CN107049990B - Microchannel preparation method of poly (trihexalactone-tricarballylic acid) administration nanoparticles - Google Patents
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Abstract
The invention provides a method for preparing a microchannel of poly (trihexalactone) -tricarballylic acid administration nanoparticles, which takes tricarballylic acid as a chain extension initiator, epsilon-caprolactone high-temperature ring-opening grafting, stannous octoate as a catalyst, and N2Preparing an amphiphilic star-shaped polyester under a protective condition; curcumin is used as a model drug, and a curcumin-nanoparticle preparation with small size, uniform particle size and high encapsulation rate is prepared by a microchannel continuous granulation technology, wherein the average particle size of the obtained curcumin-nanoparticle is 100-300nm, the polydispersity index is less than 0.3, and the encapsulation rate is more than 70%; the prepared poly (trihexalactone-tricarballylic acid) administration nanoparticles obviously improve the solubility of curcumin in water, and a formed nano drug-loaded system has a sustained-release characteristic, has no toxic or side effect as a carrier material, and is suitable for various administration modes such as oral administration and intravenous injection; in addition, the microchannel nanoparticle method adopted by the invention has high automation in the whole process, strong controllability and short time for granulation, and is easy for industrial scale-up production.
Description
(I) technical field
The invention relates to the technical field of preparation of drug polymer carriers and pharmaceutical preparations, and mainly relates to a microchannel preparation method of poly (tri-caprolactone) -tricarballylic acid administration nanoparticles.
(II) background of the invention
Cancer is a disease that restricts the development of socioeconomic and seriously threatens human health. It is reported that 820 ten thousand people died from cancer in 2012, and malignant tumor has become one of the most major diseases affecting people's physical health. WHO predicts that by 2030, more than 1310 million people will die globally from cancer. Most of traditional anticancer drugs are lipophilic compounds, and have strong cytotoxicity, water insolubility and instability. The medicine has low bioavailability in vivo, and needs long-term, multiple or large dose administration to achieve the treatment purpose. Often presents serious toxic and side effects, anaphylactic reaction and drug resistance of tumor cells, and seriously influences the effectiveness and safety of clinical application of the drug. Therefore, the research on the sustained and controlled release drug delivery system with corresponding targeting of the lipophilic insoluble drug and the related preparation method have very important significance.
The nanoparticle drug delivery system can effectively change the solubility and in-vivo distribution of the water-insoluble drug in water, prolong the half-life period of the drug in vivo, reduce toxic and side effects and realize continuous and controllable drug delivery; after the nano-scale carrier is administrated, the EPR effect can be accumulated at vascular permeability parts (inflammation and tumor), and passive targeted administration is realized. A large number of researches show that the particle size greatly influences the permeability of the tumor cells of the nanoparticles. The large particle size is beneficial to improving pharmacokinetics and the overflow rate of the medicine in blood vessels, but is not beneficial to the penetration of tumor cells; small particle size is easy for cell penetration, but short half-life and easy to eliminate. In addition, the uniformity of nanoparticle size (PDI value) also affects dosing stability. At present, the reported more ideal nanoparticle carrier mostly has a particle size range between 100 and 300 nm; the PDI value is 0.3 or less.
The star polymer exists as a hyperbranched polymer with a special structure, and the polymer has a plurality of functions and good reaction performance. The star-shaped polymer has novel structure, multiple functions and better application prospect, and gets general attention in the scientific and industrial fields. Research shows that the good hyperbranched star-shaped polymer has a large encapsulation inner cavity, can encapsulate hydrophobic drugs, can increase drug solubility, and can control the properties of nano-sized materials.
The microchannel continuous granulation method is a new nanoparticle forming technology (high specific surface area, large mass transfer rate between fluids and mild conditions) which is successfully researched recently, can prepare nanoscale solid particles with uniform sizes, greatly promotes the innovation of the traditional technology, and is used for forming and preparing nanoparticles such as polymer solid lipid nanoparticles, metal nanoparticles, inorganic nanoparticles and the like. The technology is different from the common nanoparticle preparation method, the flow of a lipid phase solution containing high polymeric carrier precursor molecules and an aqueous phase solution containing a surfactant in a microchannel can be controlled through a microchannel network, and the supersaturation of a lipid phase (a nanoparticle precursor and a lipophilic drug) is formed by utilizing the solvent diffusion mass transfer between the lipid phase solution and the aqueous phase solution so as to rapidly granulate.
Disclosure of the invention
The invention aims to provide a microchannel preparation method of poly (trihexalactone-tricarballylic acid) administration nanoparticles, which takes tricarballylic acid (hydrophilic) as a chain extension initiator, epsilon-caprolactone (hydrophobic) high-temperature ring-opening grafting, stannous octoate as a catalyst and N2Preparing an amphiphilic star-shaped polyester (Tri-CL) under a protection condition; curcumin (an FDA approved third-generation anticancer chemopreventive drug) is used as a model drug, and a curcumin-nanoparticle preparation with small size, uniform particle size and high encapsulation rate is prepared by a microchannel continuous granulation technology, wherein the average particle size of the obtained curcumin-nanoparticles is 100-300nm, the polydispersity index (PDI) is less than 0.3, and the encapsulation rate is more than 70%.
The invention adopts the following technical scheme:
a method for preparing a microchannel of a poly (trihexalactone-tricarballylic acid) administration nanoparticle comprises the following steps:
(1) preparation of TRIACETIC ACID-HEXANEOLIDE STAR-LIKE POLYESTER (TRI-CL)
Under the protection of inert gas, mixing tricarballylic acid, epsilon-caprolactone and stannous octoate, heating to 120-160 ℃, reacting for 12-48 h, cooling to room temperature (20-30 ℃, the same below), dissolving the reaction mixture by using dichloromethane, dropwise adding the dissolved reaction mixture into glacial ethyl ether (-5 ℃) to separate out a precipitate, filtering, collecting the precipitate, and drying in vacuum to obtain tricarballylic acid-caprolactone star-shaped polyester;
the ratio of the amounts of the feed materials of the tricarballylic acid, the epsilon-caprolactone and the stannous octoate is 1: 20-80: 0.05-0.20, preferably 1: 30-60: 0.05 to 0.15;
the volume usage of the dichloromethane is 2-8 mL/g based on the mass of the reaction mixture;
the volume dosage of the ethyl acetate is 25-100 mL/g based on the mass of the reaction mixture;
(2) preparation of poly (tri-caprolactone-tri-propionic acid) administration nano particle by micro-channel
The microchannel comprises a channel 1, a channel 2, a channel 3 and a channel 4, wherein the channel 1, the channel 2, the channel 3 and the channel 4 form a cross-shaped structure which is communicated with each other, the channel 1, the channel 2, the channel 3 and the channel 4 are respectively four branches of the cross shape, in addition, the channel 1 and the channel 4 are on the same straight line, and the channel 2 and the channel 3 are on the same straight line; the length ratio of the channel 1, the channel 2, the channel 3 and the channel 4 is 1: 1: 1: 2.5, and the pipe diameters are the same (as shown in fig. 2);
a. dissolving curcumin and tricarballylic acid-caprolactone star-shaped polyester in ethanol to be used as a lipid phase;
the feeding mass ratio of the curcumin to the tricarballylic acid-caprolactone star-shaped polyester is 1: 15-50, preferably 1: 15;
in the lipid phase, the concentration of curcumin is 0.25-0.35 mg/mL, and particularly preferably 0.3 mg/mL;
b. dissolving a surfactant in water to prepare a water phase;
the surfactant is P-188, Tween-85 or sodium dodecyl sulfonate, preferably sodium dodecyl sulfonate;
in the water phase, the concentration of the surfactant is 1-5 mg/mL, and particularly preferably 1 mg/mL;
c. injecting a lipid phase into a channel 1 at a flow rate of 0.25-0.45mL/min (preferably 0.40mL/min), injecting a water phase into a channel 2 and a channel 3 at a flow rate of 0.55-0.75mL/min (preferably 0.60mL/min), mixing two-phase solutions in a channel 4, supersaturating the lipid phase in a diffusion process towards the water phase to separate out nanoparticles, collecting the nanoparticle solution at the tail end of the channel 4, stirring for 6-12 h at 10-30 ℃ (to remove ethanol serving as a lipid phase solvent), filtering (filtering with a 0.45 mu m organic filter membrane to remove unencapsulated curcumin), and collecting filtrate, namely the polycaprolactone-tricaprylic acid administration nanoparticles (in a solution form).
In the present invention, the curcumin can be commercially obtained by a conventional route.
And (2) detecting the average molecular weight and the Polydispersity Index (PI) value of the tricarballylic acid-caprolactone star-shaped polyester prepared in the step (1) through GPC, and weighing to calculate the yield.
GPC conditions: mobile phase: tetrahydrofuran (1 ml/min); detecting the temperature: 35 ℃; the polymer was used in a GPC concentration of 30 mg/ml; sample introduction amount: 50 mu L of the solution; column type: HP Phenogel guard column attached to a Phenogellinear (2) 5. mu.GPC column.
The molecular weight range of the tricarballylic acid-caprolactone star-shaped polyester is 5369-14448, and the Polydispersity (PI) range is 1.18-1.39.
The particle size range of the poly (caprolactone) -tricarballylic acid) administration nanoparticles prepared in the step (2) is 100-300nm, the polydispersity is less than 0.3, and the encapsulation efficiency is more than 70%.
The invention has the beneficial effects that: the prepared poly (trihexalactone-tricarballylic acid) administration nanoparticles obviously improve the solubility of curcumin in water, and a formed nano drug-loaded system has a sustained-release characteristic, has no toxic or side effect as a carrier material, and is suitable for various administration modes such as oral administration and intravenous injection; in addition, the microchannel nanoparticle method adopted by the invention has high automation in the whole process, strong controllability and short time for granulation, and is easy for industrial scale-up production.
(IV) description of the drawings
FIG. 1: top and plan views of a "cross" microchannel device;
FIG. 2: the micro-channel structure and the plane size specifically adopted in the embodiment;
FIG. 3: the invention relates to a reaction formula.
(V) detailed description of the preferred embodiments
The present invention is further illustrated by the following specific examples, but the scope of the invention is not limited thereto.
The microchannels used in the following examples are shown in FIG. 2: the device comprises a channel 1, a channel 2, a channel 3 and a channel 4, wherein the channel 1, the channel 2, the channel 3 and the channel 4 form a cross-shaped structure which is communicated with each other, the channel 1, the channel 2, the channel 3 and the channel 4 are respectively four branches of the cross shape, in addition, the channel 1 and the channel 4 are on the same straight line, and the channel 2 and the channel 3 are on the same straight line; the lengths of the channel 1, the channel 2, the channel 3 and the channel 4 are respectively 60mm, 60mm and 151mm, and the pipe diameters are the same and are all 344 mu m.
Curcumin used in the following examples was purchased from Hangzhou ruishu Biochemical Co., Ltd. (content > 98%).
Tri-CL is synthesized, and in order to keep an oxygen-free closed environment, an ampoule bottle is used as a sealed high-temperature melting reactor.
Example 1
Dissolving 0.1761g (1.0 mmol) of tricarballylic acid and 2.2823g (20.0 mmol) of caprolactone at 120 deg.C in an ampoule, adding stannous octoate catalyst (0.0201g, 0.05mmol), shaking for mixing, and adding N in the ampoule2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 12h, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24h to obtain 1.1793g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC 5369, PI 1.39, final yield 47.97%.
Example 2
Dissolving 0.1761g (1.0 mmol) of tricarballylic acid and 3.4235g (30.0 mmol) of caprolactone at 120 deg.C in an ampoule, adding stannous octoate catalyst (0.0300g (0.075 mmol), shaking, mixing, and adding N2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 12h, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24h to obtain 2.5953g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 10904, PI 1.27, with a final yield of 72.10%.
Example 3
Adding tricarballylic acid (0.1761g, 1.0mmol), caprolactone (3.4235g, 30.0mmol) into ampoule 140 deg.CMelting, adding stannous octoate catalyst (0.0300g, 0.075mmol), shaking to mix well, adding N in ampoule bottle2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 24 hours, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24 hours to obtain 2.5698g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 10612, PI 1.18, and final yield was 71.39%.
Example 4
Dissolving 0.1761g (1.0 mmol) of tricarballylic acid and 3.4235g (30.0 mmol) of caprolactone at 120 deg.C in an ampoule, adding stannous octoate catalyst (0.0300g (0.075 mmol), shaking, mixing, and adding N2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 48h, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24h to obtain 2.9621g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 10030, PI 1.18, and final yield was 82.29%.
Example 5
Dissolving tricarballylic acid (0.1763g, 1.0mmol) and caprolactone (6.8484g, 60.0mmol) at 120 deg.C in an ampoule, adding stannous octoate catalyst (0.0600g, 0.15mmol), shaking to mix well, adding N in the ampoule2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 12h, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24h to obtain 4.4820g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 11256, PI 1.20, final yield 63.80%.
Example 6
Dissolving tricarballylic acid (0.1763g, 1.0mmol) and caprolactone (6.8484g, 60.0mmol) in ampoule at 120 deg.C, adding stannous octoate catalyst (0.0600g, 0.15mmol), shaking, and mixing wellAdding N in the bottle2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 24 hours, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24 hours to obtain 4.7324g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 12273, PI 1.29, with a final yield of 67.37%.
Example 7
Dissolving tricarballylic acid (0.1763g, 1.0mmol) and caprolactone (9.1282g, 80.0mmol) at 120 deg.C in an ampoule, adding stannous octoate catalyst (0.0800g, 0.20mmol), shaking for mixing, and adding N in the ampoule2Ensuring an oxygen-free environment, quickly sealing, reacting at 120 ℃ for 48h, cooling to room temperature after the reaction is finished, adding 20mL of dichloromethane for dissolution, then dripping 250mL of glacial ethyl ether to separate out a precipitate, filtering and collecting the precipitate, and drying in vacuum at 40 ℃ for 24h to obtain 4.1740g of Tri-CL star-shaped polyester for later use.
Average molecular weight by GPC was 14448, PI 1.26, with a final yield of 44.86%.
Microchannel granulation
Example 8
Curcumin, Tri-CL star polyester (Mn 5369) prepared according to example 1, in a mass ratio of 1: 15 dissolved in ethanol to form a lipid phase (curcumin 0.3 mg/mL); dissolving a surfactant in water to form an aqueous phase (surfactant concentration 1 mg/mL); injecting a lipid phase into a channel 1 at a flow rate of 0.4mL/min, simultaneously injecting a water phase into a channel 2 and a channel 3 at a flow rate of 0.60mL/min, respectively, mixing two-phase solutions in the channel 4, supersaturating the lipid phase in the diffusion process towards the water phase to separate out nanoparticles, collecting the nanoparticle solution at the tail end of the channel 4, stirring the collected nanoparticle solution at 25.0 ℃ overnight, removing ethanol serving as a lipid phase solvent, filtering by using a 0.45-micrometer organic filter membrane, removing unencapsulated curcumin, and collecting filtrate to obtain a product Tri-CL administration nanoparticle.
Encapsulation efficiency was tested as follows:
taking the obtained Tri-CL administration nanoparticles as a solution 1, centrifuging at 15000r/min for 60min, and taking the supernatant as a solution 2. The curcumin concentrations in solution 1 and solution 2 were measured by HPLC, and the encapsulation efficiency was 100% (solution 2 concentration/solution 1 concentration).
The surfactant adopts P-188, Tween-85 or sodium dodecyl sulfate, and the influence on the granulation of the nanoparticles is shown in Table 1.
Table 1 effect of surfactant selection on nanoparticle granulation
Preferred is sodium dodecyl sulfate
Example 9
Dosing nanoparticles were prepared according to the method of example 8: curcumin, Tri-CL star polyester (Mn 5369) prepared according to example 1, in a mass ratio of 1: 15 dissolved in ethanol to form a lipid phase (curcumin 0.3 mg/mL); dissolving sodium dodecyl sulfate which is a surfactant with different dosages in water to form a water phase; during the preparation of the microchannel, the flow rate of the water phase (0.60ml/min) and the flow rate of the lipid phase (0.40ml/min) were measured.
The effect of different surfactant levels on nanoparticle granulation is shown in table 2.
TABLE 2 Effect of sodium dodecyl sulfate on nanoparticle granulation
The change of the concentration of the surfactant has little influence on the granulation of the nano-particles, and the sodium dodecyl sulfate (1 mg/ml) is preferred in consideration of economic factors.
Example 10
Dosing nanoparticles were prepared according to the method of example 8: curcumin and Tri-CL star-shaped polyester with different average molecular weights are mixed according to the mass ratio of 1: 15 dissolved in ethanol to form a lipid phase (curcumin 0.3 mg/mL); dissolving a surfactant sodium dodecyl sulfate in water to form a water phase (the concentration of the surfactant is 1 mg/mL); during the preparation of the microchannel, the flow rate of the water phase (0.60ml/min) and the flow rate of the lipid phase (0.40ml/min) were measured.
The effect of the average Tri-CL molecular weight on nanoparticle granulation is shown in Table 3.
TABLE 3Tri-CL molecular weight effect on nanoparticle granulation
Tri-CL with a molecular weight of 10030 is preferred
Example 11
Dosing nanoparticles were prepared according to the method of example 8: curcumin, Tri-CL star polyester (Mn 10030) prepared according to example 4, was dissolved in ethanol at different mass ratios to form a lipid phase (curcumin 0.3 mg/mL); dissolving a surfactant sodium dodecyl sulfate in water to form a water phase (the concentration of the surfactant is 1 mg/mL); during the preparation of the microchannel, the flow rate of the water phase (0.60ml/min) and the flow rate of the lipid phase (0.40ml/min) were measured.
The effect of curcumin to Tri-CL ratio on nanoparticle granulation is shown in Table 4.
TABLE 4 curcumin/Tri-CL ratio effect on nanoparticle granulation
Preferably curcumin/Tri-CL 1/15
Example 12
Dosing nanoparticles were prepared according to the method of example 8: curcumin, Tri-CL star polyester (Mn 10030) prepared according to example 4, in a mass ratio of 1: 15 dissolved in ethanol to form a lipid phase (curcumin 0.3 mg/mL); dissolving a surfactant sodium dodecyl sulfate in water to form a water phase (the concentration of the surfactant is 1 mg/mL); during the microchannel preparation, the flow rates of the aqueous phase and the lipid phase are shown in Table 5 (0.40 ml/min).
TABLE 5 Effect of aqueous phase flow Rate on nanoparticle granulation
The flow rate of the aqueous phase is in the range of 0.55-0.75ml/min, preferably 0.60ml/min
Example 13
Dosing nanoparticles were prepared according to the method of example 8: curcumin, Tri-CL star polyester (Mn 10030) prepared according to example 4, in a mass ratio of 1: 15 dissolved in ethanol to form a lipid phase (curcumin 0.3 mg/mL); dissolving a surfactant sodium dodecyl sulfate in water to form a water phase (the concentration of the surfactant is 1 mg/mL); the flow rates of the aqueous phase (0.60ml/min) and the different lipid phases during the microchannel preparation are shown in Table 6.
TABLE 6 lipid phase flow Rate effects on nanoparticle granulation
The lipid phase flow rate is in the range of 0.25-0.45ml/min, preferably 0.40 ml/min.
Claims (10)
1. A microchannel preparation method of a poly (trihexalactone-tricarballylic acid) administration nanoparticle is characterized by comprising the following steps:
(1) preparation of polytrimethylene-caprolactone star polyester
Under the protection of inert gas, mixing tricarballylic acid, epsilon-caprolactone and stannous octoate, heating to 120-160 ℃, reacting for 12-48 h, cooling to room temperature, dissolving the reaction mixture with dichloromethane, dropwise adding the reaction mixture into ethyl glacial ether to separate out a precipitate, filtering, collecting the precipitate, and drying in vacuum to obtain tricarballylic acid-caprolactone star-shaped polyester;
the ratio of the amounts of the feed materials of the tricarballylic acid, the epsilon-caprolactone and the stannous octoate is 1: 20-80: 0.05 to 0.20;
(2) preparation of poly (tri-caprolactone-tri-propionic acid) administration nano particle by micro-channel
The microchannel comprises a channel 1, a channel 2, a channel 3 and a channel 4, wherein the channel 1, the channel 2, the channel 3 and the channel 4 form a cross-shaped structure which is communicated with each other, the channel 1, the channel 2, the channel 3 and the channel 4 are respectively four branches of the cross shape, in addition, the channel 1 and the channel 4 are on the same straight line, and the channel 2 and the channel 3 are on the same straight line; the length ratio of the channel 1, the channel 2, the channel 3 and the channel 4 is 1: 1: 1: 2.5, and the pipe diameters are the same;
a. dissolving curcumin and tricarballylic acid-caprolactone star-shaped polyester in ethanol to be used as a lipid phase;
the feeding mass ratio of the curcumin to the tricarballylic acid-caprolactone star-shaped polyester is 1: 15-50;
in the lipid phase, the concentration of curcumin is 0.25-0.35 mg/mL;
b. dissolving a surfactant in water to prepare a water phase;
the surfactant is P-188, Tween-85 or sodium dodecyl sulfate;
in the water phase, the concentration of the surfactant is 1-5 mg/mL;
c. injecting a lipid phase into a channel 1 at a flow rate of 0.25-0.45mL/min, injecting a water phase into a channel 2 and a channel 3 at a flow rate of 0.55-0.75mL/min, respectively, mixing two-phase solutions in the channel 4, supersaturating the lipid phase in a diffusion process towards the water phase to separate out nanoparticles, collecting a nanoparticle solution at the tail end of the channel 4, stirring for 6-12 hours at 10-30 ℃, filtering, and collecting filtrate to obtain the poly (caprolactone-tricarballylic acid) administration nanoparticles.
2. The method for preparing the microchannel of the polytriglycerolactone-tricarballylic acid nanoparticles as claimed in claim 1, wherein in step (1), the ratio of the amounts of the materials for feeding tricarballylic acid, epsilon-caprolactone and stannous octoate is 1: 30-60: 0.05 to 0.15.
3. The method for preparing the microchannel of claim 1, wherein the volume of the dichloromethane used in step (1) is 2-8 mL/g based on the mass of the reaction mixture.
4. The method for preparing the microchannel of claim 1, wherein the volume of the glacial ethyl ether used in step (1) is 25-100 mL/g based on the mass of the reaction mixture.
5. The method for preparing the microchannel of the polytriglycerolactone-tricarballylic acid administration nanoparticle as claimed in claim 1, wherein in the step (2), the feeding mass ratio of the curcumin to the tricarballylic acid-caprolactone star-shaped polyester is 1: 15.
6. the method for preparing the microchannel of claim 1, wherein the concentration of curcumin in the lipid phase is 0.3 mg/mL.
7. The method for preparing the microchannel of claim 1, wherein the surfactant is sodium dodecyl sulfate in step (2).
8. The method for preparing the microchannel of claim 1, wherein the surfactant is present in the aqueous phase at a concentration of 1mg/mL in the step (2).
9. The method of claim 1, wherein in step (2), the lipid phase flow rate is 0.40 mL/min.
10. The method for preparing the microchannel of claim 1, wherein the flow rate of the aqueous phase in step (2) is 0.60 mL/min.
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| CN111110650B (en) * | 2019-11-20 | 2022-09-20 | 浙江工业大学 | Preparation method of enzyme-sensitive amphiphilic polyester drug-loaded nanoparticles |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101961494A (en) * | 2010-09-26 | 2011-02-02 | 苏州同科生物材料有限公司 | Star polymer nano-medicament carrier preparation used for intracellular medicament delivery and preparation method thereof |
| CN103768012A (en) * | 2013-12-24 | 2014-05-07 | 浙江凯胜科技有限公司 | Method for preparing curcumin lipid nano-particle suspension or nano-particles |
| CN104414976A (en) * | 2013-09-06 | 2015-03-18 | 济南大学 | Curcumin nanoparticles and preparation method thereof |
-
2017
- 2017-06-12 CN CN201710436916.5A patent/CN107049990B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101961494A (en) * | 2010-09-26 | 2011-02-02 | 苏州同科生物材料有限公司 | Star polymer nano-medicament carrier preparation used for intracellular medicament delivery and preparation method thereof |
| CN104414976A (en) * | 2013-09-06 | 2015-03-18 | 济南大学 | Curcumin nanoparticles and preparation method thereof |
| CN103768012A (en) * | 2013-12-24 | 2014-05-07 | 浙江凯胜科技有限公司 | Method for preparing curcumin lipid nano-particle suspension or nano-particles |
Non-Patent Citations (3)
| Title |
|---|
| Novel star-type methoxy-poly(ethylene glycol) (PEG)–poly(e-caprolactone) (PCL) copolymeric nanoparticles for controlled release of curcumin;Feng R. L.，et al.;《Journal of Nanoparticle Research》;20130602;第15卷(第6期);第1-12页 * |
| Synthesis and Structural Analysis of Functionalized Poly(ε-caprolactone)-Based Three-Arm Star Polymers;Lang M. D.，et al.;《Journal of Polymer Science: Part A: Polymer Chemistry》;20021231;第40卷;第1127-1141页 * |
| 星形聚合物的功能化应用研究进展;张彬 等;《现代化工》;20141031;第34卷(第10期);第58-63页 * |
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