CN105919944A - Degradable polymer microsphere containing gel core as well as preparation and application of polymer microsphere - Google Patents
Degradable polymer microsphere containing gel core as well as preparation and application of polymer microsphere Download PDFInfo
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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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/41—Porphyrin- or corrin-ring-containing peptides
- A61K38/415—Cytochromes
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- 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
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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
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Abstract
The invention provides a degradable polymer microsphere containing a gel core as well as a preparation method and an application of the polymer microsphere. The preparation method of the polymer microsphere comprises the following steps: dissolving a polymer PLGA (poly(lactic-co-glycolic acid)), PCL (polycaprolactone) or PLA (polylactic acid) in dichloromethane or ethyl acetate, so that a shell material is obtained; separately dissolving hyaluronic acid and hydroxyethyl chitosan in water, so that a hyaluronic acid solution and a hydroxyethyl chitosan solution are prepared, and then uniformly mixing the hyaluronic acid solution, the hydroxyethyl chitosan solution and bovine serum albumin or cytochrome C protein, so that a physical gel core material is obtained; and preparing the degradable polymer microsphere containing the gel core by virtue of a coaxial electrospray preparation process. The degradable polymer microsphere disclosed by the invention is relatively high in drug loading capacity and encapsulation efficiency; and the degradable polymer microsphere can serve as a carrier of protein or polypeptide hydrophilic drugs.
Description
Technical field
The invention belongs to technical field of biological material, particularly relate to a kind of degradable polymer microspheres containing gel kernel and its preparation method and application.
Background technology
The medicament slow release micro-/ nano ball developed with Biodegradable polymer material, has prolongation curative effect, improves the advantage such as medicine stability, reduction side effect.Polypeptide hormone class medicine that all kinds of polypeptide, pharmaceutical grade protein, particularly biological activity are easily lost by this and cancer therapy drug, such as interferon, tumor necrosis factor, nerve growth factor, erythropoietin and recombinant human somatropin, have good practical value.In recent years, the long-acting injection microsphere for polypeptide and protein medicaments has carried out research both at home and abroad, and makes remarkable progress.At present, through existing 8 kinds of the sustained-release micro-spheres medicine based on lactic-co-glycolic acid (PLGA) that U.S. food drug control administration (FDA) is ratified, there is now the sustained-release micro-spheres listings such as injection leuprorelin, triptorelin, buserelin, octreotide, Lanreotide, minocycline.Although protein medicaments is placed high hopes by people, but it should also be noted that the problems such as the drug loading existed to: proteins and peptides medicine microspheres is the highest, burst effect and medicine stability seriously constrain extensively application and the industry development of microball preparation.
Conventional method prepared by microsphere has a lot, such as technology such as phase separation method, multi-emulsion method, supercritical fluid and spray drying methods.But, the most a lot of problems are present in microball preparation technology, particularly in preparing anticarcinogen, protein medicine microsphere drug-supplying system, have that envelop rate is low, easy in inactivation, inside and outside release have the more apparent prominent problem such as release.Compared with traditional preparation method, electrospray techniques has prepares the advantage that solid dispersion is bigger.Pan Qi etc. (Pan Qi, Huang Yanbin. electrospray prepares medicine-polymeric solid dispersion [J]. polymer material science and engineering, 2011,
(7): 133-135.) electrospray is utilized to prepare medicine, select polyvinylpyrrolidone (PVP) as water-soluble high-molecular material carrier, mixed solution is connected into electron spray equipment and prepares solid dispersion, the container of high tension generator applies voltage, collects product.Utilizing XRD etc. to characterize, the sample of the just preparation under optical microscope, particle diameter is relatively big, not crystallization.This technology is expected to be widely applied to carry polypeptide, the controlled release drug delivery system of pharmaceutical grade protein, especially with the sustained-release microsphere that biodegradable material is carrier and the research and development of microsphere long-acting injection.
Up to now, lactic acid-ethanol copolymer (PLGA) is still the main selection making Injectable microspheres preparation as framework material parcel anticarcinogen, polypeptide, protein drug.In recent years, double-deck microsphere starts to come into one's own as a kind of new micro shape preparation, and this microsphere not only overcomes some problems of monolayer microsphere, as reduced the conventional monolayers medicine easily prominent shortcoming released, but also changes release mode so that it is more meet long-acting administration requirements.
Summary of the invention
Solve the technical problem that:The drug loading and the envelop rate that exist for existing protein microsphere are low, the problem of controllable release poor performance, the invention provides a kind of degradable polymer microspheres containing gel kernel and its preparation method and application, this polymer microballoon has higher drug loading and envelop rate.
Technical scheme:A kind of preparation method of the degradable polymer microspheres containing gel kernel, the step of the method is as follows:
(1) preparation of sheathing material: dissolve the polymer in organic solvent, obtain sheathing material, wherein polymer is PLGA, PCL or PLA, and organic solvent is dichloromethane or ethyl acetate, adds 50 ~ 200mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with protein and i.e. obtain physical gel inner nuclear material, wherein the concentration of matter acid solution is 1 ~ 2mg/L, the concentration of hydroxyethyl chitosan solution is 2 ~ 10mg/L, protein is bovine serum albumin or Cyt C protein matter, and the weight of protein accounts in sheathing material the 0.5 ~ 20% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 4 ~ 8kV.
Step (1) described above adds in every 1mL organic solvent 100mg polymer.
In step (2) described above, the concentration of matter acid solution is 1mg/L, and the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of protein accounts in sheathing material the 2% of polymer weight.
A kind of degradable polymer microspheres containing gel kernel, this polymer microballoon is to prepare according to a kind of preparation method containing the degradable polymer microspheres of gel kernel described above.
A kind of degradable polymer microspheres containing gel kernel is as the application in protein, many peptides hydrophilic medicament carrier.
Beneficial effect:A kind of degradable polymer microspheres containing gel kernel that the present invention provides and its preparation method and application, have the advantages that the preparation method of the polymer microballoon of the present invention decreases contacting of medicine and organic solvent in preparation process, when solvent is volatilized, polymeric layer is few with medicament contact, thus avoid protein inactivation, protein sandwiches between kernel gel aqueous phase, the infiltration of aqueous phase Chinese medicine in hindering.Therefore, the degradable polymer microspheres containing gel kernel prepared has higher drug loading and envelop rate, it is adaptable to as protein, the carrier of many peptides hydrophilic medicament.
Accompanying drawing explanation
Fig. 1 is the electron-microscope scanning figure of the degradable polymer microspheres containing gel kernel that embodiment 1 prepares.
Fig. 2 is the 3D fluorogram of bovine serum albumin in the degradable polymer microspheres containing gel kernel that embodiment 1 prepares.
Detailed description of the invention
Hydroxyethyl chitosan (GC used in following example, deacetylation >=60%), hyaluronic acid (HA), bovine serum albumin (BSA), cytochrome C (CC) is purchased from Sigma company, lactic acid-ethanol copolymer (PLGA, LA:GA=50:50, relative molecular mass is 40,000) purchased from Lactel Absorbable Polymers company, polycaprolactone (PCL, relative molecular mass is 100,000) purchased from Shandong Prov. Medical Apparatus & Instrument Research Inst, polylactic acid (PDLLA, relative molecular mass is 40,000) purchased from Shandong Prov. Medical Apparatus & Instrument Research Inst, other reagent is commercially available analytical reagent.
Embodiment
1
A kind of preparation method of the degradable polymer microspheres containing gel kernel, the step of the method is as follows:
(1) preparation of sheathing material: be dissolved in dichloromethane by polymer P LGA, obtain sheathing material, wherein adds 100mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with bovine serum albumin and i.e. obtain physical gel inner nuclear material, wherein the concentration of hyaluronic acid solution is 1mg/L, the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of bovine serum albumin accounts in sheathing material the 2% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 6kV.
Embodiment
2
A kind of preparation method of the degradable polymer microspheres containing gel kernel, the step of the method is as follows:
(1) preparation of sheathing material: be dissolved in dichloromethane by polymer P LGA, obtain sheathing material, wherein adds 100mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with bovine serum albumin and i.e. obtain physical gel inner nuclear material, wherein the concentration of hyaluronic acid solution is 1mg/L, the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of bovine serum albumin accounts in sheathing material the 4% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 6kV.
Embodiment
3
A kind of preparation method of the degradable polymer microspheres containing gel kernel, the step of the method is as follows:
(1) preparation of sheathing material: be dissolved in dichloromethane by polymer P LGA, obtain sheathing material, wherein adds 100mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with Cyt C protein matter and i.e. obtain physical gel inner nuclear material, wherein the concentration of hyaluronic acid solution is 1mg/L, the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of Cyt C protein matter accounts in sheathing material the 2% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 6kV.
Embodiment
4
A kind of preparation method of the degradable polymer microspheres containing gel kernel, the step of the method is as follows:
(1) preparation of sheathing material: be dissolved in dichloromethane by polymer P LGA, obtain sheathing material, wherein adds 100mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with bovine serum albumin and i.e. obtain physical gel inner nuclear material, wherein the concentration of hyaluronic acid solution is 1mg/L, the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of bovine serum albumin accounts in sheathing material the 8% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 6kV.
Polymer microballoon embodiment 1 ~ 4 prepared freezing final vacuum respectively is dried 4h, removes residual organic solvents to be tested.Weigh the polymer microballoon 10mg of the embodiment 1 ~ 4 after process respectively, polymer microballoon is added in the 0.1mol/L NaOH/SDS solution of 5mL, then in 37 DEG C of water bath with thermostatic control agitators, 24h is hatched, guarantee that polymer is completely dissolved, then Micro-BCA protein method of testing carries out carrying drug ratio mensuration, and the carrying drug ratio of the polymer microballoon obtained is as shown in the table:
| Detection project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Carrying drug ratio | 90% | 91% | 95% | 92% |
After the polymer microballoon freezing final vacuum preparing embodiment 1 is dried 4h, does following two and test:
1. the polymer microballoon after pair embodiment 1 processes does surface metal spraying and disposes, and carries out electron-microscope scanning analysis, and electron-microscope scanning figure is as it is shown in figure 1, polyalcohol microspherulite diameter is homogeneous, smooth surface, pattern complete, state spherical in shape, and the microsphere prepared under the conditions of this is described is more satisfactory.
2. the polymer microballoon after embodiment 1 being processed is placed on the object stage of laser scanning co-focusing microscope, uses depth scan pattern to be scanned, and uses transmission light and the scanning of the fluorescence dual pathways, obtains vertical series two dimension slicing.The serial two-dimension picture obtained is carried out the reconstruction of Image-Pro Plus 5.1 3-D view.Laser Scanning Confocal Microscope test observes load bovine serum albumin fluorescence, and the fluorogram obtained is as shown in Figure 2.
Above the embodiment of the present invention is described in detail, for one of ordinary skill in the art, according to the thought of the embodiment of the present invention, the most all will change, in sum, this specification content should not be construed as limitation of the present invention.
Claims (5)
1. the preparation method of the degradable polymer microspheres containing gel kernel, it is characterised in that the step of the method is as follows:
(1) preparation of sheathing material: dissolve the polymer in organic solvent, obtain sheathing material, wherein polymer is PLGA, PCL or PLA, and organic solvent is dichloromethane or ethyl acetate, adds 50 ~ 200mg polymer in every 1mL organic solvent；
(2) preparation of physical gel inner nuclear material: hyaluronic acid and hydroxyethyl chitosan are dissolved in water respectively and make hyaluronic acid solution and hydroxyethyl chitosan solution, again hyaluronic acid solution, hydroxyethyl chitosan solution are mixed homogeneously with protein and i.e. obtain physical gel inner nuclear material, wherein the concentration of matter acid solution is 1 ~ 2mg/L, the concentration of hydroxyethyl chitosan solution is 2 ~ 10mg/L, protein is bovine serum albumin or Cyt C protein matter, and the weight of protein accounts in sheathing material the 0.5 ~ 20% of polymer weight；
(3) preparation of the degradable polymer microspheres containing gel kernel: use the preparation technology of coaxial electrical spraying to prepare the degradable polymer microspheres containing gel kernel, the flow velocity wherein controlling physical gel inner nuclear material is 0.2mL/h, the flow velocity of sheathing material is 2mL/h, distance between shower nozzle tip and collection table is 15cm, and high-tension electricity is 4 ~ 8kV.
The preparation method of a kind of degradable polymer microspheres containing gel kernel the most according to claim 1, it is characterised in that: described step (1) adds in every 1mL organic solvent 100mg polymer.
The preparation method of a kind of degradable polymer microspheres containing gel kernel the most according to claim 1, it is characterized in that: in described step (2), the concentration of matter acid solution is 1mg/L, the concentration of hydroxyethyl chitosan solution is 5mg/L, and the weight of protein accounts in sheathing material the 2% of polymer weight.
4. the degradable polymer microspheres containing gel kernel, it is characterised in that: this polymer microballoon is to prepare according to a kind of preparation method containing the degradable polymer microspheres of gel kernel according to any one of claim 1 ~ 3.
5. the degradable polymer microspheres containing gel kernel is as the application in protein, many peptides hydrophilic medicament carrier.
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Cited By (3)
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| CN106511315A (en) * | 2016-12-27 | 2017-03-22 | 苏州科技大学 | Degradable polymer core-shell microsphere loaded with protein drugs |
| EP3508564A4 (en) * | 2016-08-31 | 2020-04-29 | Osaka University | Cell culture carrier, cell culture carrier preparation kit, and method for producing gel/cell hybrid tissue using cell culture carrier and cell culture carrier preparation kit |
| WO2021109044A1 (en) * | 2019-12-04 | 2021-06-10 | 中国科学院深圳先进技术研究院 | Biological material for increasing drug sensitivity of cancer cells and use thereof and cell culture vessel |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3508564A4 (en) * | 2016-08-31 | 2020-04-29 | Osaka University | Cell culture carrier, cell culture carrier preparation kit, and method for producing gel/cell hybrid tissue using cell culture carrier and cell culture carrier preparation kit |
| CN106511315A (en) * | 2016-12-27 | 2017-03-22 | 苏州科技大学 | Degradable polymer core-shell microsphere loaded with protein drugs |
| WO2021109044A1 (en) * | 2019-12-04 | 2021-06-10 | 中国科学院深圳先进技术研究院 | Biological material for increasing drug sensitivity of cancer cells and use thereof and cell culture vessel |
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