CN106389356A - Method for controllable preparation of paclitaxel-carrying PLGA porous microspheres - Google Patents
Method for controllable preparation of paclitaxel-carrying PLGA porous microspheres Download PDFInfo
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- CN106389356A CN106389356A CN201610881156.4A CN201610881156A CN106389356A CN 106389356 A CN106389356 A CN 106389356A CN 201610881156 A CN201610881156 A CN 201610881156A CN 106389356 A CN106389356 A CN 106389356A
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- plga
- paclitaxel
- microsphere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention relates to the technical field of preparation of novel porous microspheres for sustained release administration and concretely relates a method for controllable preparation of paclitaxel-carrying PLGA porous microspheres. The method utilizes a double emulsion-solvent evaporation method and uses a BSA pore forming agent and PLGA carriers so that paclitaxel is coated by the microspheres. After washed precipitates are centrifuged, frozen and dried, paclitaxel-carrying PLGA porous microspheres are obtained. The tunnel structure of the PLGA porous microsphere has a large specific surface area and a large pore volume, and drugs can be adsorbed by the surface of the porous microsphere or enter the tunnels so that drug controllable release is realized through adjustment and control of microsphere sizes and pore sizes. The tunnel structure of the PLGA porous microsphere can reduce microsphere density and adjust the microsphere sizes and pore sizes so that the ideal aerodynamic properties are obtained, inhalation administration is convenient, the deposition of the drug in the lung is increased, the drug action concentration is increased and drug action time is prolonged.
Description
Technical field
The present invention relates to the preparing technical field of novel porous microsphere sustained-release administration is and in particular to carry paclitaxel PLGA porous
The controllable standby of microsphere.
Background technology
Porous microsphere, as a kind of novel pharmaceutical formulation, is applied in terms of the research and development of medicine novel formulation and the transformation of novel form
Extensively.At present, the existing method preparing porous microsphere mainly has emulsifying agent dispersion solvent volatility process, spray drying method, is separated
Method and fusion method etc., most common of which is porogen joint emulsion dispersion solvent evaporation method, and adopts NH porogen more4HCO3、
Sucrose, NaHCO3Deng.This kind of method when preparing porous microsphere often the size of microsphere uncontrollable, and the diameter in aperture is also relatively
Greatly, average pore size can reach more than 20 microns, thus have impact on the specific surface area of porous microsphere, reduces Drug absorbability micro- in porous
Content within the surface of ball or duct, the drug effect of rapid release or slow releasing preparation made by final impact microsphere.
Content of the invention
In order to solve the problems, such as prior art, the present invention provides a kind of controllable standby to carry paclitaxel PLGA porous microsphere
Method.The present invention, with protein molecular as porogen, be can control many by the content controlling protein molecular, the property becoming ball material
The diameter of hole microsphere and aperture, reach the purpose of the performance optimizing medicine carrying microballoonss.The present invention is with antitumor drug paclitaxel as mould
Type medicine, polylactic-co-glycolic acid (poly (lactic-co-glycolic acid), PLGA) is carrier, with bovine serum albumin
(BSA) is porogen in vain, using double emulsion solvent volatility process, prepares PLGA porous microsphere, simultaneously can be micro- in porous by Drug absorbability
Inside the surface of ball or duct, the control to pore structure can achieve the controlled of drug releasing rate.In addition duct in PLGA microsphere
The presence of structure can reduce Microsphere Density, adjust microspherulite diameter and aperture can obtain ideal aerodynamic property, be easy to
Inhalation, the deposition improving medicine in pulmonary, thus extending medicine activity and time, is expected to be used for the suction-type of tumor
Drug treatment.
The method that a kind of controllable standby of the present invention carries paclitaxel PLGA porous microsphere, is using double emulsion solvent volatilization
Method, with BSA as porogen, PLGA is carrier, and paclitaxel is wrapped in inside microsphere；Water washing and precipitating thing is centrifuged lyophilization
Afterwards, finally obtain load paclitaxel PLGA porous microsphere.
Specifically include following steps：
1) PLGA solid and paclitaxel solid are dissolved in a small amount of dichloromethane solution, according to a certain percentage according still further to certain
Ratio weighs BSA solid and is dissolved in a small amount of deionized water, probe type ultrasonication ice bath (20s) after mixing, then pours in 4%PVA solution；
2) mixed solution is stirred at ambient temperature 5min with homogenizer.Again above-mentioned solution is poured into 0.4%PVA solution
In, mechanical agitation overnight at room temperature.
3) mixed solution is centrifuged by the next morning, water washing and precipitating thing, takes that its supernatant is standby finally to be freezed precipitate
It is dried, obtain and carry paclitaxel PLGA porous microsphere pressed powder.
Step 1 of the present invention) in, first PLGA solid is substantially soluble in dichloromethane, adds paclitaxel fully molten
In above-mentioned solution.Purpose is so that PLGA is uniformly dispersed in dichloromethane, then paclitaxel is added in dichloromethane solution,
The uniformity of mixed thing can be improved.
Described step 1) in, PLGA is 10 with the mass ratio of paclitaxel:3.Under this ratio, the carrying drug ratio of paclitaxel is relatively
10:1 is high, and drug release rate and MTT experiment result show all there is good drug effect.
Described step 1) in, the mass ratio of BSA and PLGA is 0.6.The PLGA porous microsphere performance of this mass ratio preparation
Optimum.
Described step 1) in, the ratio of BSA/PLGA is adjustable as 0.2,0.4,0.6.Under the conditions of different proportion, control
The molecular weight of PLGA, the ratio of LA/GA is constant, changes the size in microspherulite diameter and aperture by the ratio of BSA/PLGA, and examines
Examine the MTT experiment result to non-small cell type pulmonary carcinoma (A549) cell.When BSA/PLGA is 0.2, such as embodiment one；Work as BSA/
When PLGA is 0.4, such as embodiment two；When BSA/PLGA is 0.6, such as embodiment three.
Described step 1) in, when BSA/PLGA is 0.6.With this understanding, carrying paclitaxel PLGA porous microsphere can be bright
The growth of aobvious suppression non-small cell type pulmonary carcinoma (A549) cell.
The inventive method is simple and environmentally-friendly；Compared with existing load paclitaxel PLGA microsphere sustained-release drug-supplying system, carry paclitaxel
PLGA porous microsphere, because of the increase of its specific surface area, the high-efficient carrier of achievable medicine.In addition, the key point of the present invention
It is the concentration by controlling porogen, the molecular weight of PLGA, the ratio of LA/GA, can the size of effective control microsphere and aperture
Size, to solve the porous microsphere size of prior art and means preparation and the present situation that aperture is bigger than normal, is the controlled negative of paclitaxel
Carry and provide material and architecture basics with effective slow release.The PLGA microspherulite diameter obtaining after optimal conditions of the present invention is on a 5-6 μm of left side
The right side, microsphere aperture is 0.12-0.24 μm about, and carrying drug ratio is 13.74%, and envelop rate is 51.10%.Prepared using the present invention and carry
Paclitaxel PLGA porous microsphere, not only particle diameter is more uniform, and loose structure can be easy to inhalation with control release speed,
Drug treating time can effectively be extended.
Brief description
Fig. 1 is the SEM figure of the load paclitaxel PLGA porous microsphere using the inventive method preparation.
Fig. 2 is the x-ray diffraction pattern of the load paclitaxel PLGA porous microsphere using the inventive method preparation.
Fig. 3 is the releasing curve diagram of the load paclitaxel PLGA porous microsphere using the inventive method preparation.
Fig. 4 is the load paclitaxel PLGA porous microsphere MTT experiment result figure using the inventive method preparation, carries purple with actual
The amount that the amount of China fir alcohol is multiplied by the paclitaxel of first day rate of release gained compares and compares.
Specific embodiment
First, preparation technology：
1st, embodiment 1：
1) first 50mgPLGA solid is dissolved in 1ml dichloromethane solution, then 15mg paclitaxel is dissolved in wherein, weigh
10mg BSA is dissolved in 0.2mL deionized water, probe type ultrasonication ice bath (20s) after mixing, then pours in the 4%PVA solution of 5mL.
2) mixed solution is stirred at ambient temperature 5min with homogenizer (rotating speed is 8000).Again above-mentioned solution is poured into
In the 0.4%PVA solution of 100mL, mechanical agitation at room temperature, rotating speed is 800, and overnight.
3) mixed solution is centrifuged by the next morning, and rotating speed is 6000, and water washing and precipitating thing 5 times takes its supernatant standby.?
Afterwards by precipitate lyophilization, condition is -60 degrees Celsius, obtains and carries paclitaxel PLGA porous microsphere pressed powder.
2nd, embodiment 2：
1) first 50mg PLGA solid is dissolved in 1ml dichloromethane solution, then 15mg paclitaxel is dissolved in wherein, weigh
20mg BSA is dissolved in 0.2mL deionized water, probe type ultrasonication ice bath (20s) after mixing, then pours in the 4%PVA solution of 5mL.
2) use homogenizer, mixed solution is stirred 5min for 8000 by rotating speed at ambient temperature.Again above-mentioned solution is poured into
In the 0.4%PVA solution of 100mL, mechanical agitation at room temperature, rotating speed is 800, and overnight.
3) mixed solution is centrifuged by the next morning, and rotating speed is 6000, and water washing and precipitating thing 5 times takes its supernatant standby.?
Afterwards by precipitate lyophilization, condition is subzero 60 degrees Celsius, obtains and carries paclitaxel PLGA porous microsphere pressed powder.
3rd, embodiment 3：
1) first 50mg PLGA solid is dissolved in 1mL dichloromethane solution, then 15mg paclitaxel is dissolved in wherein, weigh
30mg BSA is dissolved in 0.2mL deionized water, probe type ultrasonication ice bath (20s) after mixing, then pours in the 4%PVA solution of 5mL.
2) use homogenizer, mixed solution is stirred 5min for 8000 by rotating speed at ambient temperature.Again above-mentioned solution is poured into
In the 0.4%PVA solution of 100mL, mechanical agitation at room temperature, rotating speed is 800, and overnight.
3) mixed solution is centrifuged by the next morning, and rotating speed is 6000, and water washing and precipitating thing 5 times takes its supernatant standby.?
Afterwards by precipitate lyophilization, condition is -60 degrees Celsius, obtains and carries paclitaxel PLGA porous microsphere pressed powder.
2nd, product property：
Fig. 1 is the SEM figure of the load paclitaxel PLGA porous microsphere using the inventive method preparation, as seen from the figure, carries medicine
Microsphere size distribution, particle diameter aperture is more homogeneous.
Fig. 2 is the x-ray diffraction pattern of the load paclitaxel PLGA porous microsphere using the inventive method preparation, is penetrated according to X-
Line diffraction patterns understand, paclitaxel is wrapped in inside PLGA porous microsphere with molecular forms.
Fig. 3 is the releasing curve diagram of the load paclitaxel PLGA porous microsphere using the inventive method preparation, permissible from figure
Find out that the load paclitaxel PLGA porous microsphere of different dispensing ratios discharges about 9-10 days completely, illustrate that medicine carrying microballoonss have slow release work(
Energy.
Fig. 4 is the load paclitaxel PLGA porous microsphere MTT experiment result figure using the inventive method preparation, carries purple with actual
The amount that the amount of China fir alcohol is multiplied by the paclitaxel of first day rate of release gained compares and compares.From the results, it was seen that compared with BSA/
The ratio of PLGA is 0.2, under the conditions of 0.4, the ratio of BSA/PLGA be 0.6 load paclitaxel PLGA porous microsphere to A549 cell
There is obvious inhibitory action, and the taxol control group being multiplied by rate of release with actual drug loading is made comparisons, this is more described
The Sustained Release Drug-Carried of design has certain drug effect.
Claims (7)
1. a kind of controllable standby carry paclitaxel PLGA porous microsphere method it is characterised in that：Using double emulsion solvent volatility process, with
BSA is porogen, and PLGA is carrier, and paclitaxel is wrapped in inside microsphere；Water washing and precipitating thing is centrifuged after lyophilization, finally
Obtain carrying paclitaxel PLGA porous microsphere.
2. method according to claim 1 is it is characterised in that comprise the following steps：
1) PLGA solid and paclitaxel are dissolved in a small amount of dichloromethane solution according to a certain percentage, weigh according still further to certain ratio row
BSA is dissolved in a small amount of deionized water, probe type ultrasonication ice bath 20s after mixing, then pours in 4%PVA solution；
2) with homogenizer, mixed solution is stirred 5min at ambient temperature, more above-mentioned solution is poured in 0.4%PVA solution,
Mechanical agitation overnight at room temperature；
3) mixed solution is centrifuged by the next morning, water washing and precipitating thing, takes its supernatant standby finally by precipitate lyophilization,
Obtain and carry paclitaxel PLGA porous microsphere pressed powder.
3. preparation method according to claim 2 is it is characterised in that described step 1) in, first PLGA solid is substantially soluble in
In dichloromethane, add paclitaxel and be substantially soluble in wherein.
4. preparation method according to claim 2 is it is characterised in that described step 1) in, the mass ratio of PLGA and paclitaxel
For 10: 3.
5. preparation method according to claim 2 is it is characterised in that described step 1) in, the mass ratio of BSA and PLGA is
0.6.
6. preparation method according to claim 2 is it is characterised in that described step 2) in, the rotating speed of described homogenizer is
8000, churned mechanically rotating speed is 800.
7. preparation method according to claim 2 is it is characterised in that described step 3) in, described centrifuge speed is
6000, wash 5 times, freezer dryer controls temperature to be -60 degrees Celsius.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610881156.4A CN106389356A (en) | 2016-10-09 | 2016-10-09 | Method for controllable preparation of paclitaxel-carrying PLGA porous microspheres |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107049984A (en) * | 2017-03-14 | 2017-08-18 | 武汉理工大学 | A kind of preparation method for carrying taxol polylactic-co-glycolic acid microballoon |
| CN115006372A (en) * | 2022-06-22 | 2022-09-06 | 华东理工大学 | Nimodipine-loaded lung inhalation porous microspheres and preparation method thereof |
| CN115813865A (en) * | 2023-02-03 | 2023-03-21 | 山东大学 | Inhalable porous microsphere loaded with recombinant human relaxin-2 and preparation method thereof |
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| WO2001058466A1 (en) * | 2000-02-08 | 2001-08-16 | Institute Of Molecular Agrobiology | Biodegradable and biocompatible polymeric microspheres encapsulating salmonella enteritidisbacteria |
| CN105664242A (en) * | 2016-02-03 | 2016-06-15 | 重庆科技学院 | Method for preparing PLGA microspheres with porous surfaces |
| CN105943506A (en) * | 2016-06-22 | 2016-09-21 | 山东省药学科学院 | Absorbable self-pore-forming microsphere for injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2001058466A1 (en) * | 2000-02-08 | 2001-08-16 | Institute Of Molecular Agrobiology | Biodegradable and biocompatible polymeric microspheres encapsulating salmonella enteritidisbacteria |
| CN105664242A (en) * | 2016-02-03 | 2016-06-15 | 重庆科技学院 | Method for preparing PLGA microspheres with porous surfaces |
| CN105943506A (en) * | 2016-06-22 | 2016-09-21 | 山东省药学科学院 | Absorbable self-pore-forming microsphere for injection and preparation method thereof |
Non-Patent Citations (2)
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| TIANSHI FENG，等: "Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment", 《EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107049984A (en) * | 2017-03-14 | 2017-08-18 | 武汉理工大学 | A kind of preparation method for carrying taxol polylactic-co-glycolic acid microballoon |
| CN115006372A (en) * | 2022-06-22 | 2022-09-06 | 华东理工大学 | Nimodipine-loaded lung inhalation porous microspheres and preparation method thereof |
| CN115813865A (en) * | 2023-02-03 | 2023-03-21 | 山东大学 | Inhalable porous microsphere loaded with recombinant human relaxin-2 and preparation method thereof |
| CN115813865B (en) * | 2023-02-03 | 2023-08-22 | 山东大学 | Inhalable porous microsphere loaded with recombinant human relaxin-2 and preparation method thereof |
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