradable composite polycaprolactone microsphere and preparation method thereof
CN119039625A (en) * 2024-10-31 2024-11-29 济南磐升生物技术有限公司 A preparation method of chitosan-polycaprolactone microspheres and the obtained product

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118480193A (en) * 2024-03-21 2024-08-13 深圳聚生生物科技有限公司 Controllable and rapid degradable composite polycaprolactone microsphere and preparation method thereof
CN119039625A (en) * 2024-10-31 2024-11-29 济南磐升生物技术有限公司 A preparation method of chitosan-polycaprolactone microspheres and the obtained product

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